MULTISPECIFIC AND MULTIFUNCTIONAL MOLECULES AND USES THEREOF

Abstract

Multispecific molecules that include i) a tumor-targeting moiety; and one, two or all of: (ii) an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); (iii) a cytokine molecule; and/or (iv) a stromal modifying moiety are disclosed. Additionally disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

Description

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No. 15/465,564, filed Mar. 21, 2017, which claims the benefit of U.S. Provisional Application No. 62/310,929 filed Mar. 21, 2016, and U.S. Provisional Application 62/310,899 filed Mar. 21, 2016, the entire contents of each of which are hereby incorporated by reference.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 4, 2017, is named 53676-710.301_SL.txt and is 506,406 bytes in size.

BACKGROUND

[0003] Multispecific molecules that include a tumor-targeting moiety; and one, two or all of: an immune cell engager, a cytokine molecule or a stromal modifier, and methods of using the same, are disclosed. Also disclosed herein are multifunctional molecules that include a stromal modifying moiety and a tumor-targeting moiety; and methods of using the same, are disclosed.

SUMMARY OF THE INVENTION

[0004] The disclosure relates, inter alia, to novel multispecific or multifunctional molecules that include (i) a tumor-targeting moiety; and one, two or all of: (ii) an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); (iii) a cytokine molecule; and/or (iv) a stromal modifying moiety. In some embodiments, the multispecific molecules include (i) a stromal modifying moiety and (ii) a tumor-targeting moiety (e.g., an antibody molecule, a ligand molecule, or a receptor molecule) that binds to a tumor antigen or a stromal antigen. The terms "multispecific" or "multifunctional" are used interchangeably herein.

[0005] Without wishing to be bound by theory, the multispecific or multifunctional molecules disclosed herein are expected to target (e.g., localize, bridge and/or activate) an immune cell (e.g., an immune effector cell chosen from an NK cell, a T cell, a B cell, a dendritic cell or a macrophage), at a cancer cell and/or alter the tumor stroma, e.g., alter the tumor microenvironment near the cancer site. Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the cancer cell, thereby providing a more effective cancer therapy. Without being bound by theory, a targeted, localized immune response against the cancer cell is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein. Accordingly, provided herein are, inter alia, multispecific molecules (e.g., multispecific or multifunctional antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

[0006] Accordingly, in one aspect, the disclosure features a multispecific or multispecific molecule (e.g., polypeptide or nucleic acid encoding the same) that includes:

[0007] (i) a tumor-targeting moiety, e.g., a first tumor-targeting moiety, that binds to a cancer antigen; and

[0008] one, two or all of:

[0009] (ii) an immune cell engager chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager;

[0010] (iii) a cytokine molecule; and

[0011] (iv) a stromal modifying moiety.

[0012] In some embodiments of the aforesaid molecules:

[0013] if (ii) and (iii) are absent, then (i) and (iv) are present,

[0014] if one (i) and one (ii) are present, then (iii) or (iv) or both are present, or

[0015] if one (i) and one (iii) are present, then (ii) or (iv) or both are present.

[0016] In some embodiments, the multispecific or multifunctional molecule includes (i), (ii) and one or both of (iii) and (iv).

[0017] In some embodiments, the multispecific or multifunctional molecule includes (i), (iii) and one or both of (ii) and (iv).

[0018] In some embodiments, the multispecific or multifunctional molecule includes (i), (ii) and (iii). In other embodiments, the multispecific or multifunctional molecule includes (i), (ii) and (iv).

[0019] In yet another embodiment, the multispecific or multifunctional molecule polypeptide includes (i), (ii), (iii) and (iv).

[0020] In another aspect, provided herein is a multispecific or multifunctional molecule polypeptide that includes:

[0021] (i) at least two tumor targeting moieties, e.g., a first and second tumor-targeting moiety, that bind to one or more cancer antigens; and

[0022] one, two or all of:

[0023] (ii) an immune cell engager chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager;

[0024] (iii) a stromal modifying moiety; and

[0025] (iv) a cytokine molecule, e.g., that includes at least two non-contiguous polypeptides (e.g., a multichain cytokine). In some embodiments, the cytokine molecule comprises two chains, e.g., an alpha and beta chain (e.g., IL-12).

[0026] In some embodiments, the at least two tumor targeting moieties, e.g., the first and second tumor-targeting moieties, bind to the same or a different cancer antigen.

[0027] In some embodiments, the multispecific or multifunctional molecule includes one or two immune cell engagers as described herein. In one embodiment, the one or two immune cell engagers include an antibody molecule that binds to and/or inhibits a checkpoint molecule chosen from one or two of CTLA4, PD1, PD-L1, PD-L2, TIM3, LAG3, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), BTLA, KIR, MHC class I, MHC class II, GAL9, VISTA, BTLA, TIGIT, LAIR1, or A2aR. In one embodiment, the multispecific or multifunctional molecule includes two tumor-targeting moieties to one immune cell engager, e.g., a checkpoint binder. In one embodiment, the multispecific or multifunctional molecule includes two tumor-targeting moieties to two immune cell engagers, e.g., two checkpoint binder (e.g., the same or different checkpoint binder).

[0028] In some embodiments, the first tumor-targeting moiety binds to CD123, the second tumor-targeting moiety binds to CD47 and the T cell engager is or comprises a CD3 agonist.

[0029] In yet another aspect, the multifunctional (e.g., bifunctional) molecule includes a stromal modifying moiety and a tumor-targeting moiety (e.g., an antibody molecule, a ligand molecule, or a receptor molecule) that binds to a tumor antigen or a stromal antigen.

[0030] In embodiments of any of the aforesaid multispecific or multifunctional molecules, the molecules can further include comprising a second tumor-targeting moiety. In embodiments, the second tumor-targeting moiety binds to the same or a different cancer antigen as the first tumor-targeting moiety, e.g., the tumor-targeting moiety in (i). The second tumor-targeting moiety binds to a different epitope on the same cancer antigen as the first tumor-targeting moiety. In other embodiments, the second tumor-targeting moiety and the first tumor-targeting moiety bind to different cancer antigens. The different cancer antigens can be present on the same cell or tumor tissue, or can be present on different cells or tumor tissues.

[0031] Without wishing to be bound by theory, it is believed that systemic toxicity of an immune therapeutic, such as the multispecific molecules described herein, can be managed, e.g., reduced, by directing the immune therapeutic primarily to the tumor and/or stroma before eliciting an immunological response. This effect can be achieved by balancing the affinity of the tumor targeting moiety/moieties to be higher than the affinity for the immune cell engager(s) and/or cytokine(s). In some embodiments, the affinity, e.g., combined affinity, of the tumor-targeting moiety/moieties is at least a 10 fold higher toward the tumor and/or stroma cells compared to the affinity, e.g., combined affinity, of the multispecific molecule (e.g., the immune cell engager(s) and/or cytokine(s)) to the corresponding immune effector cells. The combined affinity can be measured using techniques known in the art. For example, using an SPR-based assay, which enables assessment of the binding activity of a bivalent-bispecific molecule in a single setup, e.g., as described in Meschendoerfer, W. et al. (2017) J Pharm Biomed Anal. 5; 132:141-147. doi: 10.1016/j.jpba.2016.09.028. Epub 2016 Sep. 26.

[0032] Thus, in some embodiments of the multispecific or multifunctional molecule, the affinity, e.g., the combined affinity, for the cancer antigens of the first tumor-targeting moiety and the second tumor-targeting moiety is equal to or greater than the affinity of (ii), (iii) or (iv) (either alone or as part of the multispecific molecule) for its corresponding binding member. For example, the affinity, e.g., the combined affinity, for the cancer antigens of the first tumor-targeting moiety and the second tumor-targeting moiety is at least 2, 5, 10, 20, 30, 40, 50, 75 or 100 times greater than the affinity of (ii), (iii) or (iv) (either alone or as part of the multispecific molecule) for its corresponding binding member.

[0033] In yet other embodiments of the multispecific or multifunctional molecule, the affinity, e.g., the combined affinity, of the first tumor-targeting moiety in and the second tumor-targeting moiety for the tumor, e.g., a cancer cell or a stromal cell, is equal to or greater than the affinity of a similar multispecific or multifunctional molecule polypeptide having only one of the tumor-targeting moiety or the second tumor-targeting moiety. For example, the affinity, e.g., the combined affinity, of the first tumor-targeting moiety and the second tumor-targeting moiety for the tumor, e.g., a cancer cell or a stromal cell, is at least 2, 5, 10, 20, 30, 40, 50, 75 or 100 times greater than the affinity of a similar multispecific or multifunctional molecule polypeptide having only one of the tumor-targeting moiety or the second tumor-targeting moiety.

[0034] In another aspect, provide herein is a multispecific or multifunctional molecule polypeptide that includes:

[0035] A, B-[dimerization module]-C, -D

[0036] wherein:

[0037] (1) the dimerization module comprises an immunoglobulin constant domain, e.g., a heavy chain constant domain (e.g., a homodimeric or heterodimeric heavy chain constant region, e.g., an Fc region), or a constant domain of an immunoglobulin variable region (e.g., a Fab region); and

[0038] (2) A, B, C, and D are independently absent; (i) a tumor-targeting moiety, e.g., a first and/or second tumor-targeting moiety; (ii) an immune cell engager chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager; (iii) a cytokine molecule; or (iv) a stromal modifying moiety.

[0039] In some embodiments, said multispecific or multifunctional molecule polypeptide includes:

[0040] (i) the tumor-targeting moiety, e.g., a first tumor-targeting moiety, that binds to a cancer antigen; and

[0041] one, two or all of:

[0042] (ii) an immune cell engager chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager;

[0043] (iii) a cytokine molecule; and

[0044] (iv) a stromal modifying moiety. In some embodiments,

[0045] if (ii) and (iii) are absent, then (i) and (iv) are present,

[0046] if one (i) and one (ii) are present, then (iii) or (iv) or both are present, or

[0047] if one (i) and one (iii) are present, then (ii) or (iv) or both are present.

[0048] Exemplary multispecific or multifunctional molecules include the following:

[0049] (i) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a first immune cell engager, and D comprises a second immune cell engager (e.g., A and B comprise same or different targeting moieties, and C and D comprise same or different immune cell engagers);

[0050] (ii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a first cytokine molecule, and D comprises a second cytokine molecule (e.g., A and B comprise same or different targeting moieties, and C and D comprise same or different cytokine molecules);

[0051] (iii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a first stromal modifying moiety, and D comprises a second stromal modifying moiety (e.g., A and B comprise same or different targeting moieties, and C and D comprise same or different stromal modifying moieties);

[0052] (iv) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises an immune cell engager, and D comprises a cytokine molecule (e.g., A and B comprise same or different targeting moieties);

[0053] (v) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a cytokine molecule, and D comprises an immune cell engager (e.g., A and B comprise same or different targeting moieties);

[0054] (vi) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises an immune cell engager, and D comprises a stromal modifying moiety (e.g., A and B comprise same or different targeting moieties);

[0055] (vii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a stromal modifying moiety, and D comprises an immune cell engager (e.g., A and B comprise same or different targeting moieties);

[0056] (viii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a cytokine molecule, and D comprises a stromal modifying moiety (e.g., A and B comprise same or different targeting moieties);

[0057] (ix) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a stromal modifying moiety, and D comprises a cytokine molecule (e.g., A and B comprise same or different targeting moieties);

[0058] (x) A comprises a tumor-targeting moiety, and at least one, two, or three of B, C, and D comprises a second tumor-targeting moiety, an immune cell engager, a cytokine molecule, a stromal modifying moiety, or is absent, provided that if (ii) and (iii) are absent, then (i) and (iv) are present;

[0059] (xi) B comprises a tumor-targeting moiety, and at least one, two, or three of A, C, and D comprises a second tumor-targeting moiety, an immune cell engager, a cytokine molecule, a stromal modifying moiety, or is absent, provided that if (ii) and (iii) are absent, then (i) and (iv) are present;

[0060] (xii) C comprises a tumor-targeting moiety, and at least one, two, or three of A, B, and D comprises a second tumor-targeting moiety, an immune cell engager, a cytokine molecule, a stromal modifying moiety, or is absent, provided that if (ii) and (iii) are absent, then (i) and (iv) are present;

[0061] (xiii) D comprises a tumor-targeting moiety, and at least one, two, or three of A, B, and C comprises a second tumor-targeting moiety, an immune cell engager, a cytokine molecule, a stromal modifying moiety, or is absent, provided that if (ii) and (iii) are absent, then (i) and (iv) are present;

[0062] (xiv) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are an immune cell engager and absent, respectively;

[0063] (xv) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are absent and an immune cell engager, respectively;

[0064] (xvi) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are a cytokine molecule and absent, respectively;

[0065] (xvii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are absent and a cytokine molecule, respectively;

[0066] (xviii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are a stromal modifying moiety and absent, respectively;

[0067] (xix) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are absent and a stromal modifying moiety, respectively;

[0068] (xx) A comprises a tumor-targeting moiety, and one of B, C or D comprises a stromal modifying moiety;

[0069] (xxi) B comprises a tumor-targeting moiety, and one of A, C or D comprises a stromal modifying moiety;

[0070] (xxii) C comprises a tumor-targeting moiety, and one of A, B or D comprises a stromal modifying moiety;

[0071] (xxiii) D comprises a tumor-targeting moiety, and one of A, B or C comprises a stromal modifying moiety;

[0072] (xiv) A or B comprises a tumor-targeting moiety, and C comprises an immune cell engager, and D comprises a cytokine molecule;

[0073] (xv) A or B comprises a tumor-targeting moiety, and D comprises an immune cell engager, and C comprises a cytokine molecule;

[0074] (xvi) A and/or B comprises one or two immune cell engagers, and D comprises a tumor-targeting moiety, and C comprises a cytokine molecule;

[0075] (xvii) A and/or B comprises one or two immune cell engagers, and C comprises a tumor-targeting moiety, and B comprises a cytokine molecule;

[0076] (xviii) A and/or B comprises one or two cytokines, and D comprises a tumor-targeting moiety, and C comprises a immune cell engager; or

[0077] (xix) A and/or B comprises one or two cytokines, and C comprises a tumor-targeting moiety, and D comprises a immune cell engager.

[0078] A selection of the exemplary molecules includes:

[0079] (i) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises an immune cell engager (e.g., dendritic cell engager), and D comprises a cytokine molecule (e.g., A and B comprise same or different targeting moieties);

[0080] (ii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C comprises a cytokine molecule, and D comprises an immune cell engager (e.g., A and B comprise same or different targeting moieties);

[0081] (iii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are an immune cell engager and absent, respectively;

[0082] (iv) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are absent and an immune cell engager, e.g., a T cell engager, respectively;

[0083] (v) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are a cytokine molecule and absent, respectively;

[0084] (vi) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are absent and a cytokine molecule, respectively;

[0085] (vii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are a stromal modifying moiety and absent, respectively;

[0086] (viii) A comprises a first tumor-targeting moiety, B comprises a second tumor-targeting moiety, C and D are absent and a stromal modifying moiety, respectively; or

[0087] (ix) A comprises a tumor-targeting moiety, and one of B, C or D comprises a stromal modifying moiety.

[0088] In some embodiments of any of the aforesaid molecules, the first and second tumor targeting moieties bind to a different epitope on the same cancer antigen or to different cancer antigens.

[0089] In other embodiments, the different cancer antigens are present on the same cell or tumor tissue or on different cells or tumor tissues.

[0090] In other embodiments of any of the aforesaid molecules, the affinity, e.g., the combined affinity, for the cancer antigens of the first and the second tumor-targeting moiety is equal to or greater than the affinity of (ii), (iii) or (iv) (either alone or as part of the multispecific molecule) for its corresponding binding member. For example, the affinity, e.g., the combined affinity, for the cancer antigens of the first and the second tumor-targeting moiety is at least 2, 5, 10, 20, 30, 40, 50, 75 or 100 times greater than the affinity of (ii), (iii) or (iv) (either alone or as part of the multispecific molecule) for its corresponding binding member.

[0091] In yet other embodiments of any of the aforesaid molecules, the affinity, e.g., the combined affinity, of the first and the second tumor-targeting moiety for the tumor, e.g., a cancer cell or a stromal cell, is equal to or greater than the affinity of a similar multispecific or multifunctional molecule polypeptide having only one of the tumor-targeting moiety or the second tumor-targeting moiety. For example, the affinity, e.g., the combined affinity, of the first and the second tumor-targeting moiety for the tumor, e.g., a cancer cell or a stromal cell, is at least 2, 5, 10, 20, 30, 40, 50, 75 or 100 times greater than the affinity of a similar multispecific or multifunctional molecule polypeptide having only one of the tumor-targeting moiety or the second tumor-targeting moiety.

[0092] In some embodiments, the tumor-targeting moiety binds to, but does not activate or modulate the cancer antigen. In other embodiments, the tumor-targeting moiety binds to, and activates or modulates the cancer antigen.

[0093] In other embodiments, the immune cell engager binds to, but does not activate, an immune cell, e.g., an effector cell. In other embodiments, the immune cell engager binds to and activates an immune cell, e.g., an effector cell.

[0094] In other embodiments, the immune cell engager binds to, but does not activate, an immune cell, e.g., an effector cell. In other embodiments, the immune cell engager binds to and activates an immune cell, e.g., an effector cell.

[0095] In some embodiments, the immune cell engager comprises a T cell engager that binds to and activates a T cell. In other embodiments, the immune cell engager comprises a T cell engager that binds and does not activate a T cell.

[0096] In some embodiments, the immune cell engager comprises a dendritic cell engager that binds to and activates a dendritic cell. In other embodiments, the immune cell engager comprises a dendritic cell engager that binds and does not activate a dendritic cell.

[0097] In some embodiments, the immune cell engager comprises a macrophage cell engager that binds to and activates a macrophage cell. In other embodiments, the immune cell engager comprises a macrophage cell engager that binds and does not activate a macrophage cell.

[0098] In yet other embodiments, the immune cell engager and/or the tumor-targeting moiety binds to, but does not inhibit, a checkpoint inhibitor (e.g., a cell, e.g., an immune cell, expressing a checkpoint inhibitor). In other embodiments, the immune cell engager and/or the tumor-targeting moiety binds to, and inhibits, a checkpoint inhibitor (e.g., a cell, e.g., an immune cell, expressing a checkpoint inhibitor). Exemplary checkpoint molecules include, but are not limited to, CTLA4, PD1, PD-L1, PD-L2, TIM3, LAG3, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), BTLA, KIR, MHC class I, MHC class II, GAL9, VISTA, BTLA, TIGIT, LAIR1, and A2aR. In one embodiment, the immune cell engager and/or the tumor-targeting moiety binds to, but does not inhibit, a PD1-PDL1 interaction. In another embodiment, the immune cell engager and/or the tumor-targeting moiety binds to and inhibits a PD1-PDL1 interaction.

[0099] In any of the embodiments disclosed herein, a multispecific molecule disclosed does not activate an immune cell when a component is presented individually, e.g., outside the context of the multispecific molecule (or in the context of a multispecific molecule having an individual component, e.g., an individual immune cell engager); but the multispecific molecule activates the immune cell when presented in the context of a multispecific molecule comprising two or more components, e.g., two or more immune cell engagers. For example, the multispecific molecule can become activated when binding the immune cell when two different receptors are bound by different moieties of the multispecific molecule or when two different epitopes on the same receptor of the effector cells are bound by the multispecific molecule (e.g. activation or inhibition of the corresponding receptor on the immune cell). The activity levels can be assessed by any of the assays described herein, e.g., by comparing the component presented individually, e.g., in the multispecific molecule to two or more components presented in combination in the multispecific molecule. Without wishing to be bound by theory, binding of two or more different moieties of the multispecific molecule is believed to trigger a change in physical state, e.g., conformation, clustering, which leads to regulated, targeted, activation of an immune response against the cancer cell; such regulated activation is believed to reduce the effects of systemic toxicity of the multispecific molecules described herein.

[0100] In other embodiments, the tumor-targeting moiety comprises an antibody molecule, a receptor molecule (e.g., a receptor, a receptor fragment or functional variant thereof), or a ligand molecule (e.g., a ligand, a ligand fragment or functional variant thereof), or a combination thereof, that binds to the cancer antigen. For example, the tumor-targeting moiety can binds to a cancer antigen present on a hematological cancer, a solid tumor, a metastatic cancer, soft tissue tumor, metastatic lesion, or a combination thereof. In other embodiments, the cancer antigen is a tumor antigen or stromal antigen, or a hematological antigen. The tumor antigen or stromal antigen can be present on a fibrotic or desmoplastic solid tumor. For example, the tumor antigen or stromal antigen is present on a tumor, e.g., a tumor of a class typified by having one or more of: limited tumor perfusion, compressed blood vessels, or fibrotic tumor interstitium.

[0101] Exemplary cancers that can be targeted include, but are not limited to the tumor, e.g., solid tumor, pancreatic (e.g., pancreatic adenocarcinoma), breast, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, or liver cancer. The cancer can also be a hematological cancer including, but not limited to, B-cell or T cell malignancy, e.g., Hodgkin's lymphoma, Non-Hodgkin's lymphoma (e.g., B cell lymphoma, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia.

[0102] In some embodiments, the cancer, e.g., solid tumor, antigen is chosen from: PDL1, CD47, mesothelin, gangloside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2/neu, Telomerase, SAP-1, Survivin, NY-ESO-1/LAGE-1, PRAME, SSX-2, Melan-A/MART-1, Gp100/pmel17, Tyrosinase, TRP-1/-2, MC1R, .beta.-catenin, BRCA1/2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-ESO-1, .beta.-catenin, CDK4, CDC27, CD47, .alpha. actinin-4, TRP1/gp75, TRP2, gp100, Melan-A/MART1, gangliosides, WT1, EphA3, Epidermal growth factor receptor (EGFR), CD20, MART-2, MART-1, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, Folate receptor alpha, L1-CAM, CAIX, EGFRvIII, gpA33, GD3, GM2, VEGFR, Intergrins (Integrin alphaVbeta3, Integrin alpha5Beta1), Carbohydrates (Le), IGF1R, EPHA3, TRAILR1, TRAILR2, or RANKL. In other embodiments, the cancer antigen is a stromal antigen can be chosen from fibroblast activating protease (FAP), TGF-beta, hyaluronic acid, collagen, e.g., collagen IV, tenascin C, or tenascin W. In embodiments where the cancer antigen is a hematological antigen, the cancer antigen can be chosen from CD19, CD33, CD47, CD123, CD20, CD99, CD30, BCMA, CD38, CD22, SLAMF7, or NY-ESO1.

[0103] In some embodiments of any of the multispecific or multifunctional molecules disclosed herein, the tumor-targeting moiety is chosen from an antibody molecule to a cancer antigen chosen from mesothelin, PDL1, HER3, IGF1R, FAP, CD47 or CD123. For example, the tumor-targeting moiety can include an antibody molecule (e.g., Fab or scFv) that binds to mesothelin or PDLi. In some embodiments, the tumor-targeting moiety binds to PDL1 and inhibits an interaction of PDL1 with PD1. In other embodiments, the tumor-targeting moiety binds to PDL1 and does not inhibit an interaction of PD L1 with PD1.

[0104] In embodiments, the multispecific or multifunctional molecule can include two or three antibody molecules to two or three cancer antigens chosen from mesothelin, PDL1, HER3, IGF1R, FAP, CD123 or CD47. For example, the first and second tumor targeting moieties are an anti-mesothelin antibody molecule and an anti-PDL1 antibody molecule, respectively; or the second and first tumor targeting moieties are an anti-mesothelin antibody molecule and an anti-PDL1 antibody molecule, respectively. Other combinations include, but are not limited to, the first and second tumor targeting moieties are an anti-FAP antibody molecule and an anti-PDL1 antibody molecule, respectively; or the second and first tumor targeting moieties are an anti-FAP antibody molecule and an anti-PDL1 antibody molecule, respectively. In other embodiments, the first and second tumor targeting moieties are an anti-HER3 antibody molecule and an anti-IGF1R antibody molecule, respectively; or the second and first tumor targeting moieties are an anti-HER3 antibody molecule and an anti-IGF1R antibody molecule, respectively. In other embodiments, the first and second tumor targeting moieties are an anti-CD123 antibody molecule and an anti-CD47 antibody molecule, respectively; or the second and first tumor targeting moieties are an anti-CD123 antibody molecule and an anti-CD47 antibody molecule, respectively.

[0105] In some embodiments, the multispecific or multifunctional molecule can include an immune cell engager is chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, or a combination thereof. In some embodiments, the immune cell engager comprises an NK cell engager that mediates binding to and activation of, an NK cell. In other embodiments, the immune cell engager comprises an NK cell engager that mediates binding to but not activation of, an NK cell. Exemplary NK cell engagers can be chosen from an antibody molecule, e.g., an antigen binding domain, or ligand that binds to (e.g., activates NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16 (e.g., CD16a, CD16b, or both), CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, or CD160. In some embodiments, the NK cell engager is an antibody molecule, e.g., an antigen binding domain that binds to NKp30 or NKp46.

[0106] In some embodiments, the immune cell engager comprises a T cell engager that mediates binding to and activation of, a T cell. In some embodiments, the immune cell engager comprises a T cell engager that mediates binding to but not activation of, a T cell.

[0107] In other embodiments of the multispecific or multifunctional molecule the NK cell engager is a ligand, optionally, the ligand further comprises an immunoglobulin constant region, e.g., an Fc region. For example, the ligand of NKp44 or NKp46 is a viral HA; the ligand of DAP10 is a coreceptor for NKG2D; the ligand of CD16 is a CD16a/b ligand, e.g., a CD16a/b ligand further comprising an antibody Fc region.

[0108] In other embodiments, the immune cell engager mediates binding to, or activation of, or both of, one or more of a B cell, T cell, a macrophage, and/or a dendritic cell.

[0109] In other embodiments of the multispecific or multifunctional molecule, the T cell engager is an agonist of CD3, TCR.alpha., TCR.beta., TCR.gamma., TCR.zeta., ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226. In other embodiments, the T cell engager binds to, but does not CD3, TCR.alpha., TCR.beta., TCR.gamma., TCR.zeta., ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226.

[0110] In some embodiments, the immune cell engager comprises a B cell, macrophage, and/or dendritic cell engager chosen from one or more of CD40 ligand (CD40L) or a CD70 ligand; an antibody molecule that binds to CD40 or CD70; an antibody molecule to OX40; an OX40 ligand (OX40L); an agonist of a Toll-like receptor (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4) or a TLR9 agonist); a 41BB; a CD2 agonist; a CD47; or a STING agonist, or a combination thereof.

[0111] In some embodiments, the B cell engager is a CD40L, an OX40L, or a CD70 ligand, or an antibody molecule that binds to OX40, CD40 or CD70.

[0112] In other embodiments, the macrophage cell engager is a CD2 agonist; a CD40L; an OX40L; an antibody molecule that binds to OX40, CD40 or CD70; an agonist of a Toll-like receptor (TLR)(e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4) or a TLR9 agonist); CD47; or a STING agonist.

[0113] In yet other embodiments, the dendritic cell engager is a CD2 agonist, an OX40 antibody, an OX40L, 41BB agonist, a Toll-like receptor agonist or a fragment thereof (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4)), CD47 agonist, or a STING agonist. For example, the STING agonist can include a cyclic dinucleotide, e.g., a cyclic di-GMP (cdGMP), a cyclic di-AMP (cdAMP), or a combination thereof, optionally with 2',5' or 3',5' phosphate linkages. The STING agonist can be covalently coupled to the multispecific or multifunctional molecule, e.g., by art known techniques.

[0114] In other embodiments, the multispecific or multifunctional molecule is chosen from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforesaid cytokines. The cytokine can be a monomer or a dimer. For example, the cytokine molecule can further include a receptor dimerizing domain, e.g., an IL15Ralpha dimerizing domain. In other embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) are not covalently linked, e.g., are non-covalently associated.

[0115] In other embodiments, the multispecific or multifunctional molecule can include a stromal modifying moiety that causes one or more of: decreases the level or production of a stromal or extracellular matrix (ECM) component; decreases tumor fibrosis; increases interstitial tumor transport; improves tumor perfusion; expands the tumor microvasculature; decreases interstitial fluid pressure (IFP) in a tumor; or decreases or enhances penetration or diffusion of an agent, e.g., a cancer therapeutic or a cellular therapy, into a tumor or tumor vasculature. For example, the stromal or ECM component decreased is chosen from a glycosaminoglycan or an extracellular protein, or a combination thereof. The glycosaminoglycan can be chosen from hyaluronan (also known as hyaluronic acid or HA), chondroitin sulfate, chondroitin, dermatan sulfate, heparan sulfate, heparin, entactin, tenascin, aggrecan or keratin sulfate. Exemplary extracellular proteins include, but are not limited to, from collagen, laminin, elastin, fibrinogen, fibronectin, or vitronectin.

[0116] In some embodiments, the multispecific or multifunctional molecule includes a stromal modifying moiety that comprises an enzyme molecule that degrades a tumor stroma or extracellular matrix (ECM). The enzyme molecule can be chosen from a hyaluronidase molecule, a collagenase molecule, a chondroitinase molecule, a matrix metalloproteinase molecule (e.g., macrophage metalloelastase), or a variant (e.g., a fragment) of any of the aforesaid.

[0117] In some embodiments, the stromal modifying moiety decreases the level or production of hyaluronic acid. For example, the stromal modifying moiety comprises a hyaluronan degrading enzyme, an agent that inhibits hyaluronan synthesis, or an antibody molecule against hyaluronic acid.

[0118] In yet other embodiments, the hyaluronan degrading enzyme is a hyaluronidase molecule or a variant (e.g., fragment thereof) thereof. The hyaluronan degrading enzyme can be active in neutral or acidic pH, e.g., pH of about 4-5. In some embodiments, the hyaluronidase molecule is a mammalian hyaluronidase molecule, e.g., a recombinant human hyaluronidase molecule, or a variant thereof (e.g., a truncated form thereof). For example, the hyaluronidase molecule can be chosen from HYAL1, HYAL2, or PH-20/SPAM1, or a variant thereof (e.g., a truncated form thereof). In yet other embodiments, the truncated form lacks a C-terminal glycosylphosphatidylinositol (GPI) attachment site or a portion of the GPI attachment site.

[0119] In yet other embodiments, the hyaluronidase molecule is glycosylated, e.g., comprises at least one N-linked glycan.

[0120] In one embodiment, the hyaluronidase molecule includes the amino acid sequence of SEQ ID NO: 61, or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 61.

[0121] In some embodiments, the hyaluronidase molecule comprises:

[0122] (i) the amino acid sequence of 36-464 of SEQ ID NO: 61;

[0123] (ii) the amino acid sequence of 36-481, 36-482, or 36-483 of PH20, wherein PH20 has the sequence of amino acids set forth in SEQ ID NO: 61; or

[0124] (iii) an amino acid sequence having at least 95% to 100% sequence identity to the polypeptide or truncated form of sequence of amino acids set forth in SEQ ID NO: 61; or

[0125] (iv) an amino acid sequence having 30, 20, 10, 5 or fewer amino acid substitutions to the amino acid sequence set forth in SEQ ID NO: 61.

[0126] In some embodiments, the hyaluronidase molecule includes an amino acid sequence at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 100%) identical to the amino acid sequence of SEQ ID NO: 61; or is encoded by a nucleotide sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, 100%) identical to the nucleotide sequence of SEQ ID NO: 61.

[0127] In other embodiments, the hyaluronidase molecule is PH20, e.g., rHuPH20.

[0128] In one embodiment, the hyaluronidase molecule is HYAL1 and comprises the amino acid sequence: SEQ ID NO: 62, or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 62.

[0129] In some embodiments, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule, further comprises a polymer, e.g., is conjugated to a polymer, e.g., PEG. For example, the hyaluronan-degrading enzyme can be a PEGylated PH20 enzyme (PEGPH20).

[0130] In some embodiments, the multispecific or multifunctional molecule polypeptide the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule, further comprises an immunoglobulin chain constant region (e.g., Fc region) chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4.

[0131] In some embodiments, the immunoglobulin constant region (e.g., the Fc region) is linked, e.g., covalently linked to, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule. In some embodiments, the immunoglobulin chain constant region (e.g., Fc region) is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function. In some embodiments, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule, forms a dimer.

[0132] In some embodiments, the stromal modifying moiety comprises an inhibitor of the synthesis of hyaluronan, e.g., an HA synthase. In some embodiments, the inhibitor comprises a sense or an antisense nucleic acid molecule against an HA synthase or is a small molecule drug. In some embodiments, the inhibitor is 4-methylumbelliferone (MU) or a derivative thereof (e.g., 6,7-dihydroxy-4-methyl coumarin or 5,7-dihydroxy-4-methyl coumarin), or leflunomide or a derivative thereof. In some embodiments, the stromal modifying moiety comprises a collagenase molecule, e.g., a mammalian collagenase molecule, or a variant (e.g., fragment) thereof. In some embodiments, the collagenase molecule is collagenase molecule IV, e.g., comprising the amino acid sequence of SEQ ID NO: 63, or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 63.

[0133] In some embodiments, the multispecific or multifunctional molecule polypeptide comprises two binding specificities or functions, e.g., it is a bispecific or a bifunctional molecule, e.g., which comprises: i) the tumor-targeting moiety and the immune cell engager, provided that when the multispecific molecule comprises the tumor-targeting moiety and the immune cell engager only, the immune cell engager is not an antibody molecule to an NK cell antigen; or ii) the tumor-targeting moiety and the stromal modifying moiety.

[0134] In some embodiments, the multispecific or multifunctional molecule polypeptide comprises three or four binding specificities or functions, e.g., is a trispecific or a tetraspecific molecule. In some embodiments, the multispecific or multifunctional molecule polypeptide comprises (i) at least two tumor-targeting moieties, the immune cell engager, and the cytokine molecule; (ii) the tumor-targeting moiety, the immune cell engager, and the stromal modifying moiety; or (iii) at least two tumor-targeting moieties that bind to two cancer antigens chosen from mesothelin, PDL1, HER3, Fibroblast Activation Protein (FAP), or insulin growth factor 1R (IGF1R), CD47 or CD123, provided that the two cancer antigens are not FAP and IGF1R; and a cytokine molecule.

[0135] In some embodiments, the multispecific or multifunctional molecule polypeptide comprises: (i) one tumor-targeting moiety; (ii) two immune cell engagers (e.g., same or different immune cell engagers); and one or both of: (iii) one cytokine molecule, or (iv) one stromal modifying moiety. In some embodiments, the multispecific or multifunctional molecule polypeptide comprises (i) two tumor-targeting moieties (e.g., same or different targeting moieties); (ii) one immune cell engager; and one or both of: (iii) one cytokine molecule, or (iv) one stromal modifying moiety. In some embodiments, the multispecific or multifunctional molecule polypeptide comprises (i) one tumor-targeting moiety; (ii) one immune cell engager; and one or both of: (iii) two cytokine molecules (e.g., same or different cytokine molecules).

[0136] In some embodiments, one of the two tumor targeting moieties binds PDL1; one of the two tumor targeting moieties binds mesothelin; the immune cell engager binds NKp46 or NKp30; and the cytokine molecule is IL2.

[0137] In some embodiments, the tumor-targeting moiety or the immune cell engager, or both, comprises (i) an antibody molecule, e.g., at least one immunoglobulin domain; and/or (ii) a receptor or a ligand, or a fragment thereof.

[0138] In some embodiments, the tumor-targeting antibody molecule binds to the solid tumor antigen and/or the stromal antigen with a dissociation constant of less than about 10 nM, and more typically, 10-100 pM.

[0139] In some embodiments, the immune cell engager antibody molecule binds to the NK cell antigen, the B cell antigen, the dendritic cell antigen, and/or the macrophage cell antigen with a dissociation constant of less than about 10 nM, and more typically, 10-100 pM.

[0140] In some embodiments, the tumor-targeting antibody molecule binds to a conformational or a linear epitope on the tumor antigen or the stromal antigen.

[0141] In some embodiments, the immune cell engager antibody molecule binds to a conformational or a linear epitope on the NK cell antigen, the B cell antigen, the dendritic cell antigen, and/or the macrophage cell antigen.

[0142] In some embodiments, the tumor-targeting antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, or a trispecific antibody molecule.

[0143] In some embodiments, the tumor-targeting antibody molecule is a monovalent antibody molecule, a bivalent antibody molecule, or a trivalent antibody molecule.

[0144] In some embodiments, the immune cell engager antibody molecule is a monospecific, a bispecific antibody molecule, or a trispecific antibody.

[0145] In some embodiments, the immune cell engager antibody molecule is a monovalent, a bivalent, or a trivalent antibody.

[0146] In some embodiments, the tumor targeting antibody molecule and/or immune cell engager antibody molecule is a full antibody (e.g., an antibody that includes at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains), or an antigen-binding fragment (e.g., a Fab, F(ab').sub.2, Fv, a single chain Fv, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[0147] In some embodiments, the tumor targeting antibody molecule and immune cell engager antibody molecule are, independently, a full antibody (e.g., an antibody that includes at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains), or an antigen-binding fragment (e.g., a Fab, F(ab').sub.2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[0148] In some embodiments, the tumor targeting antibody molecule and/or immune cell engager antibody molecule comprises a heavy chain constant region chosen from IgG1, IgG2, IgG3, or IgG4, or a fragment thereof.

[0149] In some embodiments, the tumor targeting antibody molecule and/or immune cell engager antibody molecule comprises a light chain constant region chosen from the light chain constant regions of kappa or lambda, or a fragment thereof.

[0150] In some embodiments, the tumor-targeting moiety or the immune cell engager, or both, comprises a receptor or receptor fragment, or a ligand or ligand fragment, that binds to the tumor antigen and/or the stromal antigen, or the NK cell antigen, the B cell antigen, the dendritic cell antigen, and/or the macrophage cell antigen.

[0151] In some embodiments, the multispecific or multifunctional molecule polypeptide further comprises an immunoglobulin constant region (e.g., Fc region) chosen from the heavy chain constant regions of IgG1, IgG2, and IgG4, more particularly, the heavy chain constant region of human IgG1, IgG2 or IgG4. In some embodiments, the immunoglobulin constant region (e.g., an Fc region) is linked, e.g., covalently linked to, one or more of the tumor-targeting moiety, the immune cell engager, or the cytokine molecule. In some embodiments, the immunoglobulin chain constant region (e.g., Fc region) is altered, e.g., mutated, to increase or decrease one or more of. Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.

[0152] In some embodiments, the multispecific or multifunctional polypeptide comprises at least two non-contiguous polypeptide chains.

[0153] In some embodiments, the tumor-targeting moiety or immune cell engager comprises a light chain constant region chosen from the light chain constant region of kappa or lambda, or a fragment thereof.

[0154] In some embodiments, the multispecific or multifunctional polypeptide comprises a first tumor-targeting moiety and a second tumor-targeting moiety, wherein the first tumor-targeting moiety comprises a kappa light chain constant region, or a fragment thereof, and the second tumor-targeting moiety comprises a lambda light chain constant region, or a fragment thereof.

[0155] In some embodiments, the multispecific or multifunctional polypeptide comprises a first tumor moiety and a second tumor-targeting moiety, wherein the first tumor-targeting moiety and the second tumor-targeting moiety comprise a common light chain variable region.

[0156] In some embodiments, the immunoglobulin constant region (e.g., an Fc region) is linked, e.g., covalently linked to, one or more of tumor-targeting moiety, the immune cell engager, the cytokine molecule, or the stromal modifying moiety.

[0157] In some embodiments, the multispecific or multifunctional polypeptide comprises an interface of a first and second immunoglobulin chain constant regions (e.g., Fc region) is altered, e.g., mutated, to increase or decrease dimerization, e.g., relative to a non-engineered interface.

[0158] In some embodiments, the dimerization of the immunoglobulin chain constant region (e.g., Fc region) is enhanced by providing an Fc interface of a first and a second Fc region with one or more of: a paired cavity-protuberance ("knob-in-a hole"), an electrostatic interaction, or a strand-exchange, such that a greater ratio of heteromultimer:homomultimer forms, e.g., relative to a non-engineered interface.

[0159] In some embodiments, the immunoglobulin chain constant region (e.g., Fc region) comprises an amino acid substitution at a position chosen from one or more of 347, 349, 350, 351, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407, or 409, e.g., of the Fc region of human IgG1.

[0160] In some embodiments, the immunoglobulin chain constant region (e.g., Fc region) comprises an amino acid substitution chosen from: T366S, L368A, or Y407V (e.g., corresponding to a cavity or hole), or T366W (e.g., corresponding to a protuberance or knob), or a combination thereof.

[0161] In some embodiments, the multispecific or multifunctional polypeptide further comprises a linker, e.g., a linker between one or more of: the targeting moiety and the cytokine molecule or the stromal modifying moiety, the targeting moiety and the immune cell engager, the cytokine molecule or the stromal modifying moiety, and the immune cell engager, the cytokine molecule or the stromal modifying moiety and the immunoglobulin chain constant region (e.g., the Fc region), the targeting moiety and the immunoglobulin chain constant region, or the immune cell engager and the immunoglobulin chain constant region.

[0162] In some embodiments, the linker is selected from: a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker. In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker comprises Gly and Ser.

[0163] In some embodiments, the multispecific or multifunctional polypeptide is a bispecific molecule comprising a first and a second non-contiguous polypeptides, wherein:

[0164] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor-targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a cancer antigen, e.g., a solid tumor, a stromal or a hematological antigen, connected, optionally via a linker to, a cytokine molecule, a stromal modifying moiety, or an immune cell engager, e.g., an antibody molecule, e.g., a scFv that binds to an immune cell antigen; and

[0165] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a cancer antigen, e.g., a solid tumor, a stromal or a hematological antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1).

[0166] In some embodiments, the multispecific or multifunctional polypeptide is a bispecific molecule comprising a first and a second non-contiguous polypeptides, wherein:

[0167] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor-targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a cancer antigen, e.g., a solid tumor, a stromal or a hematological antigen, connected, optionally, via a linker to, a first domain that promotes association between the first and the second polypeptide (e.g., a first immunoglobulin constant domain (e.g., a first Fc molecule as described herein);

[0168] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a cytokine molecule, a stromal modifying moiety, or an immune cell engager (e.g., an antibody molecule, e.g., a scFv, that binds to an immune cell antigen), connected, optionally, via a linker to, a second domain that promotes association between the first and the second polypeptide (e.g., a second immunoglobulin constant domain (e.g., a second Fc molecule as described herein); and

[0169] (iii) the third polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to the cancer antigen.

[0170] In some embodiments, the multispecific or multifunctional polypeptide is a trispecific molecule comprising a first, a second and a third non-contiguous polypeptide, wherein:

[0171] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor-targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a cancer antigen, connected, optionally, via a linker to, a first domain that promotes association between the first and the second polypeptide (e.g., a first immunoglobulin constant domain (e.g., a first Fc molecule as described herein);

[0172] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a cytokine molecule, a stromal modifying moiety, or an immune cell engager (e.g., an antibody molecule, e.g., a scFv, that binds to an immune cell antigen), connected, optionally, via a linker to, a second domain that promotes association between the first and the second polypeptide (e.g., a second immunoglobulin constant domain (e.g., a second Fc molecule as described herein); and

[0173] (iii) the third polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to the cancer antigen,

[0174] wherein either the first or the second polypeptide further comprise a cytokine molecule or an immune cell engager, optionally covalently linked to the C-terminus of the first or second immunoglobulin constant domain.

[0175] In some embodiments, the multispecific or multifunctional polypeptide is a tetraspecific molecule comprising a first, a second and a third non-contiguous polypeptide, wherein:

[0176] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor-targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a cancer antigen, connected, optionally, via a linker to, a first domain that promotes association between the first and the second polypeptide (e.g., a first immunoglobulin constant domain (e.g., a first Fc molecule as described herein);

[0177] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a cytokine molecule, a stromal modifying moiety, or an immune cell engager (e.g., an antibody molecule, e.g., a scFv, that binds to an immune cell antigen), connected, optionally, via a linker to, a second domain that promotes association between the first and the second polypeptide (e.g., a second immunoglobulin constant domain (e.g., a second Fc molecule as described herein); and

[0178] (iii) the third polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to the cancer antigen,

[0179] wherein the first and the second polypeptide further comprise a cytokine molecule and/or an immune cell engager, optionally covalently linked to the C-terminus of the first or second immunoglobulin constant domain.

[0180] In some embodiments, the multispecific or multifunctional polypeptide comprises a) a first polypeptide comprising: a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and two polypeptides selected from: a tumor-targeting moiety; an immune cell engager; a stromal modifying moiety, and a cytokine molecule b) a second polypeptide comprising: a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and two polypeptides selected from: a tumor-targeting moiety; an immune cell engager; and a cytokine molecule, wherein the multispecific or multifunctional molecule polypeptide comprises a tumor-targeting moiety; an immune cell engager; a stromal modifying moiety; and a cytokine molecule.

[0181] In some embodiments, the multispecific or multifunctional polypeptide comprises a tumor-targeting moiety; an immune cell engager; and two cytokine molecules or two stromal modifying moieties;

[0182] a tumor-targeting moiety; two immune cell engagers; and a cytokine molecule or a stromal modifying moiety; or

[0183] two tumor targeting moieties; an immune cell engager; and a cytokine molecule or a stromal modifying moiety.

[0184] In some embodiments, the multispecific or multifunctional polypeptide comprises two tumor targeting moieties; an immune cell engager; and a cytokine molecule, wherein one of the two tumor-targeting moiety is an antibody molecule that binds PDL1; one of the two tumor-targeting moiety binds mesothelin; the immune cell engager binds NKp46 or NKp30; and the cytokine is IL2.

[0185] In some embodiments, the multispecific or multifunctional polypeptide comprises

[0186] i) a first polypeptide comprises, e.g., in the N--C or C-N direction, a tumor-targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and an immune cell engager;

[0187] ii) a first polypeptide comprises, e.g., in the N--C or C-N direction, a tumor-targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a cytokine molecule or a stromal modifying moiety; or

[0188] iii) a first polypeptide comprises, e.g., in the N--C or C-N direction a cytokine; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and an immune cell engager; and

[0189] iv) a second polypeptide comprises, e.g., in the N--C or C-N direction, a tumor-targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and an immune cell engager;

[0190] v) a second polypeptide comprises, e.g., in the N--C or C-N direction, a tumor-targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a cytokine molecule or a stromal modifying moiety; or vi) a second polypeptide comprises, e.g., in the N--C or C-N direction a cytokine; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and an immune cell engager.

[0191] In some embodiments, (i) the tumor-targeting moiety comprises:

[0192] (ia) an antibody molecule against a solid tumor antigen chosen from: PDL1, Mesothelin, HER3, IGF-1R, GD2, PMSA, CEA, Ron Kinase, or c-Met; and/or

[0193] (ib) an antibody molecule against a stromal antigen is chosen from: FAP, hyaluronic acid, collagen IV, tenascin C, or tenascin W; or a combination of the antibody molecule against the solid tumor antigen and the antibody molecule against the stromal antigen; and

[0194] (ii) one, two or all of:

[0195] (iia) the immune cell engager chosen from one, two, three, or all of a CD40L or a CD70 ligand; an antibody molecule that binds to CD40 or CD70; an antibody molecule to OX40; an OX40L; B7-H6, or a STING agonist, or a combination thereof;

[0196] (iib) the cytokine molecule chosen from IL-2, IL-12, IL-15, IL-18, or IL-21, fragment or variant thereof, or a combination of any of the aforesaid cytokine molecules;

[0197] (iic) the stromal modifying moiety chosen from hyaluronidase or gelatinase.

[0198] In some embodiments, the multispecific or multifunctional polypeptide comprises an antibody molecule to mesothelin, e.g., human mesothelin; a CD40L polypeptide; and an IL-15 or IL-2 molecule.

[0199] In some embodiments, the antibody molecule comprises a Fab against mesothelin having a light and a heavy chain.

[0200] In some embodiments, the heavy chain of the Fab against mesothelin further comprises the IL-15 or IL-2 molecule, e.g., human IL-15 molecule, optionally, wherein the Fab and the IL-15 or IL-2 molecule are linked, e.g., via a linker comprising Gly and Ser.

[0201] In some embodiments, the multispecific or multifunctional polypeptide has the following configuration: Heavy chain of the Fab (e.g., VH-CH1) against mesothelin to IL-15 or IL-2, from N- to C-terminus, optionally, comprising a Gly-Ser linker between the Fab and the IL-15 or IL-2.

[0202] In some embodiments, the light chain of the Fab to mesothelin further comprises a CD40L, optionally, wherein the Fab and the CD40L are linked, e.g., via a linker comprising Gly and Ser.

[0203] In some embodiments, the multispecific or multifunctional polypeptide has the following configuration: Light chain of the Fab (e.g., VL-CL1) to mesothelin fused to CD40L, from N- to C-terminus, optionally, comprising a Gly-Ser linker between the Fab and the CD40L.

[0204] In some embodiments, the multispecific or multifunctional molecule comprises an antibody molecule to FAP, e.g., human FAP, and an IL-15 or IL-2 molecule. In some embodiments, the antibody molecule comprises a Fab against FAP having a light and a heavy chain. In some embodiments, the heavy chain of the Fab to FAP further comprises a first Fc region having a member of a paired cavity-protuberance (knob-in-a hole) in the Fe interface of the first Fc region.

[0205] In some embodiments, the multifunctional or multispecific molecule has the following configuration: Heavy chain of the Fab (e.g., VH-CH1) of FAP fused to First Fc region (e.g., CH2 to CH3), from N- to C-terminus.

[0206] In some embodiments, the IL-15 or IL-2 molecule, e.g., human IL-15 or IL-2 molecule, further comprises a second Fc region having a second member of a paired cavity-protuberance (knob-in-a hole) in the Fc interface of the second Fc region, e.g., connected via a linker comprising Gly and Ser.

[0207] In some embodiments, the multispecific or multifunctional polypeptide has the following configuration: IL-15 or IL-2 molecule-Second Fc region (e.g., CH2 to CH3), from N- to C-terminus, e.g., wherein the IL-15 or IL-2 molecule and the second Fc region are connected via a linker comprising Gly and Ser.

[0208] In some embodiments, the multispecific or multifunctional polypeptide further comprises an immune cell engager. In some embodiments, the immune cell engager comprises a CD40 ligand. In some embodiments, the immune cell enhancer is linked, e.g., covalently linked, to the second Fc region having the second member of the paired cavity-protuberance (knob-in-a hole) and the IL-15 or IL-2 molecule, e.g., human IL-15 or IL-2 molecule, optionally comprising a linker comprising Gly and Ser between the IL-15 or IL-2 molecule and the second Fc region, and/or between the second Fc region and the immune cell enhancer.

[0209] In some embodiments, the multispecific or multifunctional polypeptide has the following configuration: IL-15 or IL-2 molecule-Second Fc region (e.g., CH2 to CH3)--Immune cell enhancer, from N- to C-terminus, optionally comprising a linker comprising Gly and Ser between the IL-15 or IL-2 molecule and the second Fc region, and/or between the second Fc region and the immune cell enhancer.

[0210] In some embodiments the multispecific or multifunctional polypeptide further comprises a second immune cell enhancer. In some embodiments, the second immune cell enhancer comprises a B7H6 molecule. In some embodiments, the second immune cell enhancer is linked, e.g., covalently linked, to the first Fc region having the first member of the paired cavity-protuberance (knob-in-a hole) in the Fc interface of the first Fc region and the heavy chain of the Fab, optionally comprising a linker comprising Gly and Ser between the B7H6 molecule and the first Fc region.

[0211] In some embodiments, the multispecific or multifunctional polypeptide comprises a targeting antibody molecule to a solid tumor antigen or a stromal antigen, and at least two immune cell enhancers. In some embodiments, the antibody molecule binds to mesothelin or FAP. In some embodiments, the immune cell enhancers are a TLR agonist (e.g., a TLR9 agonist) or a STING agonist and an antibody molecule against OX40. In some embodiments, the STING agonist comprises a cyclic dinucleotide, e.g., a cyclic di-GMP (cdGMP), a cyclic di-AMP (cdAMP), or a combination thereof, optionally with 2',5' or 3',5' phosphate linkages, and optionally, wherein the STING agonist is coupled (e.g., directly conjugated) to the targeting antibody or the immune cell enhancer. In some embodiments, the TLR agonist comprises an unmethylated CpG sequences

[0212] In some embodiments, the multispecific or multifunctional polypeptide comprises a bispecific antibody having a first binding specificity for mesothelin or FAP, and a second binding specificity for OX40.

[0213] In some embodiments of any of the aforesaid multispecific molecules, the tumor targeting moiety is chosen from an antibody molecule to a cancer antigen chosen from mesothelin, PDL1, HER3, IGF1R or FAP. In some embodiments, the multispecific molecule comprises two or three antibody molecules to two or three cancer antigens chosen from mesothelin, PDL1, HER3, IGF1R or FAP. In some embodiments, the tumor targeting moiety binds to PD L1 and inhibits an interaction of PD L1 with its ligand, e.g., PD1. In other embodiments, the tumor targeting moiety binds to PD L1 and does not inhibit an interaction of PD L1 with its ligand, e.g., PD1.

[0214] In some embodiments, the first and second tumor targeting moieties are an anti-mesothelin antibody molecule and an anti-PDL1 antibody molecule, respectively. In some embodiments, the second and first tumor targeting moieties are an anti-mesothelin antibody molecule and an anti-PDL1 antibody molecule, respectively.

[0215] In some embodiments, the first and second tumor targeting moieties are an anti-FAP antibody molecule and an anti-PDL1 antibody molecule, respectively. In some embodiments, the second and first tumor targeting moieties are an anti-FAP antibody molecule and an anti-PDL1 antibody molecule, respectively.

[0216] In some embodiments, the first and second tumor targeting moieties are an anti-HER3 antibody molecule and an anti-IGF1R antibody molecule, respectively. In some embodiments, the second and first tumor targeting moieties are an anti-HER3 antibody molecule and an anti-IGF1R antibody molecule, respectively.

[0217] In some embodiments of any of the aforesaid multispecific molecules, the immune cell engager is chosen from an antibody molecule to NKp30, an antibody molecule to NKp46, CD40L, or 41BBL.

[0218] In some embodiments of any of the aforesaid multispecific molecules, the cytokine molecule is an IL-2 molecule (e.g., IL-2 or a functional variant thereof), an IL-15 molecule (e.g., IL-15 or a functional variant thereof), or an IL-21 molecule (e.g., IL-21 or a functional variant thereof).

[0219] In some embodiments of any of the aforesaid multispecific molecules, the stromal modifying molecule is chosen from a hyaluronidase (e.g., hyaluronidase 1), or a functional variant thereof, or gelatinase or a functional variant thereof.

[0220] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab) and IL-2 (or functional variant thereof).

[0221] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), IL-2 (or functional variant thereof), and an anti-NKp30 NK cell engager moiety (e.g., an anti-NKp30 Fab or scFv).

[0222] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab) and an anti-NKp30 NK cell engager moiety (e.g., an anti-NKp30 Fab or scFv).

[0223] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab) and an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab)

[0224] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), and IL-2 (or functional variant thereof).

[0225] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), and an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv).

[0226] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), and IL-2 (or functional variant thereof).

[0227] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), and IL-2 (or functional variant thereof).

[0228] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), and IL-2 (or functional variant thereof).

[0229] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab) and an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab).

[0230] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab) and hyaluronidase 1 (or functional variant thereof).

[0231] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), IL-2 (or functional variant thereof), and hyaluronidase 1 (or functional variant thereof).

[0232] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), and hyaluronidase 1 (or functional variant thereof).

[0233] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), IL-2 (or functional variant thereof), and hyaluronidase 1 (or functional variant thereof).

[0234] In one embodiment, the multispecific molecule comprises an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), IL-2 (or functional variant thereof), and hyaluronidase 1 (or functional variant thereof).

[0235] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab) and gelatinase (or functional variant thereof).

[0236] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), IL-2 (or functional variant thereof), and gelatinase (or functional variant thereof).

[0237] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety, IL-21 or a functional variant thereof, 41BB-L, and CD40L.

[0238] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety and CD40L.

[0239] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety and IL-15.

[0240] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab) and IL-2 (or functional variant thereof).

[0241] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), IL-2 (or functional variant thereof), and an anti-NKp30 NK cell engager moiety (e.g., an anti-NKp30 Fab or scFv).

[0242] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab) and an anti-NKp30 NK cell engager moiety (e.g., an anti-NKp30 Fab or scFv).

[0243] In one embodiment, the multispecific molecule comprises IL-2 (or functional variant thereof).

[0244] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab) and an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab).

[0245] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), and IL-2 (or functional variant thereof).

[0246] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), and an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv).

[0247] In one embodiment, the multispecific molecule comprises an anti-mesothelin tumor targeting moiety (e.g., an anti-mesothelin Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), and IL-2 (or functional variant thereof).

[0248] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), and IL-2 (or functional variant thereof).

[0249] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), and an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv).

[0250] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), and an anti-CD3 T cell engager moiety (e.g., an anti-CD3 Fab or scFv).

[0251] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), and IL-2 (or functional variant thereof).

[0252] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), an anti-CD3 T cell engager moiety (e.g., an anti-CD3 Fab or scFv), and IL-2 (or functional variant thereof).

[0253] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab) and an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab).

[0254] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), and IL-7 (or functional variant thereof).

[0255] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), an anti-CD3 T cell engager moiety (e.g., an anti-CD3 Fab or scFv), and IL-7 (or functional variant thereof).

[0256] In one embodiment, the multispecific molecule comprises an anti-HER3 tumor targeting moiety (e.g., an anti-HER3 Fab), an anti-IGF1R tumor targeting moiety (e.g., an anti-IGF1R Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), and IL-7 (or functional variant thereof).

[0257] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab) and hyaluronidase 1 (or functional variant thereof).

[0258] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), IL-2 (or functional variant thereof), and hyaluronidase 1 (or functional variant thereof).

[0259] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), IL-2 (or functional variant thereof), and hyaluronidase 1 (or functional variant thereof).

[0260] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), and hyaluronidase 1 (or functional variant thereof).

[0261] In one embodiment, the multispecific molecule comprises an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), an anti-NKp46 NK cell engager moiety (e.g., an anti-NKp46 Fab or scFv), IL-2 (or functional variant thereof), and hyaluronidase 1 (or functional variant thereof).

[0262] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab) and gelatinase (or functional variant thereof).

[0263] In one embodiment, the multispecific molecule comprises an anti-FAP tumor targeting moiety (e.g., an anti-FAP Fab), an anti-PDL1 tumor targeting moiety (e.g., an anti-PDL1 Fab), IL-2 (or functional variant thereof), and gelatinase (or functional variant thereof).

[0264] In another aspect, the disclosure provides an isolated nucleic acid molecule encoding any multispecific or multifunctional molecule polypeptide described herein.

[0265] In another aspect, the disclosure provides an isolated nucleic acid molecule, which comprises the nucleotide sequence encoding any of the multispecific or multifunctional molecules described herein, or a nucleotide sequence substantially homologous thereto (e.g., at least 95% to 99.9% identical thereto).

[0266] In another aspect, the disclosure provides a vector, e.g., an expression vector, comprising one or more of any nucleic acid molecules described herein.

[0267] In another aspect, the disclosure provides a host cell comprising a nucleic acid molecule or a vector described herein.

[0268] In another aspect, the disclosure provides a method of making, e.g., producing, a multispecific or multifunctional molecule polypeptide described herein, comprising culturing a host cell described herein, under suitable conditions, e.g., conditions suitable for gene expression and/or homo- or heterodimerization.

[0269] In another aspect, the disclosure provides an pharmaceutical composition comprising a multispecific or multifunctional molecule polypeptide described herein and a pharmaceutically acceptable carrier, excipient, or stabilizer.

[0270] In another aspect, the disclosure provides a method of treating a cancer, comprising administering to a subject in need thereof a multispecific or multifunctional molecule polypeptide described herein, wherein the multispecific antibody is administered in an amount effective to treat the cancer.

[0271] In some embodiments, the cancer is a solid tumor cancer, or a metastatic lesion. In some embodiments, the solid tumor cancer is one or more of pancreatic (e.g., pancreatic adenocarcinoma), breast, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, or liver cancer. In some embodiments, the cancer is a hematological cancer.

[0272] In some embodiments, the method further comprises administering a second therapeutic treatment. In some embodiments, second therapeutic treatment comprises a therapeutic agent (e.g., a chemotherapeutic agent, a biologic agent, hormonal therapy), radiation, or surgery. In some embodiments, therapeutic agent is selected from: a chemotherapeutic agent, or a biologic agent.

[0273] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0274] Other features and advantages of the invention will be apparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0275] FIGS. 1A-1C depict schematic representations of multispecific molecules that include a single polypeptide chain, e.g., a scFv-based format. The bispecific and trispecific molecules can include a scFv core. Partner A can be connected to the N-terminal end of the VH or the C-terminal end of the VL (FIG. 1A or FIG. 1B, respectively), optionally connected by a linker, wherein partner A corresponds to binding moiety 2 in the bispecific format. Partner A can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1 and binding moiety 2 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partner A, corresponding to binding moiety 2, can be chosen from a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0276] In embodiments of a trispecific format, partners A and B are connected, e.g., via a linker, to the scFv as binding moieties 2 and 3, respectively (FIG. 1C). Partner A and partner B can be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1, binding moiety 2 and binding moiety 3 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partners A and B are each independently chosen from a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0277] Partner A can be a stromal modifying moiety, e.g., as described herein. In some embodiments, binding moiety 1 is a tumor targeting moiety and binding moiety 2 is a stromal modifying moiety. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partner A, corresponding to binding moiety 2, is a stromal modifying moiety, e.g., as described herein. In embodiments of a trispecific format, partners A and B are connected, e.g., via a linker, to the scFv as binding moieties 2 and 3, respectively (FIG. 1C). The trispecific molecule adds fusion partner B, binding moiety 3, which may be a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. Fusion partners A and B may be on the heavy chain and light chain of the Fab or the light chain and heavy chain of the scFv, respectively. In some embodiments, Partner A is a stromal modifying moiety, e.g., as described herein. In some embodiments, binding moiety 1 is a tumor targeting moiety and binding moiety 2 is a stromal modifying moiety.

[0278] FIGS. 2A-2C depict schematic representations of multispecific molecules that include a single polypeptide chain, e.g., a scFv-based format. The bispecific and trispecific molecules can include a scFv core. Partner A can be connected to the C terminal end of the VH or the N terminal end of the VL (FIG. 2A or FIG. 2B, respectively), optionally connected by a linker, wherein partner A corresponds to binding moiety 2 in the bispecific format. Partner A can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partner A, corresponding to binding moiety 2, is chosen from a cytokine, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In some embodiments, binding moiety 1 and binding moiety 2 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0279] In embodiments of a trispecific format, partners A and B are connected, e.g., via a linker, to the scFv as binding moieties 2 and 3, respectively (FIG. 2C). Partner A and partner B can be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1, binding moiety 2 and binding moiety 3 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partners A and B are each independently chosen from a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0280] Partner A can be connected to the C terminal end of the VH or the N terminal end of the VL (FIG. 2A or FIG. 2B, respectively), optionally connected by a linker, wherein partner A corresponds to binding moiety 2 in the bispecific format. In some embodiments, binding moiety 1 is a tumor targeting moiety and binding moiety 2 is a stromal modifying moiety. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partner A, corresponding to binding moiety 2, is a stromal modifying moiety, e.g., as described herein. In embodiments of a trispecific format, partners A and B are connected, e.g., via a linker, to the scFv as binding moieties 2 and 3, respectively (FIG. 2C). The trispecific molecule adds fusion partner B, binding moiety 3, which may be a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. Fusion partners A and B may be on the heavy chain and light chain of the Fab or the light chain and heavy chain of the scFv respectively. In some embodiments, Partner A is a stromal modifying moiety, e.g., as described herein. In some embodiments, binding moiety 1 is a tumor targeting moiety and binding moiety 2 is a stromal modifying moiety.

[0281] FIGS. 3A-3C depict schematic representations of multispecific molecules that include a first and second polypeptide chains, e.g., an Fab-based format with a C-terminal fusion. The bispecific and trispecific molecules can include a Fab core. The VH and VL of the Fab can function as binding moiety 1 of the molecule. Partner A can be connected to the C-terminal end of either CL or CH1 (FIG. 3A or FIG. 3B, respectively), optionally connected by a linker, wherein partner A corresponds to binding moiety 2 in the bispecific format. Partner A can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1 and binding moiety 2 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a Fab that binds to a cancer antigen; and partner A, corresponding to binding moiety 2, is chosen from a cytokine, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0282] In embodiments of a trispecific format, partners A and B are connected, e.g., via a linker, to the C-terminus of the Fab as binding moieties 2 and 3, respectively (FIG. 3C). Partner A and partner B can each be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1, binding moiety 2 and binding moiety 3 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a scFv that binds to a cancer antigen; and partners A and B are each independently chosen from a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0283] The VH and VL of the Fab function as binding moiety 1 of the molecule. Fusion partner A, which can be fused to the C-terminal end of either CL or CH1 (FIG. 3A and FIG. 3B, respectively) connected by a linker, is binding moiety 2 in the bispecific format. In some embodiments of the bispecific format, binding moiety 1 is tumor targeting Fab and fusion partner A, binding moiety 2, is a stromal modifying molecule. The trispecific format can have fusion partners A and B on the C-terminus of the Fab as binding moieties 2 and 3 respectively (FIG. 3C). The trispecific molecule adds fusion partner B, binding moiety 3, which may be a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. Fusion partners A and B may be on the heavy chain and light chain of the Fab or the light chain and heavy chain of the Fab respectively.

[0284] FIGS. 4A-4C depict schematic representations of multispecific molecules that include a first and second polypeptide chains, e.g., an Fab-based format with an N-terminal fusion. The bispecific and trispecific molecules depicted include a Fab core. The VH and VL of the Fab can function as binding moiety 1 of the molecule. Partner A can be connected to the N-terminal end of either VL or VH (FIG. 4A or FIG. 4B, respectively), optionally connected by a linker, wherein partner A corresponds to binding moiety 2 in the bispecific format. Partner A can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1 and binding moiety 2 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a Fab that binds to a cancer antigen; and partner A, corresponding to binding moiety 2, is chosen from a cytokine, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0285] In embodiments of a trispecific format, partners A and B are connected, e.g., via a linker, to the N-terminus of the Fab as binding moieties 2 and 3, respectively (FIG. 4C). Partner A and partner B can be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, binding moiety 1, binding moiety 2 and binding moiety 3 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety as described herein, e.g., a Fab that binds to a cancer antigen; and partner A and partner B, corresponding to binding moiety 2 and binding moiety 3, are each independently chosen from a cytokine, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0286] The bispecific and trispecific molecules can include a Fab core. The VH and VL of the Fab can function as binding moiety 1 of the molecule. Fusion partner A, which can be fused to the N-terminal end of either CL or CH1 (FIG. 4A and FIG. 4B, respectively) connected by a linker, is binding moiety 2 in the bispecific format. In embodiments of the bispecific format, binding moiety 1 is tumor targeting Fab and fusion partner A, binding moiety 2, is a stromal modifying molecule. In embodiments, the trispecific format has fusion partners A and B on the C-terminus of the Fab as binding moieties 2 and 3 respectively (FIG. 4C). The trispecific molecule adds fusion partner B, binding moiety 3, which may be a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. Fusion partners A and B may be on the heavy chain and light chain of the Fab or the light chain and heavy chain of the Fab respectively.

[0287] FIGS. 5A-5C depict schematic representations of multispecific molecules that include a first and a second polypeptide chains, e.g., an Fc-based format. In the embodiments shown, the multispecific molecules include a heterodimeric Fc core (knob-in-hole (KiH)). The bispecific molecule can have partner A and B, which are depicted as binding moieties 1 and 2, respectively (FIG. 5A). Partner A and partner B can be, each independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. Partner A and partner B may be connected to either first or second member, or each of the members, of the heterodimeric Fc core. In one embodiment, partner A is connected to the N-terminal end of a --CH2-CH3-region of the first Fc molecule, and partner B is connected to the N-terminal end of a --CH2-CH3- region of the second Fc molecule. Alternatively, partner A is connected to the C-terminal end of a --CH2-CH3- region of the first Fc molecule, and partner B is connected to the C-terminal end of a --CH2-CH3- region of the second Fc molecule. Alternatively, partner A may be connected to N-terminus of the first member of the heterodimeric Fc core, and partner B may be connected to C-terminus of the second member of the heterodimeric Fc core. In other embodiments, partner B may be connected to N-terminus of the first member of the heterodimeric Fc core, and Partner A may be connected to C-terminus of the second member of the heterodimeric Fc core. In some embodiments, binding moiety 1 and binding moiety 2 can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager. an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, binding moiety 1 is a tumor targeting moiety and binding moiety 2 is chosen from a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0288] Exemplary trispecific and tetraspecific molecules are depicted in FIGS. 5B and 5C, respectively. One or two additional partners C and D, respectively, which may be single or multiple binding moieties 3 and 4, can be added to the aforesaid molecules. Partner A, partner B, partner C and partner D can each be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, partner C and partner D can be added to the C-terminus of either the first and second member of the Fc core, thus forming binding specificities 3 and 4, respectively. In some embodiments, Partners A-D (corresponding to binding specificities 1-4, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In one embodiment, partner A. In embodiments, partner A is a tumor targeting moiety and partner B, partners C and D are each independently chosen from a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0289] The bispecific molecule can have partner A and B, which are depicted as binding moieties 1 and 2, respectively (FIG. 5A). Partner A and partner B can be, each independently, a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. Partner A and partner B may be connected to either first or second member, or each of the members, of the heterodimeric Fc core. In one embodiment, partner A is connected to the N-terminal end of a --CH2-CH3- region of the first Fc molecule, and partner B is connected to the N-terminal end of a --CH2-CH3-region of the second Fc molecule. Alternatively, partner A is connected to the C-terminal end of a --CH2-CH3- region of the first Fc molecule, and partner B is connected to the C-terminal end of a --CH2-CH3- region of the second Fc molecule. Alternatively, partner A may be connected to N-terminus of the first member of the heterodimeric Fc core, and partner B may be connected to C-terminus of the second member of the heterodimeric Fc core. In other embodiments, partner B may be connected to N-terminus of the first member of the heterodimeric Fc core, and Partner A may be connected to C-terminus of the second member of the heterodimeric Fc core. In some embodiments, binding moiety 1 is a tumor targeting moiety and binding moiety 2 is a stromal modifying moiety. In other embodiments, binding moiety 2 is a tumor targeting moiety and binding moiety 1 is a stromal modifying moiety.

[0290] Exemplary trispecific and tetraspecific molecules are depicted in FIGS. 5B and 5C, respectively. One or two additional partners C and D, respectively, which may be single or multiple binding moieties 3 and 4, can be added to the aforesaid molecules. Partner A, partner B, partner C and partner D can each be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, partner C and partner D can be added to the C-terminus of either the first and second member of the Fc core, thus forming binding specificities 3 and 4, respectively. In some embodiments, Partners A-D (corresponding to binding specificities 1-4, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, or a stromal modifying moiety, e.g., as described herein. In some embodiment, one of partner A, B, C, or D is a stromal modifying moiety, one of partner A, B, C, or D is a tumor targeting moiety, and the two remaining partners are each independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0291] FIG. 6 depicts an exemplary schematic of a bispecific molecule that includes a Fab corresponding to binding site #1 fused to a binding site #2. In embodiments, binding site #1 is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; and binding site #2 is chosen from a cytokine molecule, or a ligand molecule or a scFv that is an immune cell engager, e.g., binds to an immune cell antigen. In embodiments, the bispecific molecule comprises two non-contiguous polypeptides, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, fused optionally, via a linker to, the binding site #2; and the second polypeptide has the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen.

[0292] FIG. 7 depicts an exemplary schematic of a bispecific molecule that includes a Fab corresponding to binding site #1 connected, optionally via a liker, to a first member of an immunoglobulin constant region, e.g., a first Fc molecule; and a binding site #2 connected, optionally via a liker, to a second member of the Fc molecule. In embodiments, binding site #1 is a tumor targeting moiety, e.g., binds to a tumor or stromal antigen; and binding site #2 is chosen from a cytokine molecule, or an immune cell engager, e.g., a ligand molecule, or a scFv that binds to an immune cell antigen. In embodiments, the bispecific molecule comprises three non-contiguous polypeptides, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, optionally connected via a linker to, the first member of the Fc molecule (e.g., a first CH2-CH3 region, optionally, comprising a protuberance or knob); the second polypeptide has the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen; and the third polypeptide has the following configuration from N-to-C: binding site #2 (e.g., a cytokine molecule, a ligand molecule, or a scFv that binds to, e.g., an immune cell antigen), connected, optionally, via a linker to, the second member of the Fc molecule (e.g., a second CH2-CH3 region, optionally, comprising a hole or cavity). In embodiments, the first and second members of the Fc molecule promote heterodimerization of the bispecific molecule.

[0293] FIGS. 8A-8C depict exemplary schematics of a trispecific molecule that includes a Fab corresponding to binding site #1 fused to a binding site #2 and a binding site #3. In embodiments, binding site #1 is a tumor targeting moiety, e.g., binds to a tumor or stromal antigen; and binding sites #2 and #3 are independently chosen from a cytokine molecule, or an immune cell engager, e.g., a ligand molecule or a scFv that binds to an immune cell antigen. In embodiments, the trispecific molecule comprises two non-contiguous polypeptides in FIG. 8A, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, optionally, via a linker to, the binding site #3 (e.g., chosen from a cytokine molecule, a ligand or a scFv); and the second polypeptide having the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen, fused to a scFv (e.g., a VH-VL of the scFv from N-to-C) that binds to, e.g., an immune cell antigen. FIG. 8B depicts an alternative configuration, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, optionally via a linker, to a cytokine molecule; and the second polypeptide has the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen, connected to a ligand or a scFv (e.g., a ligand or a scFv that binds to, e.g., an immune cell). FIG. 8C depicts an alternative configuration, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, optionally via a linker to, the ligand or the scFv that binds to, e.g., a first immune cell; and the second polypeptide has the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen, connected, optionally via a linker to, to the ligand or the scFv that binds to, e.g., a second immune cell.

[0294] FIGS. 9A-9B depict exemplary schematics of a trispecific molecule that includes a Fab corresponding to binding site #1, a binding site #2, a binding site #3, each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin binding domain, e.g., first and second Fc molecule. In embodiments, the trispecific molecule comprises three non-contiguous polypeptides shown in FIGS. 9A-9B. In the embodiments shown in FIG. 9A, the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, e.g., via a linker, to a first member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the first Fc molecule, optionally, comprising a protuberance or cavity), which first member can, optionally further include binding site #3 connected, optionally via a linker, to the C-terminus of the first Fc molecule; the second polypeptide includes from N-to-C orientation a binding site #2 connected, e.g., via a linker, to a second member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the second Fc molecule, optionally, comprising a protuberance or cavity); and the third polypeptide includes from N-to-C: the VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen. In the embodiments shown in FIG. 9B, the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, e.g., via a linker, to a first member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the first Fc molecule, optionally, comprising a protuberance or cavity); the second polypeptide includes from N-to-C orientation a binding site #2 connected, e.g., via a linker, to a second member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the second Fc molecule, optionally, comprising a protuberance or cavity) which second member can, optionally further include binding site #3 connected, optionally via a linker, to the C-terminus of the second Fc molecule); and the third polypeptide includes from N-to-C: the VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen. In the aforesaid embodiments, binding site #1 binds to a tumor or stromal antigen; and binding sites #2 and #3 are independently chosen from a cytokine molecule, or an immune cell engager, e.g., a ligand molecule or a scFv that binds to an immune cell antigen. In embodiments, the first and second members of the Fc molecule promote heterodimerization of the trispecific molecule.

[0295] FIGS. 10A-10C depict exemplary schematics of a tetraspecific molecule that includes a Fab corresponding to binding site #1, a binding site #2, a binding site #3, and a binding site #4, each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin constant region, e.g., a first and a second Fc molecule. In embodiments, the tetraspecific molecule comprises three non-contiguous polypeptides shown in FIGS. 10A-10C. In the embodiments shown in FIG. 10A, the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, e.g., via a linker, to a first member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the first Fc molecule, optionally, comprising a protuberance or cavity), which first member can, optionally further include binding site #3 connected, optionally via a linker, to the C-terminus of the first Fc molecule); the second polypeptide includes from N-to-C orientation a binding site #2 connected, e.g., via a linker, to a second member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the second Fc molecule, optionally, comprising a protuberance or cavity) which second member can, optionally further include binding site #4 connected, optionally via a linker, to the C-terminus of the second Fc molecule); and the third polypeptide includes from N-to-C: the VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen. In the embodiments depicted in FIG. 10A, binding site #1 binds to a tumor or stromal antigen; and binding sites #2, #3 and 4 are independently chosen from a cytokine molecule, a ligand molecule, or a scFv that binds to, e.g., an immune cell antigen. In the embodiments depicted in FIG. 10A, binding site #1 binds to a tumor or stromal antigen; and binding sites #2, #3 and 4 are independently chosen from a cytokine molecule, a ligand molecule, or a scFv that binds to, e.g., an immune cell antigen. In the embodiments depicted in FIG. 10B, binding site #1 binds to a tumor or stromal antigen; binding site #2 depicts an NK cell engager, e.g., a scFv, e.g., in a VH-VL orientation from N- to C-terminus, connected to the N-terminus of the second Fc member, e.g., via a linker; binding site #3 depicts a cytokine molecule or an immune cell engager, e.g., a scFv, connected to the C-terminus of the first Fc member, e.g., via a linker; and binding site #4 are depicts a ligand molecule, or a scFv that binds to, e.g., an immune cell antigen, connected to the C-terminus of the second Fc member, e.g., via a linker. In the embodiments depicted in FIG. 10C, binding site #1 binds to a tumor or stromal antigen; binding site #2 depicts an NK cell engager, e.g., a scFv, e.g., in a VH-VL orientation from N- to C-terminus, connected to the N-terminus of the second Fc member, e.g., via a linker; binding site #3 depicts a ligand molecule or an immune cell engager, e.g., a scFv, connected to the C-terminus of the first Fc member, e.g., via a linker; and binding site #4 are depicts a ligand molecule, or a scFv that binds to, e.g., an immune cell antigen, connected to the C-terminus of the second Fc member, e.g., via a linker. In embodiments of any of the aforesaid tetraspecific molecules, the first and second members of the Fc molecule promote heterodimerization of the tetraspecific molecule.

[0296] FIGS. 11A-11C depict an exemplary trispecific molecule. FIG. 11A shows a schematic representation of the trispecific molecule including a Fab molecule directed to the mesothelin tumor antigen, wherein first polypeptide includes the heavy chain VH-CH1 of the Fab connected via a linker to an IL-15 cytokine, and the second polypeptide of the Fab includes the light chain VL-CL connected via a linker to CD40 ligand (CD40L). FIG. 11B provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the heavy chain VH-CH1 of the Fab (shown in underline and bold for VH and CH1, respectively), connected via a Gly-Ser linker (shown in dashed underline), to a human IL-15 cytokine (shown in regular font) (SEQ ID NO: 238). FIG. 11C provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the kappa light chain VL-CL of the Fab (shown in underline and bold for VL and CL, respectively), connected via a Gly-Ser linker (shown in dashed underline), to a human CD40L (shown in regular font) (SEQ ID NO: 235).

[0297] FIGS. 12A-12D depict an exemplary bispecific molecule that includes a Fab to a stromal target and a cytokine molecule, each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin constant region, e.g., a first and a second Fc molecule. FIG. 12A shows a schematic representation of the bispecific molecule including a Fab molecule directed to the stromal antigen, wherein the first polypeptide includes the heavy chain VH-CH1 of the Fab to the stromal antigen connected to the first Fc molecule having a cavity; the second polypeptide includes the IL-15 cytokine connected to the second Fc molecule having a protuberance; and the third polypeptide includes a light chain VL-CL of the Fab to the stromal antigen. FIG. 12B provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the human IL-15 cytokine (shown in underline), and further including an optional Gly-Ser linker (shown in dashed underline) connected to the second Fc molecule having a protuberance (shown in regular font) (SEQ ID NO: 233). FIG. 12C provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the followed by the heavy chain VH-CH1 of the Fab to the stromal antigen FAP (shown in underline and bold for VH and CH1, respectively), connected to the first Fc molecule having a cavity (shown in regular font) (SEQ ID NO: 55). FIG. 12D provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the kappa light chain VL-CL of the Fab to the stromal antigen FAP (shown in underline and bold for VL and CL, respectively) (SEQ ID NO: 239).

[0298] FIGS. 13A-13D depict an exemplary tetraspecific molecule that includes a Fab to a stromal target two immune cell engagers, and a cytokine molecule, each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin constant region, e.g., a first and a second Fc molecule. FIG. 13A shows a schematic representation of the tetraspecific molecule including a Fab molecule directed to the stromal antigen, wherein the first polypeptide includes the heavy chain VH-CH1 of the Fab to the stromal antigen connected to the first Fc molecule having a cavity, and further includes a first immune cell engager, e.g., B7H6; the second polypeptide includes the IL-15 cytokine connected, optionally via a Gly-Ser linker, to the second Fc molecule having a protuberance, and further includes, e.g., via a Gly-Ser linker, a second immune cell engager, e.g., CD40L; and the third polypeptide includes a light chain VL-CL of the Fab to the stromal antigen. FIG. 13B provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the human IL-15 cytokine (shown in underline), further including an optional Gly-Ser linker (shown in dashed underline) connected to the second Fc molecule having a protuberance (shown in bold), which further includes, e.g., an optional Gly-Ser linker (shown in dashed underline, connected to the human CD40L amino acid sequence (shown in regular font) (SEQ ID NO: 58). FIG. 13C provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the followed by the heavy chain VH-CH1 of the Fab to the stromal antigen FAP (shown in underline and bold for VH and CH1, respectively), connected to the first Fc molecule having a cavity (shown in regular font), which further includes, e.g., an optional Gly-Ser linker (shown in dashed underline, connected to the human B7H6 amino acid sequence (shown in underline) (SEQ ID NO: 240). FIG. 13D provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the kappa light chain VL-CL of the Fab to the stromal antigen FAP (shown in underline and regular font for VL and CL, respectively) (SEQ ID NO: 60).

[0299] FIGS. 14A-14B depicts an exemplary tetraspecific molecule that includes a Fab to a mesothelin (molecule A) (FIG. 14A), two immune cell engagers, 41BB-ligand (molecule C) (FIG. 14B) and CD40 ligand (molecule D) (FIG. 14B), and a cytokine molecule (molecule B) (FIG. 14A), each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin constant region, e.g., a first and a second Fc molecule (knob-in-hole, KiH, Fc first member and Fc hole second member). FIGS. 14A-14B shows a schematic representation of the tetraspecific molecule including a Fab molecule directed to the mesothelin antigen, wherein the first polypeptide includes the heavy chain VH-CH1 of the Fab to the mesothelin antigen connected to the first Fc molecule having a protuberance (knob) in the CH3 region, and further includes a first immune cell engager, e.g., 41BB-ligand; the second polypeptide includes the IL-21 cytokine connected, optionally via a Gly-Ser linker, to the second Fc molecule having a cavity (hole), and further includes, e.g., via a Gly-Ser linker, a second immune cell engager, e.g., CD40L; and the third polypeptide includes a light chain VL-CL of the Fab to the mesothelin antigen (molecule A). The following amino acid sequences are shown:

[0300] (i) Molecule A corresponding to the heavy chain (SEQ ID NO: 1) and light chain (SEQ ID NO: 80), respectively, of the mesothelin binding Fab (a_hMeso_SS1_Fab);

[0301] (ii) Molecule B corresponding to human IL-21 (SEQ ID NO: 22);

[0302] (iii) Linker between the Molecule B and second Fc region (Molecule B to KiH_Fc linker) (SEQ ID NO: 43);

[0303] (iv) Linker between the first Fc region and Molecule C (KiH_Fc to Molecule C linker) (SEQ ID NO: 241);

[0304] (v) Molecule C corresponding to human 41BB ligand (SEQ ID NO: 38);

[0305] (vi) Linker between the second Fc region and Molecule D (KiH_Fc to Molecule D linker) (SEQ ID NO: 44);

[0306] (vii) Molecule C corresponding to human CD40L (SEQ ID NO: 242);

[0307] (viii) first member Fc region (Fc Knob), including from N to C orientation, the VH of the mesothelin Fab, the CH2-CH3 amino acid sequence including a substitution of S for C at position 354 and W for T at position 366, followed by a Gly-Ser linker and the human 41BB ligand; and

[0308] (ix) second member Fc region (Fc Hole), including from N to C orientation, the human IL-21, a Gly-Ser linker, the CH2-CH3 amino acid sequence including a substitution of C for Y at position 349, S for T at position 366, A for L at position 368, V for Y at position 407, followed by a Gly-Ser linker and the human CD40L.

[0309] FIGS. 15A-15J are schematic representations of exemplary bispecific antibody molecules. FIG. 15A is a schematic representation of a bispecific antibody utilizing "knob-in-hole" heterodimerization. FIG. 15B is a schematic representation of a bispecific antibody utilizing a common light chain. FIG. 15C is a schematic representation of an IgG-Fab bispecific antibody. FIG. 15D is a schematic representation of an IgG-dsscFv2 bispecific antibody. FIG. 15E is a schematic representation of a DVD bispecific antibody. FIG. 15F is a schematic representation of a diabody. FIG. 15G is a schematic representation of a DART bispecific antibody. FIG. 15H is a schematic representation of a TandAb bispecific antibody. FIG. 15I is a schematic representation of a Fab-scFv2 bispecific antibody. FIG. 15J is a schematic representation of a Fab-scFv bispecific antibody. The corresponding mRNA that encode each of the building blocks for molecules depicted in FIG. 15A-15J are depicted below the antibody molecule.

[0310] FIG. 16 depicts an exemplary schematic of a bispecific molecule that includes a Fab corresponding to binding site #1 fused to a binding site #2. In embodiments, binding site #1 is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; and binding site #2 is a stromal modifying moiety. In embodiments, the bispecific molecule comprises two non-contiguous polypeptides, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a cancer antigen, fused optionally, via a linker to, the binding site #2; and the second polypeptide has the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a cancer antigen, e.g., a tumor or stromal antigen.

[0311] FIG. 17 depicts an exemplary schematic of a bispecific molecule that includes a Fab corresponding to binding site #1 connected, optionally via a liker, to a first member of an immunoglobulin constant region, e.g., a first Fc molecule; and a binding site #2 connected, optionally via a liker, to a second member of the Fc molecule. In embodiments, binding site #1 is a tumor targeting moiety, e.g., binds to a tumor or stromal antigen; and binding site #2 is a stromal modifying moiety. In embodiments, the bispecific molecule comprises three non-contiguous polypeptides, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, optionally connected via a linker to, the first member of the Fc molecule (e.g., a first CH2-CH3 region, optionally, comprising a protuberance or knob); the second polypeptide has the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen; and the third polypeptide has the following configuration from N-to-C: binding site #2 (a stromal modifying moiety), connected, optionally, via a linker to, the second member of the Fc molecule (e.g., a second CH2-CH3 region, optionally, comprising a hole or cavity). In embodiments, the first and second members of the Fc molecule promote heterodimerization of the bispecific molecule.

[0312] FIG. 18 depict exemplary schematics of a trispecific molecule that includes a Fab corresponding to binding site #1 fused to a binding site #2 and a binding site #3. In embodiments, binding site #1 is a tumor targeting moiety, e.g., binds to a tumor or stromal antigen; binding sites #2 is chosen from a cytokine molecule, or an immune cell engager, e.g., a ligand molecule or a scFv that binds to an immune cell antigen; and binding site 3 is a stromal modifying moiety. In embodiments, the trispecific molecule comprises two non-contiguous polypeptides in FIG. 18, wherein the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, optionally, via a linker to, the binding site #3 (a stromal modifying moiety); and the second polypeptide having the following configuration from N-to-C: VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen, fused to a scFv (e.g., a VH-VL of the scFv from N-to-C) that binds to, e.g., an immune cell antigen.

[0313] FIGS. 19A-19B depict exemplary schematics of a trispecific molecule that includes a Fab corresponding to binding site #1, a binding site #2, a binding site #3, each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin binding domain, e.g., first and second Fc molecule. In embodiments, the trispecific molecule comprises three non-contiguous polypeptides shown in FIGS. 19A-19B. In the embodiments shown in FIG. 19A, the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, e.g., via a linker, to a first member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the first Fc molecule, optionally, comprising a protuberance or cavity), which first member can, optionally further include binding site #3 connected, optionally via a linker, to the C-terminus of the first Fc molecule; the second polypeptide includes from N-to-C orientation a binding site #2 connected, e.g., via a linker, to a second member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the second Fc molecule, optionally, comprising a protuberance or cavity); and the third polypeptide includes from N-to-C: the VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen. In the embodiments shown in FIG. 19B, the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, e.g., via a linker, to a first member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the first Fc molecule, optionally, comprising a protuberance or cavity); the second polypeptide includes from N-to-C orientation a binding site #2 connected, e.g., via a linker, to a second member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the second Fc molecule, optionally, comprising a protuberance or cavity) which second member can, optionally further include binding site #3 connected, optionally via a linker, to the C-terminus of the second Fc molecule); and the third polypeptide includes from N-to-C: the VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen. In the aforesaid embodiments, binding site #1 binds to a tumor or stromal antigen; binding site #2 is chosen from a cytokine molecule, or an immune cell engager, e.g., a ligand molecule or a scFv that binds to an immune cell antigen; and binding site #3 is a stromal modifying moiety. In embodiments, the first and second members of the Fc molecule promote heterodimerization of the trispecific molecule.

[0314] FIG. 20 depict an exemplary schematic of a tetraspecific molecule that includes a Fab corresponding to binding site #1, a binding site #2, a binding site #3, and a binding site #4, each of which is connected, e.g., via a linker, to a first and second member of an immunoglobulin constant region, e.g., a first and a second Fc molecule. In embodiments, the tetraspecific molecule comprises three non-contiguous polypeptides. In the embodiments, the first polypeptide has the following configuration from N-to-C: VH-CH1 of the Fab that binds to, e.g., a tumor or stromal antigen, connected, e.g., via a linker, to a first member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the first Fc molecule, optionally, comprising a protuberance or cavity), which first member can, optionally further include binding site #3 connected, optionally via a linker, to the C-terminus of the first Fc molecule); the second polypeptide includes from N-to-C orientation a binding site #2 connected, e.g., via a linker, to a second member of an Fc molecule (e.g., the N-terminus of the CH2-CH3 region of the second Fc molecule, optionally, comprising a protuberance or cavity) which second member can, optionally further include binding site #4 connected, optionally via a linker, to the C-terminus of the second Fc molecule); and the third polypeptide includes from N-to-C: the VL-CL of the Fab that binds to, e.g., a tumor or stromal antigen. In the embodiments depicted in FIG. 20, binding site #1 binds to a tumor or stromal antigen; binding sites #2 and #4 are independently chosen from a cytokine molecule, a ligand molecule, or a scFv that binds to, e.g., an immune cell antigen; and binding site #3 is a stromal modifying moiety.

[0315] FIG. 21. Gel of multispecific molecule 1.

[0316] FIG. 22. Gel of multispecific molecule 2.

[0317] FIG. 23. Gel of multispecific molecule 3.

[0318] FIG. 24. Gel of multispecific molecule 4.

[0319] FIG. 25. Gel of multispecific molecule 5.

[0320] FIG. 26. Gel of multispecific molecule 6.

[0321] FIG. 27. Gel of multispecific molecule 7.

[0322] FIG. 28. Gel of multispecific molecule 8.

[0323] FIG. 29. Gel of multispecific molecule 9.

[0324] FIG. 30. Gel of multispecific molecule 10.

[0325] FIG. 31. Gel of multispecific molecule 11.

[0326] FIG. 32. Gel of multispecific molecule 12.

[0327] FIG. 33. Gel of multispecific molecule 13.

[0328] FIG. 34. Gel of multispecific molecule 14.

[0329] FIG. 35. Gel of multispecific molecule 15.

[0330] FIG. 36. Gel of multispecific molecule 16.

[0331] FIG. 37. Gel of multispecific molecule 17.

[0332] FIG. 38. Gel of multispecific molecule 18.

[0333] FIG. 39. Gel of multispecific molecule 19.

[0334] FIG. 40. Gel of multispecific molecule 20.

[0335] FIG. 41. Gel of multispecific molecule 21.

[0336] FIG. 42. Gel of multispecific molecule 22.

[0337] FIG. 43. Size exclusion chromatogram of multispecific molecule 1.

[0338] FIG. 44. Size exclusion chromatogram of multispecific molecule 5.

[0339] FIG. 45. Size exclusion chromatogram of multispecific molecule 11.

[0340] FIG. 46. Size exclusion chromatogram of multispecific molecule 12.

[0341] FIG. 47. Size exclusion chromatogram of multispecific molecule 13.

[0342] FIG. 48. ELISA of multispecific molecule 1 (circles, solid line), multispecific molecule 2 (diamonds, dashed line), and multispecific molecule 3 (squares, dotted line) binding to human mesothelin (generated from SEQ ID NO: 181).

[0343] FIG. 49. ELISA of multispecific molecule 5 (circles, solid line), multispecific molecule 6 (diamonds, short dash line), multispecific molecule 7 (squares, dotted line), and multispecific molecule 8 (triangles, long dash line) binding to human mesothelin (generated from SEQ ID NO: 181).

[0344] FIG. 50. ELISA of multispecific molecule 9 (circles, solid line), multispecific molecule 11 (diamonds, short dash line), multispecific molecule 10 (squares, dotted line), and multispecific molecule 12 (triangles, long dash line) binding to human mesothelin (generated from SEQ ID NO: 181).

[0345] FIG. 51. ELISA of multispecific molecule 5 (circles, solid line), multispecific molecule 6 (diamonds, long dash line), multispecific molecule 7 (squares, dotted line), and multispecific molecule 9 (triangles, short dash line) binding to human PD1L1 (generated from SEQ ID NO: 178).

[0346] FIG. 52. ELISA of multispecific molecule 11 (circles, solid line), multispecific molecule 8 (diamonds, long dash line), multispecific molecule 10 (squares, dotted line), and multispecific molecule 12 (triangles, short dash line) binding to human PD1L1 (generated from SEQ ID NO: 178).

[0347] FIG. 53. ELISA of multispecific molecule 1 (circles, solid line), multispecific molecule 2 (diamonds, dashed line), and multispecific molecule 4 (squares, dotted line) binding to human IL2R.alpha. (generated from SEQ ID NO: 182).

[0348] FIG. 54. ELISA of multispecific molecule 6 (circles, solid line), multispecific molecule 8 (diamonds, long dash line), multispecific molecule 10 (squares, dotted line), and multispecific molecule 12 (triangles, short dash line) binding to human IL2R.alpha. (generated from SEQ ID NO: 182).

[0349] FIG. 55. ELISA of multispecific molecule 2 (circles, solid line) and multispecific molecule 3 (diamonds, dashed line) with human NKp30 (generated from SEQ ID NO: 180).

[0350] FIG. 56. ELISA of multispecific molecule 7 (circles, solid line), multispecific molecule 9 (diamonds, dashed line), and multispecific molecule 11 (squares, dotted line) with human NKp46 (generated from SEQ ID NO: 179).

[0351] FIG. 57. ELISA of multispecific molecule 8 (circles, solid line), multispecific molecule 10 (diamonds, dashed line), and multispecific molecule 11 (squares, dotted line) with human NKp46 (generated from SEQ ID NO: 179).

[0352] FIG. 58. Cell-killing curves for multispecific molecule 1 (circles, solid line), multispecific molecule 2 (diamonds, dotted line), multispecific molecule 3 (squares, dashed line), and multispecific molecule 4 (triangles, dashed and dotted line).

[0353] FIG. 59. Cytokine release of IFN.gamma. for multispecific molecule 1 (solid black), multispecific molecule 2 (diagonal line), multispecific molecule 3 (white), and multispecific molecule 4 (dotted).

[0354] FIG. 60. Cell-killing curves for multispecific molecule 5 (circles), multispecific molecule 6 (diamonds, short dash line), multispecific molecule 7 (squares, dotted line), and multispecific molecule 8 (triangles, long dash line).

[0355] FIG. 61. Cell-killing curves for multispecific molecule 5 (circles), multispecific molecule 6 (diamonds, short dash line), multispecific molecule 9 (squares, dotted line), and multispecific molecule 10 (triangles, long dash line).

[0356] FIG. 62. Cell-killing curves for multispecific molecule 5 (circles), multispecific molecule 6 (diamonds, short dash line), multispecific molecule 11 (squares, dotted line), and multispecific molecule 12 (triangles, long dash line).

[0357] FIG. 63. Binding of multispecific molecule 22 to human mesothelin (from SEQ ID NO: 181).

[0358] FIG. 64. Binding of multispecific molecule 22 to human PD1L1 (from SEQ ID NO: 178).

[0359] FIG. 65. ELISA of multispecific molecule 13 (circles, solid line), multispecific molecule 16 (diamonds, short dash line), multispecific molecule 17 (squares, dotted line), and multispecific molecule 22 (triangles, long dash line) binding to human IL2R.alpha. (generated from SEQ ID NO: 182).

[0360] FIG. 66. ELISA of multispecific molecule 14 (circles, solid line), multispecific molecule 21 (diamonds, short dash line), and multispecific molecule 22 (squares, dotted line) binding to human NKp46 (generated from SEQ ID NO: 179).

[0361] FIG. 67. Cell-killing curves for multispecific molecule 18 (circles, solid line), multispecific molecule 13 (diamonds, short dash line), multispecific molecule 14 (squares, dotted line), and multispecific molecule 16 (triangles, long dash line).

[0362] FIG. 68. Cytokine release of IFN.gamma. for multispecific molecule 18 (solid black), multispecific molecule 13 (dotted), multispecific molecule 14 (white), and multispecific molecule 16 (diagonal lines).

[0363] FIG. 69. Cell-killing curves for multispecific molecule 18 (circles, solid line), multispecific molecule 13 (diamonds, short dash line), multispecific molecule 15 (squares, dotted line), and multispecific molecule 17 (triangles, long dash line).

[0364] FIG. 70. Cytokine release of IFN.gamma. for multispecific molecule 18 (solid black), multispecific molecule 13 (dotted), multispecific molecule 15 (white), and multispecific molecule 17 (diagonal lines).

[0365] FIG. 71. Cell-killing curves for multispecific molecule 18 (circles, solid line), multispecific molecule 15 (squares, dotted line), and multispecific molecule 20 (triangles, long dash line).

[0366] FIG. 72. Cytokine release of IFN.gamma. for multispecific molecule 18 (solid black), multispecific molecule 15 (white), and multispecific molecule 20 (diagonal lines).

[0367] FIG. 73. Cell-killing curves for multispecific molecule 18 (circles, solid line), multispecific molecule 14 (squares, dotted line), and multispecific molecule 21 (triangles, long dash line).

[0368] FIG. 74. Cytokine release of IFN.gamma. for multispecific molecule 18 (solid black), multispecific molecule 14 (white), and multispecific molecule 21 (diagonal lines).

[0369] FIG. 75. Cell-killing curves for multispecific molecule 23 (circles, solid line) and multispecific molecule 22 (diamonds, dashed line).

[0370] FIG. 76. Cytokine release of IFN.gamma. for multispecific molecule 23 (solid black) and multispecific molecule 22 (diagonal lines).

[0371] FIG. 77. Gel of multispecific molecule 24.

[0372] FIG. 78. Gel of multispecific molecule 25.

[0373] FIG. 79. Gel of multispecific molecule 26.

[0374] FIG. 80. Gel of multispecific molecule 27.

[0375] FIG. 81. Gel of multispecific molecule 28.

[0376] FIG. 82. Gel of multispecific molecule 29.

[0377] FIG. 83. Gel of multispecific molecule 30.

[0378] FIG. 84. Gel of multispecific molecule 31.

[0379] FIG. 85. Gel of multispecific molecule 32.

[0380] FIG. 86. Size exclusion chromatogram of multispecific molecule 24.

[0381] FIG. 87. Size exclusion chromatogram of multispecific molecule 25.

[0382] FIG. 88. Size exclusion chromatogram of multispecific molecule 26.

[0383] FIG. 89. Size exclusion chromatogram of multispecific molecule 28.

[0384] FIG. 90. Size exclusion chromatogram of multispecific molecule 29.

[0385] FIG. 91. Size exclusion chromatogram of multispecific molecule 30.

[0386] FIG. 92. Size exclusion chromatogram of multispecific molecule 31.

[0387] FIG. 93. ELISA of multispecific molecule 27 (circles, solid line), multispecific molecule 28 (diamonds, short dash line), multispecific molecule 29 (squares, dotted line), and multispecific molecule 32 (triangles, long dash line) with human PDL1 from SEQ ID NO: 178.

[0388] FIG. 94. ELISA of multispecific molecule 24 (circles, solid line), multispecific molecule 25 (diamonds, short dash line), multispecific molecule 26 (squares, dotted line), and multispecific molecule 27 (triangles, long dash line) with human FAP from SEQ ID NO: 225.

[0389] FIG. 95. ELISA of multispecific molecule 28 (circles, solid line), multispecific molecule 30 (diamonds, short dash line), multispecific molecule 31 (squares, dotted line), and multispecific molecule 32 (triangles, long dash line) with human FAP from SEQ ID NO: 225.

[0390] FIG. 96. Binding of multispecific molecule 29 to human NKp46 generated from SEQ ID NO: 179.

[0391] FIG. 97. ELISA of multispecific molecule 25 (circles, solid line), multispecific molecule 28 (diamonds, short dash line), multispecific molecule 29 (squares, dotted line), and multispecific molecule 32 (triangles, long dash line) with human IL2R.alpha. from SEQ ID NO: 182.

[0392] FIG. 98. Turbidimetric enzyme assay for hyaluronidase activity of multispecific molecule 24 (circles), multispecific molecule 25 (diamonds), and multispecific molecule 26 (squares), where degradation of hyaluronic acid results in a decrease in absorbance.

[0393] FIG. 99. Turbidimetric enzyme assay for hyaluronidase activity of multispecific molecule 27 (circles), multispecific molecule 28 (diamonds), and multispecific molecule 29 (squares), where degradation of hyaluronic acid results in a decrease in absorbance.

[0394] FIG. 100. Gel-based assay for hyaluronidase activity, where the white bands represent degraded hyaluronic acid. Lane 1 is the ladder, lane 2 is multispecific molecule 24, lane 3 is multispecific molecule 25, lane 4 is multispecific molecule 26, lane 5 is multispecific molecule 27, lane 6 is multispecific molecule 28, and lane 7 is multispecific molecule 29.

[0395] FIG. 101. Type IV collagenase activity of multispecific molecule 30 (circles), multispecific molecule 31 (diamonds), and multispecific molecule 32 (squares), where degradation of gelatinase results in an increase in the fluorescence.

DETAILED DESCRIPTION OF THE INVENTION

[0396] Disclosed herein are multispecific molecules (also referred to herein as "multifunctional molecules") that include a plurality (e.g., two or more) binding specificities (or functionalities), wherein a first binding specificity selectively localizes to a cancer cell, e.g., it includes a tumor-targeting moiety; and the second (or third, or fourth) binding specificity includes one or both of: an immune cell engager (e.g., chosen from one, two, three, or all of a T cell engager, NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); and/or a cytokine molecule. In an embodiment, the multispecific molecule is a bispecific (or bifunctional) molecule, a trispecific (or trifunctional) molecule, or a tetraspecific (or tetrafunctional) molecule. Without being bound by theory, the multispecific molecules disclosed herein are expected to localize (e.g., bridge) and/or activate an immune cell (e.g., an immune effector cell chosen from an NK cell, a B cell, a dendritic cell or a macrophage), in the presence of the cancer cell. Increasing the proximity and/or activity of the immune cell, in the presence of the cancer cell, using the multispecific molecules described herein is expected to enhance an immune response against the target cancer cell, thereby providing a more effective cancer therapy. Accordingly, provided herein are, inter alia, multispecific molecules (e.g., multispecific antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

[0397] Novel multifunctional, e.g., multispecific, molecules that include (i) a stromal modifying moiety and (ii) a tumor-targeting moiety (e.g., an antibody molecule, a ligand molecule, or a receptor molecule) are disclosed. Without being bound by theory, the multifunctional molecules disclosed herein are believed to inter alia target (e.g., localize to) a cancer site, and alter the tumor stroma, e.g., alter the tumor microenvironment near the cancer site. The multifunctional molecules can further include one or both of: an immune cell engager (e.g., chosen from one, two, three, or all of a T cell engager, NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); and/or a cytokine molecule. Accordingly, provided herein are, inter alia, multifunctional, e.g., multispecific molecules, that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

[0398] Also disclosed herein are Novel multifunctional, e.g., multispecific, molecules that include (i) a stromal modifying moiety and (ii) a tumor-targeting moiety (e.g., an antibody molecule, a ligand molecule, or a receptor molecule) are disclosed. Without being bound by theory, the multifunctional molecules disclosed herein are believed to inter alia target (e.g., localize to) a cancer site, and alter the tumor stroma, e.g., alter the tumor microenvironment near the cancer site. The multifunctional molecules can further include one or both of: an immune cell engager (e.g., chosen from one, two, three, or all of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); and/or a cytokine molecule. Accordingly, provided herein are, inter alia, multifunctional, e.g., multispecific molecules, that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

Definitions

[0399] In some embodiments, the multispecific molecule includes a tumor-targeting moiety. A "tumor-targeting moiety," as used herein, refers to a binding agent that recognizes or associates with, e.g., binds to, a target in a cancer cell. The tumor-targeting moiety can be an antibody molecule, a receptor molecule (e.g., a full length receptor, receptor fragment, or fusion thereof (e.g., a receptor-Fc fusion)), or a ligand molecule (e.g., a full length ligand, ligand fragment, or fusion thereof (e.g., a ligand-Fc fusion)) that binds to the cancer antigen (e.g., the tumor and/or the stromal antigen). In embodiments, the tumor-targeting moiety specifically binds to the target tumor, e.g., binds preferentially to the target tumor. For example, when the tumor-targeting moiety is an antibody molecule, it binds to the cancer antigen (e.g., the tumor antigen and/or the stromal antigen) with a dissociation constant of less than about 10 nM, and more typically, 10-100 pM.

[0400] In some embodiments, the multispecific molecule includes an immune cell engager. "An immune cell engager" refers to one or more binding specificities that bind and/or activate an immune cell, e.g., a cell involved in an immune response. In embodiments, the immune cell is chosen from a T cell, an NK cell, a B cell, a dendritic cell, and/or the macrophage cell. The immune cell engager can be an antibody molecule, a receptor molecule (e.g., a full length receptor, receptor fragment, or fusion thereof (e.g., a receptor-Fc fusion)), or a ligand molecule (e.g., a full length ligand, ligand fragment, or fusion thereof (e.g., a ligand-Fc fusion)) that binds to the immune cell antigen (e.g., the NK cell antigen, the B cell antigen, the dendritic cell antigen, and/or the macrophage cell antigen). In embodiments, the immune cell engager specifically binds to the target immune cell, e.g., binds preferentially to the target immune cell. For example, when the immune cell engager is an antibody molecule, it binds to the immune cell antigen (e.g., the NK cell antigen, the B cell antigen, the dendritic cell antigen, and/or the macrophage cell antigen) with a dissociation constant of less than about 10 nM, and more typically, 10-100 pM.

[0401] In some embodiments, the multispecific molecule includes a cytokine molecule. As used herein, a "cytokine molecule" refers to full length, a fragment or a variant of a cytokine; a cytokine further comprising a receptor domain, e.g., a cytokine receptor dimerizing domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor, that elicits at least one activity of a naturally-occurring cytokine. In some embodiments the cytokine molecule is chosen from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforesaid cytokines. The cytokine molecule can be a monomer or a dimer. In embodiments, the cytokine molecule can further include a cytokine receptor dimerizing domain. In other embodiments, the cytokine molecule is an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor chosen from an IL-15Ra or IL-21R.

[0402] As used herein, the term "molecule" as used in, e.g., antibody molecule, cytokine molecule, receptor molecule, includes full-length, naturally-occurring molecules, as well as variants, e.g., functional variants (e.g., truncations, fragments, mutated (e.g., substantially similar sequences) or derivatized form thereof), so long as at least one function and/or activity of the unmodified (e.g., naturally-occurring) molecule remains.

[0403] In some embodiments, the multifunctional molecule includes a stromal modifying moiety. A "stromal modifying moiety," as used herein refers to an agent, e.g., a protein (e.g., an enzyme), that is capable of altering, e.g., degrading a component of, the stroma. In embodiments, the component of the stroma is chosen from, e.g., an ECM component, e.g., a glycosaminoglycan, e.g., hyaluronan (also known as hyaluronic acid or HA), chondroitin sulfate, chondroitin, dermatan sulfate, heparin sulfate, heparin, entactin, tenascin, aggrecan and keratin sulfate; or an extracellular protein, e.g., collagen, laminin, elastin, fibrinogen, fibronectin, and vitronectin.

[0404] The term "functional variant" refers to polypeptides that have a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally-occurring sequence.

[0405] Certain terms are defined below.

[0406] As used herein, the articles "a" and "an" refer to one or more than one, e.g., to at least one, of the grammatical object of the article. The use of the words "a" or "an" when used in conjunction with the term "comprising" herein may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0407] As used herein, "about" and "approximately" generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values.

[0408] "Antibody molecule" as used herein refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In an embodiment, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, is a portion of an antibody, e.g., Fab, Fab', F(ab').sub.2, F(ab).sub.2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms "antibody fragment" or "functional fragment" also include isolated fragments consisting of the variable regions, such as the "Fv" fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker ("scFv proteins"). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab', and F(ab').sub.2 fragments, and single chain variable fragments (scFvs).

[0409] As used herein, an "immunoglobulin variable domain sequence" refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain. For example, the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.

[0410] In embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope. In some embodiments, an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope. In some embodiments, an antibody molecule is a bispecific antibody molecule. "Bispecific antibody molecule" as used herein refers to an antibody molecule that has specificity for more than one (e.g., two, three, four, or more) epitope and/or antigen.

[0411] "Antigen" (Ag) as used herein refers to a molecule that can provoke an immune response, e.g., involving activation of certain immune cells and/or antibody generation. Any macromolecule, including almost all proteins or peptides, can be an antigen. Antigens can also be derived from genomic recombinant or DNA. For example, any DNA comprising a nucleotide sequence or a partial nucleotide sequence that encodes a protein capable of eliciting an immune response encodes an "antigen." In embodiments, an antigen does not need to be encoded solely by a full length nucleotide sequence of a gene, nor does an antigen need to be encoded by a gene at all. In embodiments, an antigen can be synthesized or can be derived from a biological sample, e.g., a tissue sample, a tumor sample, a cell, or a fluid with other biological components. As used, herein a "tumor antigen" or interchangeably, a "cancer antigen" includes any molecule present on, or associated with, a cancer, e.g., a cancer cell or a tumor microenvironment that can provoke an immune response. As used, herein an "immune cell antigen" includes any molecule present on, or associated with, an immune cell that can provoke an immune response.

[0412] The "antigen-binding site," or "binding portion" of an antibody molecule refers to the part of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In embodiments, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called "framework regions," (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In embodiments, in an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen. The three hypervariable regions of each of the heavy and light chains are referred to as "complementarity-determining regions," or "CDRs." The framework region and CDRs have been defined and described, e.g., in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917. Each variable chain (e.g., variable heavy chain and variable light chain) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0413] "Cancer" as used herein can encompass all types of oncogenic processes and/or cancerous growths. In embodiments, cancer includes primary tumors as well as metastatic tissues or malignantly transformed cells, tissues, or organs. In embodiments, cancer encompasses all histopathologies and stages, e.g., stages of invasiveness/severity, of a cancer. In embodiments, cancer includes relapsed and/or resistant cancer. The terms "cancer" and "tumor" can be used interchangeably. For example, both terms encompass solid and liquid tumors. As used herein, the term "cancer" or "tumor" includes premalignant, as well as malignant cancers and tumors.

[0414] As used herein, an "immune cell" refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter. In embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators in the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. The term "immune cell" includes immune effector cells.

[0415] "Immune effector cell," as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.

[0416] The term "effector function" or "effector response" refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

[0417] The compositions and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term "substantially identical" is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.

[0418] In the context of nucleotide sequence, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.

[0419] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows.

[0420] To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology").

[0421] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0422] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0423] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0424] The nucleic acid and protein sequences described herein can be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid (e.g., SEQ ID NO: 1) molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

[0425] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0426] The term "amino acid" is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof, amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term "amino acid" includes both the D- or L-optical isomers and peptidomimetics.

[0427] A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0428] The terms "polypeptide", "peptide" and "protein" (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. The polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.

[0429] The terms "nucleic acid," "nucleic acid sequence," "nucleotide sequence," or "polynucleotide sequence," and "polynucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single-stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[0430] The term "isolated," as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated. Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature.

[0431] Various aspects of the invention are described in further detail below. Additional definitions are set out throughout the specification.

Antibody Molecules

[0432] In one embodiment, the antibody molecule binds to a cancer antigen, e.g., a tumor antigen or a stromal antigen. In some embodiments, the cancer antigen is, e.g., a mammalian, e.g., a human, cancer antigen. In other embodiments, the antibody molecule binds to an immune cell antigen, e.g., a mammalian, e.g., a human, immune cell antigen. For example, the antibody molecule binds specifically to an epitope, e.g., linear or conformational epitope, on the cancer antigen or the immune cell antigen.

[0433] In an embodiment, an antibody molecule is a monospecific antibody molecule and binds a single epitope. E.g., a monospecific antibody molecule having a plurality of immunoglobulin variable domain sequences, each of which binds the same epitope.

[0434] In an embodiment an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domains sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In an embodiment the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment the first and second epitopes overlap. In an embodiment the first and second epitopes do not overlap. In an embodiment the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein). In an embodiment a multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain. In an embodiment, a multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

[0435] In an embodiment a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In an embodiment the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment the first and second epitopes overlap. In an embodiment the first and second epitopes do not overlap. In an embodiment the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein). In an embodiment a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a scFv or a Fab, or fragment thereof, have binding specificity for a first epitope and a scFv or a Fab, or fragment thereof, have binding specificity for a second epitope.

[0436] In an embodiment, an antibody molecule comprises a diabody, and a single-chain molecule, as well as an antigen-binding fragment of an antibody (e.g., Fab, F(ab').sub.2, and Fv). For example, an antibody molecule can include a heavy (H) chain variable domain sequence (abbreviated herein as VH), and a light (L) chain variable domain sequence (abbreviated herein as VL). In an embodiment an antibody molecule comprises or consists of a heavy chain and a light chain (referred to herein as a half antibody. In another example, an antibody molecule includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequence, thereby forming two antigen binding sites, such as Fab, Fab', F(ab').sub.2, Fc, Fd, Fd', Fv, single chain antibodies (scFv for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which may be produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind with their respective antigen or receptor. Antibodies and antibody fragments can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass (e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. The a preparation of antibody molecules can be monoclonal or polyclonal. An antibody molecule can also be a human, humanized, CDR-grafted, or in vitro generated antibody. The antibody can have a heavy chain constant region chosen from, e.g., IgG1, IgG2, IgG3, or IgG4. The antibody can also have a light chain chosen from, e.g., kappa or lambda. The term "immunoglobulin" (Ig) is used interchangeably with the term "antibody" herein.

[0437] Examples of antigen-binding fragments of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv), see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) a single domain antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0438] Antibody molecules include intact molecules as well as functional fragments thereof. Constant regions of the antibody molecules can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).

[0439] Antibody molecules can also be single domain antibodies. Single domain antibodies can include antibodies whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be any of the art, or any future single domain antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, fish, shark, goat, rabbit, and bovine. According to another aspect of the invention, a single domain antibody is a naturally occurring single domain antibody known as heavy chain antibody devoid of light chains. Such single domain antibodies are disclosed in WO 9404678, for example. For clarity reasons, this variable domain derived from a heavy chain antibody naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be derived from antibodies raised in Camelidae species, for example in camel, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain antibodies naturally devoid of light chain; such VHHs are within the scope of the invention.

[0440] The VH and VL regions can be subdivided into regions of hypervariability, termed "complementarity determining regions" (CDR), interspersed with regions that are more conserved, termed "framework regions" (FR or FW).

[0441] The extent of the framework region and CDRs has been precisely defined by a number of methods (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. See, generally, e.g., Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

[0442] The terms "complementarity determining region," and "CDR," as used herein refer to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. In general, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, LCDR3).

[0443] The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme). As used herein, the CDRs defined according the "Chothia" number scheme are also sometimes referred to as "hypervariable loops."

[0444] For example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Under Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).

[0445] Each VH and VL typically includes three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0446] The antibody molecule can be a polyclonal or a monoclonal antibody.

[0447] The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. A monoclonal antibody can be made by hybridoma technology or by methods that do not use hybridoma technology (e.g., recombinant methods).

[0448] The antibody can be recombinantly produced, e.g., produced by phage display or by combinatorial methods.

[0449] Phage display and combinatorial methods for generating antibodies are known in the art (as described in, e.g., Ladner et al. U.S. Pat. No. 5,223,409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271; Winter et al. International Publication WO 92/20791; Markland et al. International Publication No. WO 92/15679; Breitling et al. International Publication WO 93/01288; McCafferty et al. International Publication No. WO 92/01047; Garrard et al. International Publication No. WO 92/09690; Ladner et al. International Publication No. WO 90/02809; Fuchs et al. (1991) Bio Technology 9:1370-1372; Hay et al. (1992) Hum AntibodHybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982, the contents of all of which are incorporated by reference herein).

[0450] In one embodiment, the antibody is a fully human antibody (e.g., an antibody made in a mouse which has been genetically engineered to produce an antibody from a human immunoglobulin sequence), or a non-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g., monkey), camel antibody. Preferably, the non-human antibody is a rodent (mouse or rat antibody). Methods of producing rodent antibodies are known in the art.

[0451] Human monoclonal antibodies can be generated using transgenic mice carrying the human immunoglobulin genes rather than the mouse system. Splenocytes from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinities for epitopes from a human protein (see, e.g., Wood et al. International Application WO 91/00906, Kucherlapati et al. PCT publication WO 91/10741; Lonberg et al. International Application WO 92/03918; Kay et al. International Application 92/03917; Lonberg, N. et al. 1994 Nature 368:856-859; Green, L. L. et al. 1994 Nature Genet. 7:13-21; Morrison, S. L. et al. 1994 Proc. Natl. Acad. Sci. USA 81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon et al. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

[0452] An antibody molecule can be one in which the variable region, or a portion thereof, e.g., the CDRs, are generated in a non-human organism, e.g., a rat or mouse. Chimeric, CDR-grafted, and humanized antibodies are within the invention. Antibody molecules generated in a non-human organism, e.g., a rat or mouse, and then modified, e.g., in the variable framework or constant region, to decrease antigenicity in a human are within the invention.

[0453] An "effectively human" protein is a protein that does substantially not evoke a neutralizing antibody response, e.g., the human anti-murine antibody (HAMA) response. HAMA can be problematic in a number of circumstances, e.g., if the antibody molecule is administered repeatedly, e.g., in treatment of a chronic or recurrent disease condition. A HAMA response can make repeated antibody administration potentially ineffective because of an increased antibody clearance from the serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and also because of potential allergic reactions (see, e.g., LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).

[0454] Chimeric antibodies can be produced by recombinant DNA techniques known in the art (see Robinson et al., International Patent Publication PCT/US86/02269; Akira, et al., European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., International Application WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567; Cabilly et al., European Patent Application 125,023; Better et al. (1988 Science 240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218; Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

[0455] A humanized or CDR-grafted antibody will have at least one or two but generally all three recipient CDRs (of heavy and or light immuoglobulin chains) replaced with a donor CDR. The antibody may be replaced with at least a portion of a non-human CDR or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding to the antigen. Preferably, the donor will be a rodent antibody, e.g., a rat or mouse antibody, and the recipient will be a human framework or a human consensus framework. Typically, the immunoglobulin providing the CDRs is called the "donor" and the immunoglobulin providing the framework is called the "acceptor." In one embodiment, the donor immunoglobulin is a non-human (e.g., rodent). The acceptor framework is a naturally-occurring (e.g., a human) framework or a consensus framework, or a sequence about 85% or higher, preferably 90%, 95%, 99% or higher identical thereto.

[0456] As used herein, the term "consensus sequence" refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (See e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of proteins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence. A "consensus framework" refers to the framework region in the consensus immunoglobulin sequence.

[0457] An antibody molecule can be humanized by methods known in the art (see e.g., Morrison, S. L., 1985, Science 229:1202-1207, by Oi et al., 1986, BioTechniques 4:214, and by Queen et al. U.S. Pat. Nos. 5,585,089, 5,693,761 and 5,693,762, the contents of all of which are hereby incorporated by reference).

[0458] Humanized or CDR-grafted antibody molecules can be produced by CDR-grafting or CDR substitution, wherein one, two, or all CDRs of an immunoglobulin chain can be replaced. See, e.g., U.S. Pat. No. 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter U.S. Pat. No. 5,225,539, the contents of all of which are hereby expressly incorporated by reference. Winter describes a CDR-grafting method which may be used to prepare the humanized antibodies of the present invention (UK Patent Application GB 2188638A, filed on Mar. 26, 1987; Winter U.S. Pat. No. 5,225,539), the contents of which is expressly incorporated by reference.

[0459] Also within the scope of the invention are humanized antibody molecules in which specific amino acids have been substituted, deleted or added. Criteria for selecting amino acids from the donor are described in U.S. Pat. No. 5,585,089, e.g., columns 12-16 of U.S. Pat. No. 5,585,089, e.g., columns 12-16 of U.S. Pat. No. 5,585,089, the contents of which are hereby incorporated by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP 519596 A1, published on Dec. 23, 1992.

[0460] The antibody molecule can be a single chain antibody. A single-chain antibody (scFv) may be engineered (see, for example, Colcher, D. et al. (1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52). The single chain antibody can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target protein.

[0461] In yet other embodiments, the antibody molecule has a heavy chain constant region chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly, chosen from, e.g., the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In another embodiment, the antibody molecule has a light chain constant region chosen from, e.g., the (e.g., human) light chain constant regions of kappa or lambda. The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, and/or complement function). In one embodiment the antibody has: effector function; and can fix complement. In other embodiments the antibody does not; recruit effector cells; or fix complement. In another embodiment, the antibody has reduced or no ability to bind an Fc receptor. For example, it is a isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region.

[0462] Methods for altering an antibody constant region are known in the art. Antibodies with altered function, e.g. altered affinity for an effector ligand, such as FcR on a cell, or the C1 component of complement can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see e.g., EP 388,151 A1, U.S. Pat. Nos. 5,624,821 and 5,648,260, the contents of all of which are hereby incorporated by reference). Similar type of alterations could be described which if applied to the murine, or other species immunoglobulin would reduce or eliminate these functions.

[0463] An antibody molecule can be derivatized or linked to another functional molecule (e.g., another peptide or protein). As used herein, a "derivatized" antibody molecule is one that has been modified. Methods of derivatization include but are not limited to the addition of a fluorescent moiety, a radionucleotide, a toxin, an enzyme or an affinity ligand such as biotin. Accordingly, the antibody molecules of the invention are intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptide that can mediate association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).

[0464] One type of derivatized antibody molecule is produced by crosslinking two or more antibodies (of the same type or of different types, e.g., to create bispecific antibodies). Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

Multispecific Antibody Molecules

[0465] Exemplary structures of multispecific and multifunctional molecules defined herein are described throughout. Exemplary structures are further described in: Weidle U et al. (2013) The Intriguing Options of Multispecific Antibody Formats for Treatment of Cancer. Cancer Genomics & Proteomics 10: 1-18 (2013); and Spiess C et al. (2015) Alternative molecular formats and therapeutic applications for bispecific antibodies. Molecular Immunology 67: 95-106; the full contents of each of which is incorporated by reference herein).

[0466] In embodiments, multispecific antibody molecules can comprise more than one antigen-binding site, where different sites are specific for different antigens. In embodiments, multispecific antibody molecules can bind more than one (e.g., two or more) epitopes on the same antigen. In embodiments, multispecific antibody molecules comprise an antigen-binding site specific for a target cell (e.g., cancer cell) and a different antigen-binding site specific for an immune effector cell. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. Bispecific antibody molecules can be classified into five different structural groups: (i) bispecific immunoglobulin G (BsIgG); (ii) IgG appended with an additional antigen-binding moiety; (iii) bispecific antibody fragments; (iv) bispecific fusion proteins; and (v) bispecific antibody conjugates.

[0467] BsIgG is a format that is monovalent for each antigen. Exemplary BsIgG formats include but are not limited to crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, knobs-in-holes common LC, knobs-in-holes assembly, charge pair, Fab-arm exchange, SEEDbody, triomab, LUZ-Y, Fcab, dk-body, orthogonal Fab. See Spiess et al. Mol. Immunol. 67(2015):95-106. Exemplary BsIgGs include catumaxomab (Fresenius Biotech, Trion Pharma, Neopharm), which contains an anti-CD3 arm and an anti-EpCAM arm; and ertumaxomab (Neovii Biotech, Fresenius Biotech), which targets CD3 and HER2. In some embodiments, BsIgG comprises heavy chains that are engineered for heterodimerization. For example, heavy chains can be engineered for heterodimerization using a "knobs-into-holes" strategy, a SEED platform, a common heavy chain (e.g., in .kappa..lamda.-bodies), and use of heterodimeric Fc regions. See Spiess et al. Mol. Immunol. 67(2015):95-106. Strategies that have been used to avoid heavy chain pairing of homodimers in BsIgG include knobs-in-holes, duobody, azymetric, charge pair, HA-TF, SEEDbody, and differential protein A affinity. See Id. BsIgG can be produced by separate expression of the component antibodies in different host cells and subsequent purification/assembly into a BsIgG. BsIgG can also be produced by expression of the component antibodies in a single host cell. BsIgG can be purified using affinity chromatography, e.g., using protein A and sequential pH elution.

[0468] IgG appended with an additional antigen-binding moiety is another format of bispecific antibody molecules. For example, monospecific IgG can be engineered to have bispecificity by appending an additional antigen-binding unit onto the monospecific IgG, e.g., at the N- or C-terminus of either the heavy or light chain. Exemplary additional antigen-binding units include single domain antibodies (e.g., variable heavy chain or variable light chain), engineered protein scaffolds, and paired antibody variable domains (e.g., single chain variable fragments or variable fragments). See Id. Examples of appended IgG formats include dual variable domain IgG (DVD-Ig), IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, zybody, and DVI-IgG (four-in-one). See Spiess et al. Mol. Immunol. 67(2015):95-106. An example of an IgG-scFv is MM-141 (Merrimack Pharmaceuticals), which binds IGF-1R and HER3. Examples of DVD-Ig include ABT-981 (AbbVie), which binds IL-1.alpha. and IL-1.beta.; and ABT-122 (AbbVie), which binds TNF and IL-17A.

[0469] Bispecific antibody fragments (BsAb) are a format of bispecific antibody molecules that lack some or all of the antibody constant domains. For example, some BsAb lack an Fc region. In embodiments, bispecific antibody fragments include heavy and light chain regions that are connected by a peptide linker that permits efficient expression of the BsAb in a single host cell. Exemplary bispecific antibody fragments include but are not limited to nanobody, nanobody-HAS, BiTE, Diabody, DART, TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab')2, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, Diabody-Fc, tandem scFv-Fc, and intrabody. See Id. For example, the BiTE format comprises tandem scFvs, where the component scFvs bind to CD3 on T cells and a surface antigen on cancer cells

[0470] Bispecific fusion proteins include antibody fragments linked to other proteins, e.g., to add additional specificity and/or functionality. An example of a bispecific fusion protein is an immTAC, which comprises an anti-CD3 scFv linked to an affinity-matured T-cell receptor that recognizes HLA-presented peptides. In embodiments, the dock-and-lock (DNL) method can be used to generate bispecific antibody molecules with higher valency. Also, fusions to albumin binding proteins or human serum albumin can be extend the serum half-life of antibody fragments. See Id

[0471] In embodiments, chemical conjugation, e.g., chemical conjugation of antibodies and/or antibody fragments, can be used to create BsAb molecules. See Id. An exemplary bispecific antibody conjugate includes the CovX-body format, in which a low molecular weight drug is conjugated site-specifically to a single reactive lysine in each Fab arm or an antibody or fragment thereof. In embodiments, the conjugation improves the serum half-life of the low molecular weight drug. An exemplary CovX-body is CVX-241 (NCT01004822), which comprises an antibody conjugated to two short peptides inhibiting either VEGF or Ang2. See Id

[0472] The antibody molecules can be produced by recombinant expression, e.g., of at least one or more component, in a host system. Exemplary host systems include eukaryotic cells (e.g., mammalian cells, e.g., CHO cells, or insect cells, e.g., SF9 or S2 cells) and prokaryotic cells (e.g., E. coli). Bispecific antibody molecules can be produced by separate expression of the components in different host cells and subsequent purification/assembly. Alternatively, the antibody molecules can be produced by expression of the components in a single host cell. Purification of bispecific antibody molecules can be performed by various methods such as affinity chromatography, e.g., using protein A and sequential pH elution. In other embodiments, affinity tags can be used for purification, e.g., histidine-containing tag, myc tag, or streptavidin tag.

CDR-Grafted Scaffolds

[0473] In embodiments, the antibody molecule is a CDR-grafted scaffold domain. In embodiments, the scaffold domain is based on a fibronectin domain, e.g., fibronectin type III domain. The overall fold of the fibronectin type III (Fn3) domain is closely related to that of the smallest functional antibody fragment, the variable domain of the antibody heavy chain. There are three loops at the end of Fn3; the positions of BC, DE and FG loops approximately correspond to those of CDR1, 2 and 3 of the VH domain of an antibody. Fn3 does not have disulfide bonds; and therefore Fn3 is stable under reducing conditions, unlike antibodies and their fragments (see, e.g., WO 98/56915; WO 01/64942; WO 00/34784). An Fn3 domain can be modified (e.g., using CDRs or hypervariable loops described herein) or varied, e.g., to select domains that bind to an antigen/marker/cell described herein.

[0474] In embodiments, a scaffold domain, e.g., a folded domain, is based on an antibody, e.g., a "minibody" scaffold created by deleting three beta strands from a heavy chain variable domain of a monoclonal antibody (see, e.g., Tramontano et al., 1994, J Mol. Recognit. 7:9; and Martin et al., 1994, EMBO J. 13:5303-5309). The "minibody" can be used to present two hypervariable loops. In embodiments, the scaffold domain is a V-like domain (see, e.g., Coia et al. WO 99/45110) or a domain derived from tendamistatin, which is a 74 residue, six-strand beta sheet sandwich held together by two disulfide bonds (see, e.g., McConnell and Hoess, 1995, J Mol. Biol. 250:460). For example, the loops of tendamistatin can be modified (e.g., using CDRs or hypervariable loops) or varied, e.g., to select domains that bind to a marker/antigen/cell described herein. Another exemplary scaffold domain is a beta-sandwich structure derived from the extracellular domain of CTLA-4 (see, e.g., WO 00/60070).

[0475] Other exemplary scaffold domains include but are not limited to T-cell receptors; MHC proteins; extracellular domains (e.g., fibronectin Type III repeats, EGF repeats); protease inhibitors (e.g., Kunitz domains, ecotin, BPTI, and so forth); TPR repeats; trifoil structures; zinc finger domains; DNA-binding proteins; particularly monomeric DNA binding proteins; RNA binding proteins; enzymes, e.g., proteases (particularly inactivated proteases), RNase; chaperones, e.g., thioredoxin, and heat shock proteins; and intracellular signaling domains (such as SH2 and SH3 domains). See, e.g., US 20040009530 and U.S. Pat. No. 7,501,121, incorporated herein by reference.

[0476] In embodiments, a scaffold domain is evaluated and chosen, e.g., by one or more of the following criteria: (1) amino acid sequence, (2) sequences of several homologous domains, (3) 3-dimensional structure, and/or (4) stability data over a range of pH, temperature, salinity, organic solvent, oxidant concentration. In embodiments, the scaffold domain is a small, stable protein domain, e.g., a protein of less than 100, 70, 50, 40 or 30 amino acids. The domain may include one or more disulfide bonds or may chelate a metal, e.g., zinc.

Antibody-Based Fusions

[0477] A variety of formats can be generated which contain additional binding entities attached to the N or C terminus of antibodies. These fusions with single chain or disulfide stabilized Fvs or Fabs result in the generation of tetravalent molecules with bivalent binding specificity for each antigen. Combinations of scFvs and scFabs with IgGs enable the production of molecules which can recognize three or more different antigens.

Antibody-Fab Fusion

[0478] Antibody-Fab fusions are bispecific antibodies comprising a traditional antibody to a first target and a Fab to a second target fused to the C terminus of the antibody heavy chain. Commonly the antibody and the Fab will have a common light chain. Antibody fusions can be produced by (1) engineering the DNA sequence of the target fusion, and (2) transfecting the target DNA into a suitable host cell to express the fusion protein. It seems like the antibody-scFv fusion may be linked by a (Gly)-Ser linker between the C-terminus of the CH3 domain and the N-terminus of the scFv, as described by Coloma, J. et al. (1997) Nature Biotech 15:159.

Antibody-scFv Fusion

[0479] Antibody-scFv Fusions are bispecific antibodies comprising a traditional antibody and a scFv of unique specificity fused to the C terminus of the antibody heavy chain. The scFv can be fused to the C terminus through the Heavy Chain of the scFv either directly or through a linker peptide. Antibody fusions can be produced by (1) engineering the DNA sequence of the target fusion, and (2) transfecting the target DNA into a suitable host cell to express the fusion protein. It seems like the antibody-scFv fusion may be linked by a (Gly)-Ser linker between the C-terminus of the CH3 domain and the N-terminus of the scFv, as described by Coloma, J. et al. (1997) Nature Biotech 15:159.

Variable Domain Immunoglobulin DVD

[0480] A related format is the dual variable domain immunoglobulin (DVD), which are composed of VH and VL domains of a second specificity place upon the N termini of the V domains by shorter linker sequences.

[0481] Other exemplary multispecific antibody formats include, e.g., those described in the following US20160114057A1, US20130243775A1, US20140051833, US20130022601, US20150017187A1, US20120201746A1, US20150133638A1, US20130266568A1, US20160145340A1, WO2015127158A1, US20150203591A1, US20140322221A1, US20130303396A1, US20110293613, US20130017200A1, US20160102135A1, WO2015197598A2, WO2015197582A1, U.S. Pat. No. 9,359,437, US20150018529, WO2016115274A1, WO2016087416A1, US20080069820A1, U.S. Pat. Nos. 9,145,588B, 7,919,257, and US20150232560A1. Exemplary multispecific molecules utilizing a full antibody-Fab/scFab format include those described in the following, U.S. Pat. No. 9,382,323B2, US20140072581A1, US20140308285A1, US20130165638A1, US20130267686A1, US20140377269A1, U.S. Pat. No. 7,741,446B2, and WO1995009917A1. Exemplary multispecific molecules utilizing a domain exchange format include those described in the following, US20150315296A1, WO2016087650A1, US20160075785A1, WO2016016299A1, US20160130347A1, US20150166670, U.S. Pat. No. 8,703,132B2, US20100316645, U.S. Pat. No. 8,227,577B2, US20130078249.

Fc-Containing Entities (Mini-Antibodies)

[0482] Fc-containing entities, also known as mini-antibodies, can be generated by fusing scFv to the C-termini of constant heavy region domain 3 (CH3-scFv) and/or to the hinge region (scFv-hinge-Fc) of an antibody with a different specificity. Trivalent entities can also be made which have disulfide stabilized variable domains (without peptide linker) fused to the C-terminus of CH3 domains of IgGs.

Fc-Containing Multispecific Molecules

[0483] In some embodiments, the multispecific molecules disclosed herein includes an immunoglobulin constant region (e.g., an Fc region). Exemplary Fc regions can be chosen from the heavy chain constant regions of IgG1, IgG2, IgG3 or IgG4; more particularly, the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4.

[0484] In some embodiments, the immunoglobulin chain constant region (e.g., the Fc region) is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.

[0485] In other embodiments, an interface of a first and second immunoglobulin chain constant regions (e.g., a first and a second Fc region) is altered, e.g., mutated, to increase or decrease dimerization, e.g., relative to a non-engineered interface, e.g., a naturally-occurring interface. For example, dimerization of the immunoglobulin chain constant region (e.g., the Fc region) can be enhanced by providing an Fc interface of a first and a second Fc region with one or more of: a paired protuberance-cavity ("knob-in-a hole"), an electrostatic interaction, or a strand-exchange, such that a greater ratio of heteromultimer to homomultimer forms, e.g., relative to a non-engineered interface.

[0486] In some embodiments, the multispecific molecules include a paired amino acid substitution at a position chosen from one or more of 347, 349, 350, 351, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407, or 409, e.g., of the Fc region of human IgG1 For example, the immunoglobulin chain constant region (e.g., Fc region) can include a paired an amino acid substitution chosen from: T366S, L368A, or Y407V (e.g., corresponding to a cavity or hole), and T366W (e.g., corresponding to a protuberance or knob).

[0487] In other embodiments, the multifunctional molecule includes a half-life extender, e.g., a human serum albumin or an antibody molecule to human serum albumin.

Heterodimerized Antibody Molecules & Methods of Making

[0488] Various methods of producing multispecific antibodies have been disclosed to address the problem of incorrect heavy chain pairing. Exemplary methods are described below. Exemplary multispecific antibody formats and methods of making said multispecific antibodies are also disclosed in e.g., Speiss et al. Molecular Immunology 67 (2015) 95-106; and Klein et al mAbs 4:6, 653-663; November/December 2012; the entire contents of each of which are incorporated by reference herein.

[0489] Heterodimerized bispecific antibodies are based on the natural IgG structure, wherein the two binding arms recognize different antigens. IgG derived formats that enable defined monovalent (and simultaneous) antigen binding are generated by forced heavy chain heterodimerization, combined with technologies that minimize light chain mispairing (e.g., common light chain). Forced heavy chain heterodimerization can be obtained using, e.g., knob-in-hole OR strand exchange engineered domains (SEED).

[0490] Knob-In-Hole

[0491] Knob-in-Hole as described in U.S. Pat. Nos. 5,731,116, 7,476,724 and Ridgway, J. et al. (1996) Prot. Engineering 9(7): 617-621, broadly involves: (1) mutating the CH3 domain of one or both antibodies to promote heterodimerization; and (2) combining the mutated antibodies under conditions that promote heterodimerization. "Knobs" or "protuberances" are typically created by replacing a small amino acid in a parental antibody with a larger amino acid (e.g., T366Y or T366W); "Holes" or "cavities" are created by replacing a larger residue in a parental antibody with a smaller amino acid (e.g., Y407T, T366S, L368A and/or Y407V).

[0492] For bispecific antibodies including an Fc domain, introduction of specific mutations into the constant region of the heavy chains to promote the correct heterodimerization of the Fc portion can be utilized. Several such techniques are reviewed in Klein et al. (mAbs (2012) 4:6, 1-11), the contents of which are incorporated herein by reference in their entirety. These techniques include the "knobs-into-holes" (KiH) approach which involves the introduction of a bulky residue into one of the CH3 domains of one of the antibody heavy chains. This bulky residue fits into a complementary "hole" in the other CH3 domain of the paired heavy chain so as to promote correct pairing of heavy chains (see e.g., U.S. Pat. No. 7,642,228).

[0493] Exemplary KiH mutations include S354C, T366W in the "knob" heavy chain and Y349C, T366S, L368A, Y407V in the "hole" heavy chain. Other exemplary KiH mutations are provided in Table 1, with additional optional stabilizing Fc cysteine mutations.

TABLE-US-00001 TABLE 19 Exemplary Fc KiH mutations and optional Cysteine mutations Position Knob Mutation Hole Mutation T366 T366W T366S L368 -- L368A Y407 -- Y407V Additional Cysteine Mutations to form a stabilizing disulfide bridge Position Knob CH3 Hole CH3 S354 S354C -- Y349 -- Y349C

[0494] Other Fc mutations are provided by Igawa and Tsunoda who identified 3 negatively charged residues in the CH3 domain of one chain that pair with three positively charged residues in the CH3 domain of the other chain. These specific charged residue pairs are: E356-K439, E357-K370, D399-K409 and vice versa. By introducing at least two of the following three mutations in chain A: E356K, E357K and D399K, as well as K370E, K409D, K439E in chain B, alone or in combination with newly identified disulfide bridges, they were able to favor very efficient heterodimerization while suppressing homodimerization at the same time (Martens T et al. A novel one-armed antic-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006; 12:6144-52; PMID:17062691). Xencor defined 41 variant pairs based on combining structural calculations and sequence information that were subsequently screened for maximal heterodimerization, defining the combination of S364H, F405A (HA) on chain A and Y349T, T394F on chain B (TF) (Moore G L et al. A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens. MAbs 2011; 3:546-57; PMID: 22123055).

[0495] Other exemplary Fc mutations to promote heterodimerization of multispecific antibodies include those described in the following references, the contents of each of which is incorporated by reference herein, WO2016071377A1, US20140079689A1, US20160194389A1, US20160257763, WO2016071376A2, WO2015107026A1, WO2015107025A1, WO2015107015A1, US20150353636A1, US20140199294A1, U.S. Pat. No. 7,750,128B2, US20160229915A1, US20150344570A1, U.S. Pat. No. 8,003,774A1, US20150337049A1, US20150175707A1, US20140242075A1, US20130195849A1, US20120149876A1, US20140200331A1, U.S. Pat. No. 9,309,311B2, U.S. Pat. No. 8,586,713, US20140037621A1, US20130178605A1, US20140363426A1, US20140051835A1 and US20110054151A1.

[0496] Stabilizing cysteine mutations have also been used in combination with KiH and other Fc heterodimerization promoting variants, see e.g., U.S. Pat. No. 7,183,076. Other exemplary cysteine modifications include, e.g., those disclosed in US20140348839A1, U.S. Pat. No. 7,855,275B2, and U.S. Pat. No. 9,000,130B2.

[0497] Strand Exchange Engineered Domains (SEED)

[0498] Heterodimeric Fc platform that support the design of bispecific and asymmetric fusion proteins by devising strand-exchange engineered domain (SEED) C(H)3 heterodimers are known. These derivatives of human IgG and IgA C(H)3 domains create complementary human SEED C(H)3 heterodimers that are composed of alternating segments of human IgA and IgG C(H)3 sequences. The resulting pair of SEED C(H)3 domains preferentially associates to form heterodimers when expressed in mammalian cells. SEEDbody (Sb) fusion proteins consist of [IgG1 hinge]-C(H)2-[SEED C(H)3], that may be genetically linked to one or more fusion partners (see e.g., Davis J H et al. SEEDbodies: fusion proteins based on strand exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng Des Sel 2010; 23:195-202; PMID:20299542 and U.S. Pat. No. 8,871,912. The contents of each of which are incorporated by reference herein).

[0499] Duobody

[0500] "Duobody" technology to produce bispecific antibodies with correct heavy chain pairing are known. The DuoBody technology involves three basic steps to generate stable bispecific human IgGlantibodies in a post-production exchange reaction. In a first step, two IgG1s, each containing single matched mutations in the third constant (CH3) domain, are produced separately using standard mammalian recombinant cell lines. Subsequently, these IgG1 antibodies are purified according to standard processes for recovery and purification. After production and purification (post-production), the two antibodies are recombined under tailored laboratory conditions resulting in a bispecific antibody product with a very high yield (typically >95%) (see e.g., Labrijn et al, PNAS 2013; 110(13):5145-5150 and Labrijn et al. Nature Protocols 2014; 9(10):2450-63, the contents of each of which are incorporated by reference herein).

[0501] Electrostatic Interactions

[0502] Methods of making multispecific antibodies using CH3 amino acid changes with charged amino acids such that homodimer formation is electrostatically unfavorable are disclosed. EP1870459 and WO 2009089004 describe other strategies for favoring heterodimer formation upon co-expression of different antibody domains in a host cell. In these methods, one or more residues that make up the heavy chain constant domain 3 (CH3), CH3-CH3 interfaces in both CH3 domains are replaced with a charged amino acid such that homodimer formation is electrostatically unfavorable and heterodimerization is electrostatically favorable. Additional methods of making multispecific molecules using electrostatic interactions are described in the following references, the contents of each of which is incorporated by reference herein, include US20100015133, U.S. Pat. No. 8,592,562B2, U.S. Pat. No. 9,200,060B2, US20140154254A1, and U.S. Pat. No. 9,358,286A1.

[0503] Common Light Chain

[0504] Light chain mispairing needs to be avoided to generate homogenous preparations of bispecific IgGs. One way to achieve this is through the use of the common light chain principle, i.e. combining two binders that share one light chain but still have separate specificities. An exemplary method of enhancing the formation of a desired bispecific antibody from a mixture of monomers is by providing a common variable light chain to interact with each of the heteromeric variable heavy chain regions of the bispecific antibody. Compositions and methods of producing bispecific antibodies with a common light chain as disclosed in, e.g., U.S. Pat. No. 7,183,076B2, US20110177073A1, EP2847231A1, WO2016079081A1, and EP3055329A1, the contents of each of which is incorporated by reference herein.

[0505] CrossMab

[0506] Another option to reduce light chain mispairing is the CrossMab technology which avoids non-specific L chain mispairing by exchanging CHI and CL domains in the Fab of one half of the bispecific antibody. Such crossover variants retain binding specificity and affinity, but make the two arms so different that L chain mispairing is prevented. The CrossMab technology (as reviewed in Klein et al. Supra) involves domain swapping between heavy and light chains so as to promote the formation of the correct pairings. Briefly, to construct a bispecific IgG-like CrossMab antibody that could bind to two antigens by using two distinct light chain-heavy chain pairs, a two-step modification process is applied. First, a dimerization interface is engineered into the C-terminus of each heavy chain using a heterodimerization approach, e.g., Knob-into-hole (KiH) technology, to ensure that only a heterodimer of two distinct heavy chains from one antibody (e.g., Antibody A) and a second antibody (e.g., Antibody B) is efficiently formed. Next, the constant heavy 1 (CH1) and constant light (CL) domains of one antibody are exchanged (Antibody A), keeping the variable heavy (VH) and variable light (VL) domains consistent. The exchange of the CH1 and CL domains ensured that the modified antibody (Antibody A) light chain would only efficiently dimerize with the modified antibody (antibody A) heavy chain, while the unmodified antibody (Antibody B) light chain would only efficiently dimerize with the unmodified antibody (Antibody B) heavy chain; and thus only the desired bispecific CrossMab would be efficiently formed (see e.g., Cain, C. SciBX 4(28); doi:10.1038/scibx.2011.783, the contents of which are incorporated by reference herein).

[0507] Common Heavy Chain

[0508] An exemplary method of enhancing the formation of a desired bispecific antibody from a mixture of monomers is by providing a common variable heavy chain to interact with each of the heteromeric variable light chain regions of the bispecific antibody. Compositions and methods of producing bispecific antibodies with a common heavy chain are disclosed in, e.g., US20120184716, US20130317200, and US20160264685A1, the contents of each of which is incorporated by reference herein.

[0509] Amino Acid Modifications

[0510] Alternative compositions and methods of producing multispecific antibodies with correct light chain pairing include various amino acid modifications. For example, Zymeworks describes heterodimers with one or more amino acid modifications in the CH1 and/or CL domains, one or more amino acid modifications in the VH and/or VL domains, or a combination thereof, which are part of the interface between the light chain and heavy chain and create preferential pairing between each heavy chain and a desired light chain such that when the two heavy chains and two light chains of the heterodimer pair are co-expressed in a cell, the heavy chain of the first heterodimer preferentially pairs with one of the light chains rather than the other (see e.g., WO2015181805). Other exemplary methods are described in WO2016026943 (Argen-X), US20150211001, US20140072581A1, US20160039947A1, and US20150368352.

[0511] Lambda/Kappa Formats

[0512] Multispecific molecules (e.g., multispecific antibody molecules) that include the lambda light chain polypeptide and a kappa light chain polypeptides, can be used to allow for heterodimerization. Methods for generating bispecific antibody molecules comprising the lambda light chain polypeptide and a kappa light chain polypeptides are disclosed in U.S. Ser. No. 62/399,319 filed on Sep. 23, 2016, incorporated herein by reference in its entirety.

[0513] In embodiments, the multispecific molecules includes a multispecific antibody molecule, e.g., an antibody molecule comprising two binding specificities, e.g., a bispecific antibody molecule. The multispecific antibody molecule includes:

[0514] a lambda light chain polypeptide 1 (LLCP1) specific for a first epitope;

[0515] a heavy chain polypeptide 1 (HCP1) specific for the first epitope;

[0516] a kappa light chain polypeptide 2 (KLCP2) specific for a second epitope; and

[0517] a heavy chain polypeptide 2 (HCP2) specific for the second epitope.

[0518] "Lambda light chain polypeptide 1 (LLCP1)", as that term is used herein, refers to a polypeptide comprising sufficient light chain (LC) sequence, such that when combined with a cognate heavy chain variable region, can mediate specific binding to its epitope and complex with an HCP1. In an embodiment it comprises all or a fragment of a CH1 region. In an embodiment, an LLCP1 comprises LC-CDR1, LC-CDR2, LC-CDR3, FR1, FR2, FR3, FR4, and CH1, or sufficient sequence therefrom to mediate specific binding of its epitope and complex with an HCP1. LLCP1, together with its HCP1, provide specificity for a first epitope (while KLCP2, together with its HCP2, provide specificity for a second epitope). As described elsewhere herein, LLCP1 has a higher affinity for HCP1 than for HCP2.

[0519] "Kappa light chain polypeptide 2 (KLCP2)", as that term is used herein, refers to a polypeptide comprising sufficient light chain (LC) sequence, such that when combined with a cognate heavy chain variable region, can mediate specific binding to its epitope and complex with an HCP2. In an embodiments it comprises all or a fragment of a CH1 region. In an embodiment, a KLCP2 comprises LC-CDR1, LC-CDR2, LC-CDR3, FR1, FR2, FR3, FR4, and CH1, or sufficient sequence therefrom to mediate specific binding of its epitope and complex with an HCP2. KLCP2, together with its HCP2, provide specificity for a second epitope (while LLCP1, together with its HCP1, provide specificity for a first epitope).

[0520] "Heavy chain polypeptide 1 (HCP1)", as that term is used herein, refers to a polypeptide comprising sufficient heavy chain (HC) sequence, e.g., HC variable region sequence, such that when combined with a cognate LLCP1, can mediate specific binding to its epitope and complex with an HCP1. In an embodiments it comprises all or a fragment of a CH1 region. In an embodiment, it comprises all or a fragment of a CH2 and/or CH3 region. In an embodiment an HCP1 comprises HC-CDR1, HC-CDR2, HC-CDR3, FR1, FR2, FR3, FR4, CH1, CH2, and CH3, or sufficient sequence therefrom to: (i) mediate specific binding of its epitope and complex with an LLCP1, (ii) to complex preferentially, as described herein to LLCP1 as opposed to KLCP2; and (iii) to complex preferentially, as described herein, to an HCP2, as opposed to another molecule of HCP1. HCP1, together with its LLCP1, provide specificity for a first epitope (while KLCP2, together with its HCP2, provide specificity for a second epitope).

[0521] "Heavy chain polypeptide 2 (HCP2)", as that term is used herein, refers to a polypeptide comprising sufficient heavy chain (HC) sequence, e.g., HC variable region sequence, such that when combined with a cognate LLCP1, can mediate specific binding to its epitope and complex with an HCP1. In an embodiments it comprises all or a fragment of a CH1 region. In an embodiments it comprises all or a fragment of a CH2 and/or CH3 region. In an embodiment an HCP1 comprises HC-CDR1, HC-CDR2, HC-CDR3, FR1, FR2, FR3, FR4, CH1, CH2, and CH3, or sufficient sequence therefrom to: (i) mediate specific binding of its epitope and complex with an KLCP2, (ii) to complex preferentially, as described herein to KLCP2 as opposed to LLCP1; and (iii) to complex preferentially, as described herein, to an HCP1, as opposed to another molecule of HCP2. HCP2, together with its KLCP2, provide specificity for a second epitope (while LLCP1, together with its HCP1, provide specificity for a first epitope).

[0522] In some embodiments of the multispecific antibody molecule disclosed herein:

[0523] LLCP1 has a higher affinity for HCP1 than for HCP2; and/or

[0524] KLCP2 has a higher affinity for HCP2 than for HCP1.

[0525] In embodiments, the affinity of LLCP1 for HCP1 is sufficiently greater than its affinity for HCP2, such that under preselected conditions, e.g., in aqueous buffer, e.g., at pH 7, in saline, e.g., at pH 7, or under physiological conditions, at least 75%, 80, 90, 95, 98, 99, 99.5, or 99.9% of the multispecific antibody molecule molecules have a LLCP1 complexed, or interfaced with, a HCP1.

[0526] In some embodiments of the multispecific antibody molecule disclosed herein:

[0527] the HCP1 has a greater affinity for HCP2, than for a second molecule of HCP1; and/or

[0528] the HCP2 has a greater affinity for HCP1, than for a second molecule of HCP2.

[0529] In embodiments, the affinity of HCP1 for HCP2 is sufficiently greater than its affinity for a second molecule of HCP1, such that under preselected conditions, e.g., in aqueous buffer, e.g., at pH 7, in saline, e.g., at pH 7, or under physiological conditions, at least 75%, 80, 90, 95, 98, 99 99.5 or 99.9% of the multispecific antibody molecule molecules have a HCP1 complexed, or interfaced with, a HCP2.

[0530] In another aspect, disclosed herein is a method for making, or producing, a multispecific antibody molecule. The method includes:

[0531] (i) providing a first heavy chain polypeptide (e.g., a heavy chain polypeptide comprising one, two, three or all of a first heavy chain variable region (first VH), a first CH1, a first heavy chain constant region (e.g., a first CH2, a first CH3, or both));

[0532] (ii) providing a second heavy chain polypeptide (e.g., a heavy chain polypeptide comprising one, two, three or all of a second heavy chain variable region (second VH), a second CH1, a second heavy chain constant region (e.g., a second CH2, a second CH3, or both));

[0533] (iii) providing a lambda chain polypeptide (e.g., a lambda light variable region (VL.lamda.), a lambda light constant chain (VL.lamda.), or both) that preferentially associates with the first heavy chain polypeptide (e.g., the first VH); and

[0534] (iv) providing a kappa chain polypeptide (e.g., a kappa light variable region (VL.kappa.), a kappa light constant chain (VL.kappa.), or both) that preferentially associates with the second heavy chain polypeptide (e.g., the second VH),

[0535] under conditions where (i)-(iv) associate.

[0536] In embodiments, the first and second heavy chain polypeptides form an Fc interface that enhances heterodimerization.

[0537] In embodiments, (i)-(iv) (e.g., nucleic acid encoding (i)-(iv)) are introduced in a single cell, e.g., a single mammalian cell, e.g., a CHO cell. In embodiments, (i)-(iv) are expressed in the cell.

[0538] In embodiments, (i)-(iv) (e.g., nucleic acid encoding (i)-(iv)) are introduced in different cells, e.g., different mammalian cells, e.g., two or more CHO cell. In embodiments, (i)-(iv) are expressed in the cells.

[0539] In one embodiments, the method further comprises purifying a cell-expressed antibody molecule, e.g., using a lambda- and/or- kappa-specific purification, e.g., affinity chromatography.

[0540] In embodiments, the method further comprises evaluating the cell-expressed multispecific antibody molecule. For example, the purified cell-expressed multispecific antibody molecule can be analyzed by techniques known in the art, include mass spectrometry. In one embodiment, the purified cell-expressed antibody molecule is cleaved, e.g., digested with papain to yield the Fab moieties and evaluated using mass spectrometry.

[0541] In embodiments, the method produces correctly paired kappa/lambda multispecific, e.g., bispecific, antibody molecules in a high yield, e.g., at least 75%, 80, 90, 95, 98, 99 99.5 or 99.9%.

[0542] In other embodiments, the multispecific, e.g., a bispecific, antibody molecule that includes:

[0543] (i) a first heavy chain polypeptide (HCP1) (e.g., a heavy chain polypeptide comprising one, two, three or all of a first heavy chain variable region (first VH), a first CH1, a first heavy chain constant region (e.g., a first CH2, a first CH3, or both)), e.g., wherein the HCP1 binds to a first epitope;

[0544] (ii) a second heavy chain polypeptide (HCP2) (e.g., a heavy chain polypeptide comprising one, two, three or all of a second heavy chain variable region (second VH), a second CH1, a second heavy chain constant region (e.g., a second CH2, a second CH3, or both)), e.g., wherein the HCP2 binds to a second epitope;

[0545] (iii) a lambda light chain polypeptide (LLCP1) (e.g., a lambda light variable region (VLl), a lambda light constant chain (VLl), or both) that preferentially associates with the first heavy chain polypeptide (e.g., the first VH), e.g., wherein the LLCP1 binds to a first epitope; and

[0546] (iv) a kappa light chain polypeptide (KLCP2) (e.g., a lambda light variable region (VLk), a lambda light constant chain (VLk), or both) that preferentially associates with the second heavy chain polypeptide (e.g., the second VH), e.g., wherein the KLCP2 binds to a second epitope.

[0547] In embodiments, the first and second heavy chain polypeptides form an Fc interface that enhances heterodimerization. In embodiments, the multispecific antibody molecule has a first binding specificity that includes a hybrid VLl-CLl heterodimerized to a first heavy chain variable region connected to the Fc constant, CH2-CH3 domain (having a knob modification) and a second binding specificity that includes a hybrid VLk-CLk heterodimerized to a second heavy chain variable region connected to the Fc constant, CH2-CH3 domain (having a hole modification).

Exemplary Multispecific Configurations:

[0548] In some embodiments, the multispecific molecule includes a first and a second non-contiguous polypeptide, wherein:

[0549] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a cancer antigen, e.g., a solid tumor, a stromal or a hematological antigen, connected, optionally, via a linker to, a cytokine molecule or an immune cell engager, e.g., an antibody molecule, e.g., a scFv that binds to an immune cell antigen; and

[0550] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1). In some embodiments, the multispecific molecule includes a Fab molecule connected, optionally, via a linker to, a scFv. In embodiments, the multispecific molecule is a bispecific molecule.

[0551] In other embodiments, the multispecific molecule includes a first, a second and a third non-contiguous polypeptide, wherein:

[0552] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a tumor or a stromal antigen, connected, optionally, via a linker to, a first domain that promotes association between the first and the second polypeptide (e.g., a first immunoglobulin constant domain (e.g., a first Fc molecule as described herein);

[0553] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a cytokine molecule or an immune cell engager (e.g., an antibody molecule, e.g., a scFv, that binds to an immune cell antigen), connected, optionally, via a linker to, a second domain that promotes association between the first and the second polypeptide (e.g., a second immunoglobulin constant domain (e.g., a second Fc molecule as described herein); and

[0554] (iii) the third polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1). In some embodiments, the multispecific molecule includes a Fab molecule connected, optionally, via a linker to, a first Fc molecule, a cytokine or immune cell engager (e.g., a scFv), connected, optionally, via a linker to, a second Fc molecule. In embodiments, the multispecific molecule is a bispecific molecule.

[0555] In other embodiments, the multispecific molecule includes a first, a second and a third non-contiguous polypeptide, wherein:

[0556] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a cancer antigen, connected, optionally, via a linker to, a first domain that promotes association between the first and the second polypeptide (e.g., a first immunoglobulin constant domain (e.g., a first Fc molecule as described herein);

[0557] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a cytokine molecule or an immune cell engager (e.g., an antibody molecule, e.g., a scFv, that binds to an immune cell antigen), connected, optionally, via a linker to, a second domain that promotes association between the first and the second polypeptide (e.g., a second immunoglobulin constant domain (e.g., a second Fc molecule as described herein); and

[0558] (iii) the third polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1). In some embodiments, the multispecific molecule includes a Fab molecule connected, optionally, via a linker to, a first Fc molecule, a cytokine or immune cell engager (e.g., a scFv), connected, optionally, via a linker to, a second Fc molecule,

[0559] wherein either the first or the second polypeptide further comprise a cytokine molecule or an immune cell engager, optionally covalently linked to the C-terminus of the first or second immunoglobulin constant domain. In embodiments, the multispecific molecule is a trispecific molecule.

[0560] In other embodiments, the multispecific molecule includes a first, a second and a third non-contiguous polypeptide, wherein:

[0561] (i) the first polypeptide includes, e.g., in the N- to C-orientation, a tumor targeting moiety, e.g., an antibody molecule (e.g., a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule), that binds to, e.g., a tumor or a stromal antigen, connected, optionally, via a linker to, a first domain that promotes association between the first and the second polypeptide (e.g., a first immunoglobulin constant domain (e.g., a first Fc molecule as described herein);

[0562] (ii) the second polypeptide includes, e.g., in the N- to C-orientation, a cytokine molecule or an immune cell engager (e.g., an antibody molecule, e.g., a scFv, that binds to an immune cell antigen), connected, optionally, via a linker to, a second domain that promotes association between the first and the second polypeptide (e.g., a second immunoglobulin constant domain (e.g., a second Fc molecule as described herein); and

[0563] (iii) the third polypeptide includes, e.g., in the N- to C-orientation, a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1). In some embodiments, the multispecific molecule includes a Fab molecule connected, optionally, via a linker to, a first Fc molecule, a cytokine or immune cell engager (e.g., a scFv), connected, optionally, via a linker to, a second Fc molecule,

[0564] wherein either the first and the second polypeptide further comprise a cytokine molecule, an immune cell engager or both, optionally covalently linked to the C-terminus of the first or second immunoglobulin constant domain. In embodiments, the multispecific molecule is a tetraspecific molecule.

[0565] In other embodiments, the multispecific molecule comprises a first and a second polypeptide, wherein the first polypeptide comprises, e.g., in the N to C direction:

[0566] a tumor targeting moiety;

[0567] (optionally) a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and

[0568] a first polypeptide comprising an immune cell engager or a cytokine molecule; and,

[0569] wherein the second polypeptide comprises, e.g., in the N to C direction:

[0570] a tumor targeting moiety, or subunit thereof;

[0571] (optionally) a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and

[0572] a second polypeptide comprising an immune cell engager or a cytokine molecule,

[0573] wherein the first and second polypeptide are different.

[0574] In embodiments, the tumor targeting moiety of the first polypeptide comprises a light chain variable domain of a tumor targeting molecule (e.g., Fab); and the tumor targeting moiety of the second polypeptide comprises a heavy chain variable domain of a tumor targeting molecule (e.g., Fab).

[0575] In other embodiments, the first tumor targeting moiety of the first polypeptide comprises a heavy chain variable domain of a tumor targeting molecule (e.g., Fab); and the second tumor targeting moiety of the second polypeptide comprises a light chain variable domain of a tumor targeting molecule (e.g., Fab).

[0576] In other embodiments, the first tumor targeting moiety of the first polypeptide comprises a light chain variable domain of a tumor targeting molecule (e.g., Fab); and the second tumor targeting moiety of the second polypeptide comprises a heavy chain variable domain of a tumor targeting molecule (e.g., Fab).

[0577] In other embodiments, the tumor targeting moiety of the first polypeptide comprises a tumor targeting scFv; and the tumor targeting moiety of the second polypeptide comprises a tumor targeting scFv.

[0578] In other embodiments, the multispecific molecule comprises:

[0579] a) a first polypeptide comprising:

[0580] a first domain that promotes association of the first and second polypeptide, e.g., a first Fc molecule; and

[0581] two polypeptides chosen from: a tumor targeting moiety; an immune cell engager; or a cytokine molecule; and

[0582] b) a second polypeptide comprising:

[0583] a second domain that promotes association of the first and second polypeptide, e.g., an second Fc molecule; and

[0584] two polypeptides chosen from: a tumor targeting moiety; an immune cell engager; or a cytokine molecule,

[0585] wherein the multispecific molecule comprises a tumor targeting moiety; an immune cell engager; and a cytokine molecule.

[0586] In embodiments, the multispecific molecule includes one of the following:

[0587] (i) a tumor targeting moiety; an immune cell engager; and two cytokine molecules;

[0588] (ii) a tumor targeting moiety; two immune cell engagers; and a cytokine molecules; or

[0589] (iii) two tumor targeting moieties; an immune cell engager; and a cytokine molecule.

[0590] In other embodiments, the multispecific molecule includes a first polypeptide and a second polypeptide, wherein:

[0591] i) the first polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a first domain that promotes association of the first and second polypeptide, e.g., a first Fc molecule; and an immune cell engager;

[0592] ii) a first polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a first domain that promotes association of the first and second polypeptide, e.g., a first Fc molecule; and a cytokine molecule; or

[0593] iii) a first polypeptide comprises, e.g., in the N--C or C-N direction a cytokine; a first domain that promotes association of the first and second polypeptide, e.g., a first Fc molecule; and an immune cell engager; and

[0594] iv) the second polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a second domain that promotes association of the first and second polypeptide, e.g., a second Fc molecule; and an immune cell engager;

[0595] ii) the second polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a second domain that promotes association of the first and second polypeptide, e.g., a second Fc molecule; and a cytokine molecule; or

[0596] iii) a second polypeptide comprises, e.g., in the N--C or C-N direction a cytokine; a second domain that promotes association of the first and second polypeptide, e.g., a second Fc molecule; and an immune cell engager.

[0597] Additional features and embodiments of the application include one or more of the following.

[0598] In another aspect, the invention features a multispecific (e.g., bi- or trispecific) molecule comprising the following formula in an N terminal to C terminal orientation:

[0599] R1-(optionally L1)-R2-(optionally L2)-R3;

[0600] R1-(optionally L1)-R3-(optionally L2)-R2;

[0601] R2-(optionally L1)-R1-(optionally L2)-R3;

[0602] R2-(optionally L1)-R3-(optionally L2)-R1;

[0603] R3-(optionally L1)-R1-(optionally L2)-R2; or

[0604] R3-(optionally L1)-R2-(optionally L2)-R1;

[0605] wherein:

[0606] (i) R1 is an tumor targeting moiety as described herein, wherein R1 can be 0 only when R2 and R3 are present, or R1 comprises 1, 2 or more tumor targeting moieties (e.g., the same or different tumor targeting moieties);

[0607] (ii) R2 is an immune cell engager as described herein, wherein R2 can be 0 only when R1 and R3 are present, or R2 comprises 1, 2 or more immune cell engagers (e.g., the same or different immune cell engagers);

[0608] (iii) R3 is a cytokine molecule as described herein, wherein R3 can be 0 only when R1 and R2 are present, or R3 comprises 1, 2 or more cytokine molecules (e.g., the same or different cytokine molecules); and

[0609] (iv) optionally, L1 and/or L2 are any of the linkers described herein.

[0610] In some embodiments, R1 and/or R2 is a full antibody (e.g., an antibody that includes at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains), or an antigen-binding fragment (e.g., a Fab, F(ab').sub.2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody)

[0611] In other embodiments, R1 and R2 is chosen from a common light chain bispecific IgG; a dual acting Fab (DAF), a CrossMab, an IgG-dssc-Fv2, a DVD (dual variable domain), an IgG-dsFv, an IgG-scFab, a scFab-dsscFv, an Fv2-Fc, a Fab-scFv2, a Fab-scFv, a scFv-scFv, a whole antibody-Fab, a whole antibody-scFv, a diabody, a DART (dual affinity retargeting molecule), or a TandAb.

[0612] In other embodiments, the multispecific molecule further includes R4, wherein R4 is a second tumor targeting moiety; a second immune cell engager (e.g., an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); or a second cytokine molecule.

[0613] In other embodiments, the multispecific molecule can further include L3, wherein L3 is a linker (e.g., a linker described herein).

[0614] In some embodiments, R4 is a full antibody (e.g., an antibody that includes at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains), or an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).

[0615] In other embodiments, R1 and R4 is a common light chain bispecific IgG; a dual acting Fab (DAF), a CrossMab, an IgG-dssc-Fv2, a DVD (dual variable domain), an IgG-dsFv, an IgG-scFab, a scFab-dsscFv, an Fv2-Fc, a Fab-scFv2, a Fab-scFv, a scFv-scFv, a whole antibody-Fab, a whole antibody-scFv, a diabody, a DART (dual affinity retargeting molecule), or a TandAb.

[0616] In other embodiments, R2 and R4 is a common light chain bispecific IgG; a dual acting Fab (DAF), a CrossMab, an IgG-dssc-Fv2, a DVD (dual variable domain), an IgG-dsFv, an IgG-scFab, a scFab-dsscFv, an Fv2-Fc, a Fab-scFv2, a Fab-scFv, a scFv-scFv, a whole antibody-Fab, a whole antibody-scFv, a diabody, a DART (dual affinity retargeting molecule), or a TandAb.

[0617] In another aspect, the invention features a multispecific molecule, comprising R1 and R2, wherein:

[0618] (i) R1 is the tumor targeting moiety described herein, e.g., R1 comprises 1, 2 or more tumor targeting moieties (e.g., the same or different tumor targeting moieties);

[0619] (ii) R2 is the cytokine molecule described herein, e.g., R2 comprises 1, 2 or more cytokine molecules (e.g., the same or different cytokine molecules); and

[0620] (iii) optionally, L1 and/or L2 are the linkers described herein.

[0621] In some embodiments, R1 is an anti-FAP Fab and R2 is an IL-15 polypeptide. In some embodiments, R1 and R2 are dimerized via a knob-in-hole Fc dimer (e.g., as shown in Fig. XA), e.g., comprising a first and second Fc. In some embodiments, the first Fc comprises an amino acid substitution selected from: T366S; L368A; or Y407V. In some embodiments, the second Fc comprises an amino acid substitution selected from: T366W.

[0622] In another aspect, the invention features a multispecific molecule comprising R1, R2, and R3, wherein:

[0623] (i) R1 is the tumor targeting moiety described herein, e.g., R1 comprises 1, 2 or more tumor targeting moieties (e.g., the same or different tumor targeting moieties);

[0624] (ii) R2 is the immune cell engager described herein, e.g., R2 comprises 1, 2 or more immune cell engagers (e.g., the same or different immune cell engagers);

[0625] (iii) R3 is the cytokine molecule described herein, e.g., R3 comprises 1, 2 or more cytokine molecules (e.g., the same or different cytokine molecules); and

[0626] (iv) optionally, L1 and/or L2 are the linkers described herein.

[0627] In some embodiments, R1 is an anti-mesothelin Fab, R2 is an IL-15 polypeptide, and R3 is a CD40L polypeptide. In some embodiments, R1 and R2 are dimerized via a knob-in-hole Fe, e.g., comprising a first and second Fc. In some embodiments, the first Fc comprises an amino acid substitution at position 366, 368 and/or 407, e.g., selected from: T366S; L368A; or Y407V. In some embodiments, the second Fc comprises an amino acid substitution at position 366, e.g., T366W.

[0628] In another aspect, the invention features a multispecific molecule comprising: R1, R2, R3, and R4, wherein:

[0629] (i) R1 is the tumor targeting moiety described herein;

[0630] (ii) R2 and R4 are each a first and second immune cell engager described herein;

[0631] (iii) R3 is the cytokine molecule described herein; and

[0632] (iv) optionally, L1 and/or L2 are the linkers described herein.

[0633] In some embodiments, R1 is an anti-FAP Fab, R3 is an IL-15 polypeptide, R2 is a CD40L polypeptide, and R4 is a B7H6 polypeptide. In some embodiments, R1, R2, R3, and R4 are dimerized via an Fe dimer. In some embodiments, the Fc comprises an amino acid substitution selected from: T366S; L368A; or Y407V. In some embodiments, the Fc comprises an amino acid substitution selected from: T366W.

Tumor-Targeting Moieties

[0634] The present disclosure provides, inter alia, multispecific (e.g., bi-, tri-, tetra-specific) molecules, that include, e.g., are engineered to contain, one or more tumor specific targeting moieties that direct the molecule to a tumor cell.

[0635] In certain embodiments, the multispecific molecules disclosed herein include a tumor-targeting moiety. The tumor targeting moiety can be chosen from an antibody molecule (e.g., an antigen binding domain as described herein), a receptor or a receptor fragment, or a ligand or a ligand fragment, or a combination thereof. In some embodiments, the tumor targeting moiety associates with, e.g., binds to, a tumor cell (e.g., a molecule, e.g., antigen, present on the surface of the tumor cell). In certain embodiments, the tumor targeting moiety targets, e.g., directs the multispecific molecules disclosed herein to a cancer (e.g., a cancer or tumor cells). In some embodiments, the cancer is chosen from a hematological cancer, a solid cancer, a metastatic cancer, or a combination thereof.

[0636] In some embodiments, the multispecific molecule, e.g., the tumor-targeting moiety, binds to a solid tumor antigen or a stromal antigen. The solid tumor antigen or stromal antigen can be present on a solid tumor, or a metastatic lesion thereof. In some embodiments, the solid tumor is chosen from one or more of pancreatic (e.g., pancreatic adenocarcinoma), breast, colorectal, lung (e.g., small or non-small cell lung cancer), skin, ovarian, or liver cancer. In one embodiment, the solid tumor is a fibrotic or desmoplastic solid tumor. For example, the solid tumor antigen or stromal antigen can be present on a tumor, e.g., a tumor of a class typified by having one or more of: limited tumor perfusion, compressed blood vessels, or fibrotic tumor interstitium.

[0637] In certain embodiments, the solid tumor antigen is chosen from one or more of: PDL1, CD47, mesothelin, gangloside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2/neu, Telomerase, SAP-1, Survivin, NY-ESO-1/LAGE-1, PRAME, SSX-2, Melan-A/MART-1, Gp100/pmel17, Tyrosinase, TRP-1/-2, MC1R, .beta.-catenin, BRCA1/2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, MUC-1, CA-125, BAGE, GAGE, NY-ESO-1, .beta.-catenin, CDK4, CDC27, CD47, .alpha. actinin-4, TRP1/gp75, TRP2, gp100, Melan-A/MART1, gangliosides, WT1, EphA3, Epidermal growth factor receptor (EGFR), CD20, MART-2, MART-1, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TRP1, TSTA, Folate receptor alpha, L1-CAM, CAIX, EGFRvIII, gpA33, GD3, GM2, VEGFR, Intergrins (Integrin alphaVbeta3, Integrin alpha5Beta1), Carbohydrates (Le), IGF1R, EPHA3, TRAILR1, TRAILR2, or RANKL.

[0638] In some embodiments, the solid tumor antigen is chosen from: PDL1, Mesothelin, CD47, GD2, PMSA, PSCA, CEA, Ron Kinase, or c-Met.

[0639] In one embodiment, the tumor-targeting moiety includes an antibody molecule (e.g., Fab or scFv) that binds to mesothelin. In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from the heavy chain variable domain sequence of: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSS (SEQ ID NO: 1), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 1.

[0640] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs selected from GYSFTGYTMN (SEQ ID NO: 2); LITPYNGASSYNQKFRG (SEQ ID NO: 3); and GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0641] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 comprises GYSFTGYTMN (SEQ ID NO: 2); CDR2 comprises: LITPYNGASSYNQKFRG (SEQ ID NO: 3); and CDR3 comprises GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0642] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 consists of GYSFTGYTMN (SEQ ID NO: 2); CDR2 consists of LITPYNGASSYNQKFRG (SEQ ID NO: 3); and CDR3 consists of GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0643] In embodiments, the antibody molecule to mesothelin includes the heavy chain variable domain sequence of: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSS (SEQ ID NO: 1), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 1.

[0644] In embodiments, the antibody molecule to mesothelin is a Fab and further comprises a heavy chain constant region (CH1) having the amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT (SEQ ID NO: 5), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6).

[0645] Alternatively, or in combination with the heavy chain to mesothelin disclosed herein, the antibody molecule to mesothelin comprises one, two, three CDRs from the light chain variable domain sequence of: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIK (SEQ ID NO: 7), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 7.

[0646] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from SASSSVSYMH (SEQ ID NO: 8); DTSKLAS (SEQ ID NO: 9); and QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0647] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 comprises SASSSVSYMH (SEQ ID NO: 8); CDR2 comprises: DTSKLAS (SEQ ID NO: 9); and CDR3 comprises QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0648] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 consists of SASSSVSYMH (SEQ ID NO: 8); CDR2 consists of DTSKLAS (SEQ ID NO: 9); and CDR3 consists of QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0649] In some embodiments, the antibody molecule to mesothelin comprises the light chain variable domain sequence of: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIK (SEQ ID NO: 7), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 7.

[0650] In some embodiments, the antibody molecule to mesothelin is a Fab and further comprises a light chain constant region (CL1) having the amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 11. In embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12).

[0651] In other embodiments, the multispecific molecule, e.g., the tumor-targeting moiety, binds to a stromal antigen. In embodiments, the stromal antigen is chosen from one or more of: fibroblast activating protease (FAP), TGF-beta, hyaluronic acid, collagen, e.g., collagen IV, tenascin C, or tenascin W.

[0652] In one embodiment, the tumor-targeting moiety includes an antibody molecule (e.g., Fab or scFv) that binds to FAP, e.g., human FAP. In some embodiments, the antibody molecule to FAP comprises one, two, three CDRs from the heavy chain variable domain sequence depicted in underline in FIG. 12C (SEQ ID NO: 13), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 13. In some embodiments, the antibody molecule to FAP includes the heavy chain variable domain sequence depicted in underline in FIG. 12C (SEQ ID NO: 13), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 13.

[0653] In embodiments, the antibody molecule to FAP is a Fab and further comprises a heavy chain constant region (CH1) having the amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC (SEQ ID NO: 14), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 14. In embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MEFGLSWVFLVALFRGVQCEV (SEQ ID NO: 15).

[0654] Alternatively, or in combination with the heavy chain to FAP disclosed herein, the antibody molecule to FAP comprises one, two, three CDRs from the light chain variable domain sequence depicted in underline in FIG. 12D (SEQ ID NO: 16), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 16. In some embodiments, the antibody molecule to FAP includes the light chain variable domain sequence depicted in underline in FIG. 12D (SEQ ID NO: 16), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 16.

[0655] In embodiments, the antibody molecule to FAP is a Fab and further comprises a light chain constant region (CL1) having the amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12).

[0656] In other embodiments, the multispecific molecule, e.g., the tumor-targeting moiety, binds to a molecule, e.g., antigen, present on the surface of a hematological cancer, e.g., a leukemia or a lymphoma. In some embodiments, the hematological cancer is a B-cell or T cell malignancy. In some embodiments, the hematological cancer is chosen from one or more of a Hodgkin's lymphoma, Non-Hodgkin's lymphoma (e.g., B cell lymphoma, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome (MDS), multiple myeloma, or acute lymphocytic leukemia. In embodiments, the cancer is other than acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In embodiments, the hematological antigen is chosen from CD19, CD33, CD123, or CD20. In embodiments, the hematological antigen is other than CD33. CD19, In embodiments, the hematological antigen is chosen from CD19, CD20, CD33, CD47, CD123, CD20, CD99, CD30, BCMA, CD38, CD22, SLAMF7, or NY-ESO1.

Cytokine Molecules

[0657] The cytokines are generally polypeptides that influence cellular activity, for example, through signal transduction pathways. Accordingly, a cytokine of the multispecific or multifunctional polypeptide is useful and can be associated with receptor-mediated signaling that transmits a signal from outside the cell membrane to modulate a response within the cell. Cytokines are proteinaceous signaling compounds that are mediators of the immune response. They control many different cellular functions including proliferation, differentiation and cell survival/apoptosis; cytokines are also involved in several pathophysiological processes including viral infections and autoimmune diseases. Cytokines are synthesized under various stimuli by a variety of cells of both the innate (monocytes, macrophages, dendritic cells) and adaptive (T- and B-cells) immune systems. Cytokines can be classified into two groups: pro- and anti-inflammatory. Pro-inflammatory cytokines, including IFN.gamma., IL-1, IL-6 and TNF-alpha, are predominantly derived from the innate immune cells and Th1 cells. Anti-inflammatory cytokines, including IL-10, IL-4, IL-13 and IL-5, are synthesized from Th2 immune cells.

[0658] The present disclosure provides, inter alia, multi-specific (e.g., bi-, tri-, quad-specific) proteins, that include, e.g., are engineered to contain, one or more cytokine molecules, e.g., immunomodulatory (e.g., proinflammatory) cytokines and variants, e.g., functional variants, thereof. Accordingly, in some embodiments, the cytokine molecule is an interleukin or a variant, e.g., a functional variant thereof. In some embodiments the interleukin is a proinflammatory interleukin. In some embodiments the interleukin is chosen from interleukin-2 (IL-2), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), interleukin-7 (IL-7), or interferon gamma. In some embodiments, the cytokine molecule is a proinflammatory cytokine.

[0659] In certain embodiments, the cytokine is a single chain cytokine. In certain embodiments, the cytokine is a multichain cytokine (e.g., the cytokine comprises 2 or more (e.g., 2) polypeptide chains. An exemplary multichain cytokine is IL-12.

[0660] Examples of useful cytokines include, but are not limited to, GM-CSF, IL-1.alpha., IL-1.beta., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-21, IFN-.alpha., IFN-.beta., IFN-.gamma., MIP-1.alpha., MIP-1.beta., TGF-.beta., TNF-.alpha., and TNF.beta.. In one embodiment the cytokine of the multispecific or multifunctional polypeptide is a cytokine selected from the group of GM-CSF, IL-2, IL-7, IL-8, IL-10, IL-12, IL-15, IL-21, IFN-.alpha., IFN-.gamma., MIP-1.alpha., MIP-1.theta. and TGF-.beta.. In one embodiment the cytokine of the i the multispecific or multifunctional polypeptide is a cytokine selected from the group of IL-2, IL-7, IL-10, IL-12, IL-15, IFN-.alpha., and IFN-.gamma.. In certain embodiments the cytokine is mutated to remove N- and/or O-glycosylation sites. Elimination of glycosylation increases homogeneity of the product obtainable in recombinant production.

[0661] In one embodiment, the cytokine of the multispecific or multifunctional polypeptide is IL-2. In a specific embodiment, the IL-2 cytokine can elicit one or more of the cellular responses selected from the group consisting of: proliferation in an activated T lymphocyte cell, differentiation in an activated T lymphocyte cell, cytotoxic T cell (CTL) activity, proliferation in an activated B cell, differentiation in an activated B cell, proliferation in a natural killer (NK) cell, differentiation in a NK cell, cytokine secretion by an activated T cell or an NK cell, and NK/lymphocyte activated killer (LAK) antitumor cytotoxicity. In another particular embodiment the IL-2 cytokine is a mutant IL-2 cytokine having reduced binding affinity to the .alpha.-subunit of the IL-2 receptor. Together with the .beta.- and .gamma.-subunits (also known as CD122 and CD132, respectively), the .alpha.-subunit (also known as CD25) forms the heterotrimeric high-affinity IL-2 receptor, while the dimeric receptor consisting only of the 0- and 7-subunits is termed the intermediate-affinity IL-2 receptor. As described in PCT patent application number PCT/EP2012/051991, which is incorporated herein by reference in its entirety, a mutant IL-2 polypeptide with reduced binding to the .alpha.-subunit of the IL-2 receptor has a reduced ability to induce IL-2 signaling in regulatory T cells, induces less activation-induced cell death (AICD) in T cells, and has a reduced toxicity profile in vivo, compared to a wild-type IL-2 polypeptide. The use of such an cytokine with reduced toxicity is particularly advantageous in a multispecific or multifunctional polypeptide according to the invention, having a long serum half-life due to the presence of an Fc domain. In one embodiment, the mutant IL-2 cytokine of the multispecific or multifunctional polypeptide according to the invention comprises at least one amino acid mutation that reduces or abolishes the affinity of the mutant IL-2 cytokine to the .alpha.-subunit of the IL-2 receptor (CD25) but preserves the affinity of the mutant IL-2 cytokine to the intermediate-affinity IL-2 receptor (consisting of the .beta. and .gamma. subunits of the IL-2 receptor), compared to the non-mutated IL-2 cytokine. In one embodiment the one or more amino acid mutations are amino acid substitutions. In a specific embodiment, the mutant IL-2 cytokine comprises one, two or three amino acid substitutions at one, two or three position(s) selected from the positions corresponding to residue 42, 45, and 72 of human IL-2. In a more specific embodiment, the mutant IL-2 cytokine comprises three amino acid substitutions at the positions corresponding to residue 42, 45 and 72 of human IL-2. In an even more specific embodiment, the mutant IL-2 cytokine is human IL-2 comprising the amino acid substitutions F42A, Y45A and L72G. In one embodiment the mutant IL-2 cytokine additionally comprises an amino acid mutation at a position corresponding to position 3 of human IL-2, which eliminates the O-glycosylation site of IL-2. Particularly, said additional amino acid mutation is an amino acid substitution replacing a threonine residue by an alanine residue. A particular mutant IL-2 cytokine useful in the invention comprises four amino acid substitutions at positions corresponding to residues 3, 42, 45 and 72 of human IL-2. Specific amino acid substitutions are T3A, F42A, Y45A and L72G. As demonstrated in PCT patent application number PCT/EP2012/051991 and in the appended Examples, said quadruple mutant IL-2 polypeptide (IL-2 qm) exhibits no detectable binding to CD25, reduced ability to induce apoptosis in T cells, reduced ability to induce IL-2 signaling in T.sub.reg cells, and a reduced toxicity profile in vivo. However, it retains ability to activate IL-2 signaling in effector cells, to induce proliferation of effector cells, and to generate IFN-.gamma. as a secondary cytokine by NK cells.

[0662] The IL-2 or mutant IL-2 cytokine according to any of the above embodiments may comprise additional mutations that provide further advantages such as increased expression or stability. For example, the cysteine at position 125 may be replaced with a neutral amino acid such as alanine, to avoid the formation of disulfide-bridged IL-2 dimers. Thus, in certain embodiments the IL-2 or mutant IL-2 cytokine of the multispecific or multifunctional polypeptide according to the invention comprises an additional amino acid mutation at a position corresponding to residue 125 of human IL-2. In one embodiment said additional amino acid mutation is the amino acid substitution C125A.

[0663] In a specific embodiment the IL-2 cytokine of the multispecific or multifunctional polypeptide comprises the polypeptide sequence of SEQ ID NO: 227 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCL EEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFAQSIISTLT. In another specific embodiment the IL-2 cytokine of the multispecific or multifunctional polypeptide comprises the polypeptide sequence of SEQ ID NO: 228 APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFAMPKKATELKHLQCL EEELKPLEEVLNGAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFAQSIISTLT.

[0664] In another embodiment the cytokine of the multispecific or multifunctional polypeptide is IL-12. In a specific embodiment said IL-12 cytokine is a single chain IL-12 cytokine. In an even more specific embodiment the single chain IL-12 cytokine comprises the polypeptide sequence of SEQ ID NO: 229 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVK EFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGR FTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSA CPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEY PDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSS SWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQ KARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRK TSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFN SETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS. In one embodiment, the IL-12 cytokine can elicit one or more of the cellular responses selected from the group consisting of: proliferation in a NK cell, differentiation in a NK cell, proliferation in a T cell, and differentiation in a T cell.

[0665] In another embodiment the cytokine of the multispecific or multifunctional polypeptide is IL-10. In a specific embodiment said IL-10 cytokine is a single chain IL-10 cytokine. In an even more specific embodiment the single chain IL-10 cytokine comprises the polypeptide sequence of SEQ ID NO: 230 SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGY LGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKS KAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRNGGGGSGGGGSGGGGSG GGGSSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLED FKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPC ENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN. In another specific embodiment the IL-10 cytokine is a monomeric IL-10 cytokine. In a more specific embodiment the monomeric IL-10 cytokine comprises the polypeptide sequence of SEQ ID NO: 231 [SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKG YLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENG GGSGGKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN]. In one embodiment, the IL-10 cytokine can elicit one or more of the cellular responses selected from the group consisting of: inhibition of cytokine secretion, inhibition of antigen presentation by antigen presenting cells, reduction of oxygen radical release, and inhibition of T cell proliferation. A multispecific or multifunctional polypeptide according to the invention wherein the cytokine is IL-10 is particularly useful for downregulation of inflammation, e.g. in the treatment of an inflammatory disorder.

[0666] In another embodiment, the cytokine of the multispecific or multifunctional polypeptide is IL-15. In a specific embodiment said IL-15 cytokine is a mutant IL-15 cytokine having reduced binding affinity to the .alpha.-subunit of the IL-15 receptor. Without wishing to be bound by theory, a mutant IL-15 polypeptide with reduced binding to the .alpha.-subunit of the IL-15 receptor has a reduced ability to bind to fibroblasts throughout the body, resulting in improved pharmacokinetics and toxicity profile, compared to a wild-type IL-15 polypeptide. The use of an cytokine with reduced toxicity, such as the described mutant IL-2 and mutant IL-15 effector moieties, is particularly advantageous in a multispecific or multifunctional polypeptide according to the invention, having a long serum half-life due to the presence of an Fc domain. In one embodiment the mutant IL-15 cytokine of the multispecific or multifunctional polypeptide according to the invention comprises at least one amino acid mutation that reduces or abolishes the affinity of the mutant IL-15 cytokine to the .alpha.-subunit of the IL-15 receptor but preserves the affinity of the mutant IL-15 cytokine to the intermediate-affinity IL-15/IL-2 receptor (consisting of the .beta.- and .gamma.-subunits of the IL-15/IL-2 receptor), compared to the non-mutated IL-15 cytokine. In one embodiment the amino acid mutation is an amino acid substitution. In a specific embodiment, the mutant IL-15 cytokine comprises an amino acid substitution at the position corresponding to residue 53 of human IL-15. In a more specific embodiment, the mutant IL-15 cytokine is human IL-15 comprising the amino acid substitution E53A. In one embodiment the mutant IL-15 cytokine additionally comprises an amino acid mutation at a position corresponding to position 79 of human IL-15, which eliminates the N-glycosylation site of IL-15. Particularly, said additional amino acid mutation is an amino acid substitution replacing an asparagine residue by an alanine residue. In an even more specific embodiment the IL-15 cytokine comprises the polypeptide sequence of SEQ ID NO: 232 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLASGDASIH DTVENLIILANNSLSSNGAVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS. In one embodiment, the IL-15 cytokine can elicit one or more of the cellular responses selected from the group consisting of: proliferation in an activated T lymphocyte cell, differentiation in an activated T lymphocyte cell, cytotoxic T cell (CTL) activity, proliferation in an activated B cell, differentiation in an activated B cell, proliferation in a natural killer (NK) cell, differentiation in a NK cell, cytokine secretion by an activated T cell or an NK cell, and NK/lymphocyte activated killer (LAK) antitumor cytotoxicity.

[0667] Mutant cytokine molecules useful as effector moieties in the multispecific or multifunctional polypeptide can be prepared by deletion, substitution, insertion or modification using genetic or chemical methods well known in the art. Genetic methods may include site-specific mutagenesis of the encoding DNA sequence, PCR, gene synthesis, and the like. The correct nucleotide changes can be verified for example by sequencing. Substitution or insertion may involve natural as well as non-natural amino acid residues. Amino acid modification includes well known methods of chemical modification such as the addition or removal of glycosylation sites or carbohydrate attachments, and the like.

[0668] In one embodiment, the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is GM-CSF. In a specific embodiment, the GM-CSF cytokine can elicit proliferation and/or differentiation in a granulocyte, a monocyte or a dendritic cell. In one embodiment, the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is IFN-.alpha.. In a specific embodiment, the IFN-.alpha. cytokine can elicit one or more of the cellular responses selected from the group consisting of: inhibiting viral replication in a virus-infected cell, and upregulating the expression of major histocompatibility complex I (MHC I). In another specific embodiment, the IFN-.alpha. cytokine can inhibit proliferation in a tumor cell. In one embodiment the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is IFN.gamma.. In a specific embodiment, the IFN-.gamma. cytokine can elicit one or more of the cellular responses selected from the group of: increased macrophage activity, increased expression of MHC molecules, and increased NK cell activity. In one embodiment the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is IL-7. In a specific embodiment, the IL-7 cytokine can elicit proliferation of T and/or B lymphocytes. In one embodiment, the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is IL-8. In a specific embodiment, the IL-8 cytokine can elicit chemotaxis in neutrophils. In one embodiment, the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide, is MIP-1.alpha.. In a specific embodiment, the MIP-1.alpha.cytokine can elicit chemotaxis in monocytes and T lymphocyte cells. In one embodiment, the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is MIP-10. In a specific embodiment, the MIP-10 cytokine can elicit chemotaxis in monocytes and T lymphocyte cells. In one embodiment, the cytokine, particularly a single-chain cytokine, of the multispecific or multifunctional polypeptide is TGF-.beta.. In a specific embodiment, the TGF-.beta. cytokine can elicit one or more of the cellular responses selected from the group consisting of: chemotaxis in monocytes, chemotaxis in macrophages, upregulation of IL-1 expression in activated macrophages, and upregulation of IgA expression in activated B cells.

[0669] In one embodiment, the multispecific or multifunctional polypeptide of the invention binds to an cytokine receptor with a dissociation constant (K.sub.D) that is at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 times greater than that for a control cytokine. In another embodiment, the multispecific or multifunctional polypeptide binds to an cytokine receptor with a K.sub.D that is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times greater than that for a corresponding multispecific or multifunctional polypeptide comprising two or more effector moieties. In another embodiment, the multispecific or multifunctional polypeptide binds to an cytokine receptor with a dissociation constant K.sub.D that is about 10 times greater than that for a corresponding the multispecific or multifunctional polypeptide comprising two or more cytokines.

[0670] In some embodiments, the multispecific molecules disclosed herein include a cytokine molecule. In embodiments, the cytokine molecule includes a full length, a fragment or a variant of a cytokine; a cytokine receptor domain, e.g., a cytokine receptor dimerizing domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor.

[0671] In some embodiments the cytokine molecule is chosen from IL-2, IL-12, IL-15, IL-18, IL-7, IL-21, or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforesaid cytokines. The cytokine molecule can be a monomer or a dimer. In embodiments, the cytokine molecule can further include a cytokine receptor dimerizing domain.

[0672] In other embodiments, the cytokine molecule is an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor chosen from an IL-15Ra or IL-21R.

[0673] In one embodiment, the cytokine molecule is IL-15, e.g., human IL-15 (e.g., comprising the amino acid sequence: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 17), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 17.

[0674] In some embodiments, the cytokine molecule comprises a receptor dimerizing domain, e.g., an IL15Ralpha dimerizing domain. In one embodiment, the IL15Ralpha dimerizing domain comprises the amino acid sequence: MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHADIWVKSYSLYSRERYICN SGFKRKAGTSSLTECVL (SEQ ID NO: 18), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) of the multispecific molecule are covalently linked, e.g., via a linker (e.g., a Gly-Ser linker, e.g., a linker comprising the amino acid sequence SGGSGGGGSGGGSGGGGSLQ (SEQ ID NO: 19). In other embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) of the multispecific molecule are not covalently linked, e.g., are non-covalently associated.

[0675] In other embodiments, the cytokine molecule is IL-2, e.g., human IL-2 (e.g., comprising the amino acid sequence: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCL EEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFCQSIISTLT (SEQ ID NO: 20), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 20).

[0676] In other embodiments, the cytokine molecule is IL-18, e.g., human IL-18 (e.g., comprising the amino acid sequence: YFGKLESKL SVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGM AVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEG YFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 21), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 21).

[0677] In other embodiments, the cytokine molecule is IL-21, e.g., human IL-21 (e.g., comprising the amino acid sequence: QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSA NTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMI HQHLSSRTHGSEDS (SEQ ID NO: 22), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 22).

[0678] In yet other embodiments, the cytokine molecule is interferon gamma, e.g., human interferon gamma (e.g., comprising the amino acid sequence: QDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFK NFKDDQSIQKSVETIKEDMNVKFFNSNKKKRDDFEKLTNYSVTDLNVQRKAHIELIQVM AELSPAAKTGKRKRSQMLFRG (SEQ ID NO: 23), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 23).

Immune Cell Engagers

[0679] The immune cell engagers of the multispecific molecules disclosed herein can mediate binding to, and/or activation of, an immune cell, e.g., an immune effector cell. In some embodiments, the immune cell is chosen from an NK cell, a B cell, a dendritic cell, or a macrophage cell engager, or a combination thereof. In some embodiments, the immune cell engager is chosen from one, two, three, or all of a T cell engager, NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, or a combination thereof. The immune cell engager can be an agonist of the immune system. In some embodiments, the immune cell engager can be an antibody molecule, a ligand molecule (e.g., a ligand that further comprises an immunoglobulin constant region, e.g., an Fc region), a small molecule, a nucleotide molecule.

Natural Killer Cell Engagers

[0680] Natural Killer (NK) cells recognize and destroy tumors and virus-infected cells in an antibody-independent manner. The regulation of NK cells is mediated by activating and inhibiting receptors on the NK cell surface. One family of activating receptors is the natural cytotoxicity receptors (NCRs) which include NKp30, NKp44 and NKp46. The NCRs initiate tumor targeting by recognition of heparan sulfate on cancer cells. NKG2D is a receptor that provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity. DNAM1 is a receptor involved in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-lymphocyte (CTL) and NK cell. DAP10 (also known as HCST) is a transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and U (optionally L1)6-binding proteins (ULBPs); it KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells. CD16 is a receptor for the Fc region of IgG, which binds complexed or aggregated IgG and also monomeric IgG and thereby mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.

[0681] In some embodiments, the NK cell engager is a viral hemagglutinin (HA), HA is a glycoprotein found on the surface of influenza viruses. It is responsible for binding the virus to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes. HA has at least 18 different antigens. These subtypes are named H1 through H18. NCRs can recognize viral proteins. NKp46 has been shown to be able to interact with the HA of influenza and the HA-NA of Paramyxovirus, including Sendai virus and Newcastle disease virus. Besides NKp46, NKp44 can also functionally interact with HA of different influenza subtypes.

[0682] The present disclosure provides, inter alia, multi-specific (e.g., bi-, tri-, quad-specific) proteins, that are engineered to contain one or more NK cell engager that mediate binding to and/or activation of an NK cell. Accordingly, in some embodiments, the NK cell engager is selected from an antigen binding domain or ligand that binds to (e.g., activates): NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16 (e.g., CD16a, CD16b, or both), CRTAM, CD27, PSGL1, CD96, CD100 (SEMA4D), NKp80, CD244 (also known as SLAMF4 or 2B4), SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, or CD160.

[0683] In one embodiment, the NK cell engager is a ligand of NKp30 is a B7-6, e.g., comprises the amino acid sequence of: DLKVEMMAGGTQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFDKEVKVFEFFGD HQEAFRPGAIVSPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQGTVQLEVVASP ASRLLLDQVGMKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISEDVITGPTIKNM DGTFNVTSCLKLNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSL SETEKTDNFS (SEQ ID NO: 24), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 24.

[0684] In other embodiments, the NK cell engager is a ligand of NKp44 or NKp46, which is a viral HA. Viral hemagglutinins (HA) are glyco proteins which are on the surface of viruses. HA proteins allow viruses to bind to the membrane of cells via sialic acid sugar moieties which contributes to the fusion of viral membranes with the cell membranes (see e.g., Eur J Immunol. 2001 September; 31(9):2680-9 "Recognition of viral hemagglutinins by NKp44 but not by NKp30"; and Nature. 2001 Feb. 22; 409(6823):1055-60 "Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells" the contents of each of which are incorporated by reference herein).

[0685] In other embodiments, the NK cell engager is a ligand of NKG2D chosen from MICA, MICB, or ULBP1, e.g., wherein:

(i) MICA comprises the amino acid sequence: EPHSLRYNLTVL SWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNK TWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGEL FLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLK SGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSSHDTQQWG DVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW (SEQ ID NO: 25), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 25; (ii) MICB comprises the amino acid sequence: AEPHSLRYNLMVLSQDESVQSGFLAEGHLDGQPFLRYDRQKRRAKPQGQWAEDVLGA KTWDTETEDLTENGQDLRRTLTHIKDQKGGLHSLQEIRVCEHiEDSSTRGSRHFYYDGEL FLSQNLETQESTVPQSSRAQTLAMNVTNFWKEDAMKTKTHYRAMQADCLQKLQRYLK SGVAIRRTVPPMVNVTCSEVSEGNITVTCRASSFYPRNITLTWRQDGVSLSHNTQQWGD VLPDGNGTYQTWVATRIRQGEEQRFTCYMEHSGNHGTHPVPSGKVLVLQSQRTD (SEQ ID NO: 26), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 26; or (iii) ULBP1 comprises the amino acid sequence: GWVDTHCLCYDFIITPKSRPEPQWCEVQGLVDERPFLHYDCVNHKAKAFASLGKKVNV TKTWEEQTETLRDVVDFLKGQLLDIQVENLIPIEPL TLQARMSCEHEAHGHGRGSWQFL FNGQKFLLFDSNNRKWTALHPGAKKMTEKWEKNRDVTMFFQKISLGDCKMWLEEFL MYWEQMLDPTKPPSLAPG (SEQ ID NO: 27), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 27.

[0686] In other embodiments, the NK cell engager is a ligand of DNAM1 chosen from NECTIN2 or NECL5, e.g., wherein:

(i) NECTIN2 comprises the amino acid sequence: QDVRVQVLPEVRGQLGGTVELPCHLLPPVPGLYISLVTWQRPDAPANHQNVAAFHPKM GPSFPSPKPGSERL SFVSAKQSTGQDTEAELQDATLALHGLTVEDEGNYTCEFATFPKGS VRGMTWLRVIAKPKNQAEAQKVTFSQDPTTVALCISKEGRPPARISWL SSLDWEAKETQ VSGTLAGTVTVTSRFTLVPSGRADGVTVTCKVEHESFEEPALIPVTLSVRYPPEVSISGYD DNWYLGRTDATLSCDVRSNPEPTGYDWSTTSGTFPTSAVAQGSQLVIHAVDSLFNTTFV CTVTNAVGMGRAEQVIFVRETPNTAGAGATGG (SEQ ID NO: 28), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 28; or (ii) NECL5 comprises the amino acid sequence: WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAV FHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVD IWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPG FLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNN WYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICN VTNALGARQAELTVQVKEGPPSEHSGISRN (SEQ ID NO: 29), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 29.

[0687] In yet other embodiments, the NK cell engager is a ligand of DAP10, which is an adapter for NKG2D (see e.g., Proc Natl Acad Sci USA. 2005 May 24; 102(21): 7641-7646; and Blood, 15 Sep. 2011 Volume 118, Number 11, the full contents of each of which is incorporated by reference herein).

[0688] In other embodiments, the NK cell engager is a ligand of CD16, which is a CD16a/b ligand, e.g., a CD16a/b ligand further comprising an antibody Fc region (see e.g., Front Immunol. 2013; 4: 76 discusses how antibodies use the Fc to trigger NK cells through CD16, the full contents of which are incorporated herein).

[0689] In other embodiments, the NK cell engager is a ligand of CRTAM, which is NECL2, e.g., wherein NECL2 comprises the amino acid sequence: QNLFTKDVTVIEGEVATISCQVNKSDDSVIQLLNPNRQTIYFRDFRPLKDSRFQLLNFSSS ELKVSLTNVSISDEGRYFCQLYTDPPQESYTTITVLVPPRNLMIDIQKDTAVEGEEIEVNC TAMASKPATTIRWFKGNTELKGKSEVEEWSDMYTVTSQLMLKVHKEDDGVPVICQVE HPAVTGNLQTQRYLEVQYKPQVHIQMTYPLQGLTREGDALELTCEAIGKPQPVMVTWV RVDDEMPQHAVLSGPNLFINNLNKTDNGTYRCEASNIVGKAHSDYMLYVYDPPTTIPPP TTTTTTTTTTTTTILTIITDSRAGEEGSIRAVDH (SEQ ID NO: 30), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 30.

[0690] In other embodiments, the NK cell engager is a ligand of CD27, which is CD70, e.g., wherein CD70 comprises the amino acid sequence: QRFAQAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALGRSFLHGPELDKGQ LRIIHRDGIYMVHIQVTLAICSSTTASRHHPTTLAVGICSPASRSISLLRLSFHQGCTIASQR LTPLARGDTLCTNLTGTLLPSRNTDETFFGVQWVRP (SEQ ID NO: 31), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 31.

[0691] In other embodiments, the NK cell engager is a ligand of PSGL1, which is L-selectin (CD62L), e.g., wherein L-selectin comprises the amino acid sequence: WTYHYSEKPMNWQRARRFCRDNYTDLVAIQNKAEIEYLEKTLPFSRSYYWIGIRKIGGI WTWVGTNKSLTEEAENWGDGEPNNKKNKEDCVEIYIKRNKDAGKWNDDACHKLKAA LCYTASCQPWSCSGHGECVEIINNYTCNCDVGYYGPQCQFVIQCEPLEAPELGTMDCTH PLGNFSFSSQCAFSCSEGTNLTGIEETTCGPFGNWSSPEPTCQVIQCEPLSAPDLGIMNCSH PLASFSFTSACTFICSEGTELIGKKKTICESSGIWSNPSPICQKLDKSFSMIKEGDYN (SEQ ID NO: 32), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 32.

[0692] In other embodiments, the NK cell engager is a ligand of CD96, which is NECL5, e.g., wherein NECL5 comprises the amino acid sequence: WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAV FHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVD IWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPG FLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNN WYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICN VTNALGARQAELTVQVKEGPPSEHSGISRN (SEQ ID NO: 29), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 30.

[0693] In other embodiments, the NK cell engager is a ligand of CD100 (SEMA4D), which is CD72, e.g., wherein CD72 comprises the amino acid sequence: RYLQVSQQLQQTNRVLEVTNSSLRQQLRLKITQLGQSAEDLQGSRRELAQSQEALQVEQ RAHQAAEGQLQACQADRQKTKETLQSEEQQRRALEQKLSNMENRLKPFFTCGSADTCC PSGWIMHQKSCFYISLTSKNWQESQKQCETLSSKLATFSEIYPQSHSYYFLNSLLPNGGS GNSYWTGLSSNKDWKLTDDTQRTRTYAQSSKCNKVHKTWSWWTLESESCRSSLPYICE MTAFRFPD (SEQ ID NO: 33), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 33.

[0694] In other embodiments, the NK cell engager is a ligand of NKp80, which is CLEC2B (AICL), e.g., wherein CLEC2B (AICL) comprises the amino acid sequence: KLTRDSQSLCPYDWIGFQNKCYYFSKEEGDWNSSKYNCSTQHADLTIIDNIEEMNFLRR YKCSSDHWIGLKMAKNRTGQWVDGATFTKSFGMRGSEGCAYLSDDGAATARCYTER KWICRKRIH (SEQ ID NO: 34), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 34.

[0695] In other embodiments, the NK cell engager is a ligand of CD244, which is CD48, e.g., wherein CD48 comprises the amino acid sequence: QGHLVHMTVVSGSNVTLNISESLPENYKQLTWFYTFDQKIVEWDSRKSKYFESKFKGR VRLDPQSGALYISKVQKEDNSTYIMRVLKKTGNEQEWKIKLQVLDPVPKPVIKIEKIEDM DDNCYLKLSCVIPGESVNYTWYGDKRPFPKELQNSVLETTLMPHNYSRCYTCQVSNSVS SKNGTVCLSPPCTLARS (SEQ ID NO: 35), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 35.

T Cell Engagers

[0696] The present disclosure provides, inter alia, multi-specific (e.g., bi-, tri-, quad-specific) proteins, that are engineered to contain one or more T cell engager that mediate binding to and/or activation of a T cell. Accordingly, in some embodiments, the T cell engager is selected from an antigen binding domain or ligand that binds to (e.g., and in some embodiments activates) one or more of CD3, TCR.alpha., TCR.beta., TCR.gamma., TCR.zeta., ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226. In other embodiments, the T cell engager is selected from an antigen binding domain or ligand that binds to and does not activate one or more of CD3, TCR.alpha., TCR.beta., TCR.gamma., TCR.zeta., ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226. In some embodiments, the T cell engager binds to CD3.

B Cell, Macrophage & Dendritic Cell Engagers

[0697] Broadly, B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present antigen (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines. Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign substances, microbes, cancer cells via phagocytosis. Besides phagocytosis, they play important roles in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. For example, they are important as antigen presenters to T cells. Beyond increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines. Dendritic cells (DCs) are antigen-presenting cells that function in processing antigen material and present it on the cell surface to the T cells of the immune system.

[0698] The present disclosure provides, inter alia, multi-specific (e.g., bi-, tri-, quad-specific) proteins, that include, e.g., are engineered to contain, one or more B cell, macrophage, and/or dendritic cell engager that mediate binding to and/or activation of a B cell, macrophage, and/or dendritic cell.

[0699] Accordingly, in some embodiments, the immune cell engager comprises a B cell, macrophage, and/or dendritic cell engager chosen from one or more of CD40 ligand (CD40L) or a CD70 ligand; an antibody molecule that binds to CD40 or CD70; an antibody molecule to OX40; an OX40 ligand (OX40L); an agonist of a Toll-like receptor (e.g., as described herein, e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4), or a TLR9 agonists); a 41BB; a CD2; a CD47; or a STING agonist, or a combination thereof.

[0700] In some embodiments, the B cell engager is a CD40L, an OX40L, or a CD70 ligand, or an antibody molecule that binds to OX40, CD40 or CD70.

[0701] In some embodiments, the macrophage engager is a CD2 agonist. In some embodiments, the macrophage engager is an antigen binding domain that binds to: CD40L or antigen binding domain or ligand that binds CD40, a Toll like receptor (TLR) agonist (e.g., as described herein), e.g., a TLR9 or TLR4 (e.g., caTLR4 (constitutively active TLR4), CD47, or a STING agonist. In some embodiments, the STING agonist is a cyclic dinucleotide, e.g., cyclic di-GMP (cdGMP) or cyclic di-AMP (cdAMP). In some embodiments, the STING agonist is biotinylated.

[0702] In some embodiments, the dendritic cell engager is a CD2 agonist. In some embodiments, the dendritic cell engager is a ligand, a receptor agonist, or an antibody molecule that binds to one or more of: OX40L, 41BB, a TLR agonist (e.g., as described herein) (e.g., TLR9 agonist, TLR4 (e.g., caTLR4 (constitutively active TLR4)), CD47, or and a STING agonist. In some embodiments, the STING agonist is a cyclic dinucleotide, e.g., cyclic di-GMP (cdGMP) or cyclic di-AMP (cdAMP). In some embodiments, the STING agonist is biotinylated.

[0703] In other embodiments, the immune cell engager mediates binding to, or activation of, one or more of a B cell, a macrophage, and/or a dendritic cell. Exemplary B cell, macrophage, and/or dendritic cell engagers can be chosen from one or more of CD40 ligand (CD40L) or a CD70 ligand; an antibody molecule that binds to CD40 or CD70; an antibody molecule to OX40; an OX40 ligand (OX40L); a Toll-like receptor agonist (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4) or a TLR9 agonist); a 41BB agonist; a CD2; a CD47; or a STING agonist, or a combination thereof.

[0704] In some embodiments, the B cell engager is chosen from one or more of a CD40L, an OX40L, or a CD70 ligand, or an antibody molecule that binds to OX40, CD40 or CD70.

[0705] In other embodiments, the macrophage cell engager is chosen from one or more of a CD2 agonist; a CD40L; an OX40L; an antibody molecule that binds to OX40, CD40 or CD70; a Toll-like receptor agonist or a fragment thereof (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4)); a CD47 agonist; or a STING agonist.

[0706] In other embodiments, the dendritic cell engager is chosen from one or more of a CD2 agonist, an OX40 antibody, an OX40L, 41BB agonist, a Toll-like receptor agonist or a fragment thereof (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4)), CD47 agonist, or a STING agonist.

[0707] In one embodiment, the OX40L comprises the amino acid sequence: QVSHRYPRIQSIKVQF TEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQ EVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGE LILIHQNPGEFCVL (SEQ ID NO: 36), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 36.

[0708] In another embodiment, the CD40L comprises the amino acid sequence: MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLY YIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFE LQPGASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 37), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 37.

[0709] In yet other embodiments, the STING agonist comprises a cyclic dinucleotide, e.g., a cyclic di-GMP (cdGMP), a cyclic di-AMP (cdAMP), or a combination thereof, optionally with 2',5' or 3',5' phosphate linkages.

[0710] In one embodiment, the immune cell engager includes 41BB ligand, e.g., comprising the amino acid sequence: ACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPL S WYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALH LQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHL SAGQRLGVHLHTEARARH AWQLTQGATVLGLFRVTPEIPAGLPSPRSE (SEQ ID NO: 38), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 38.

Toll-Like Receptors

[0711] Toll-Like Receptors (TLRs) are evolutionarily conserved receptors are homologues of the Drosophila Toll protein, and recognize highly conserved structural motifs known as pathogen-associated microbial patterns (PAMPs), which are exclusively expressed by microbial pathogens, or danger-associated molecular patterns (DAMPs) that are endogenous molecules released from necrotic or dying cells. PAMPs include various bacterial cell wall components such as lipopolysaccharide (LPS), peptidoglycan (PGN) and lipopeptides, as well as flagellin, bacterial DNA and viral double-stranded RNA. DAMPs include intracellular proteins such as heat shock proteins as well as protein fragments from the extracellular matrix. Stimulation of TLRs by the corresponding PAMPs or DAMPs initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-.kappa.B and interferon regulatory factors (IRFs). Signaling by TLRs results in a variety of cellular responses, including the production of interferons (IFNs), pro-inflammatory cytokines and effector cytokines that direct the adaptive immune response. TLRs are implicated in a number of inflammatory and immune disorders and play a role in cancer (Rakoff-Nahoum S. & Medzhitov R., 2009. Toll-like receptors and cancer. Nat Revs Cancer 9:57-63.)

[0712] TLRs are type I transmembrane proteins characterized by an extracellular domain containing leucine-rich repeats (LRRs) and a cytoplasmic tail that contains a conserved region called the Toll/IL-1 receptor (TIR) domain. Ten human and twelve murine TLRs have been characterized, TLR1 to TLR10 in humans, and TLR1 to TLR9, TLR11, TLR12 and TLR13 in mice, the homolog of TLR10 being a pseudogene. TLR2 is essential for the recognition of a variety of PAMPs from Gram-positive bacteria, including bacterial lipoproteins, lipomannans and lipoteichoic acids. TLR3 is implicated in virus-derived double-stranded RNA. TLR4 is predominantly activated by lipopolysaccharide. TLR5 detects bacterial flagellin and TLR9 is required for response to unmethylated CpG DNA. Finally, TLR7 and TLR8 recognize small synthetic antiviral molecules, and single-stranded RNA was reported to be their natural ligand. TLR11 has been reported to recognize uropathogenic E. coli and a profilin-like protein from Toxoplasma gondii. The repertoire of specificities of the TLRs is apparently extended by the ability of TLRs to heterodimerize with one another. For example, dimers of TLR2 and TLR6 are required for responses to diacylated lipoproteins while TLR2 and TLR1 interact to recognize triacylated lipoproteins. Specificities of the TLRs are also influenced by various adapter and accessory molecules, such as MD-2 and CD14 that form a complex with TLR4 in response to LPS.

[0713] TLR signaling consists of at least two distinct pathways: a MyD88-dependent pathway that leads to the production of inflammatory cytokines, and a MyD88-independent pathway associated with the stimulation of IFN-.beta. and the maturation of dendritic cells. The MyD88-dependent pathway is common to all TLRs, except TLR3 (Adachi O. et al., 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 9(1):143-50). Upon activation by PAMPs or DAMPs, TLRs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic TTR domain. Individual TLRs induce different signaling responses by usage of the different adaptor molecules. TLR4 and TLR2 signaling requires the adaptor TIRAP/Mal, which is involved in the MyD88-dependent pathway. TLR3 triggers the production of IFN-.beta. in response to double-stranded RNA, in a MyD88-independent manner, through the adaptor TRIF/TICAM-1. TRAM/TICAM-2 is another adaptor molecule involved in the MyD88-independent pathway which function is restricted to the TLR4 pathway.

[0714] TLR3, TLR7, TLR8 and TLR9 recognize viral nucleic acids and induce type I IFNs. The signaling mechanisms leading to the induction of type I IFNs differ depending on the TLR activated. They involve the interferon regulatory factors, IRFs, a family of transcription factors known to play a critical role in antiviral defense, cell growth and immune regulation. Three IRFs (IRF3, TRF5 and IRF7) function as direct transducers of virus-mediated TLR signaling. TLR3 and TLR4 activate IRF3 and IRF7, while TLR7 and TLR8 activate IRF5 and IRF7 (Doyle S. et al., 2002. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity. 17(3):251-63). Furthermore, type I IFN production stimulated by TLR9 ligand CpG-A has been shown to be mediated by PI(3)K and mTOR (Costa-Mattioli M. & Sonenberg N. 2008. RAPping production of type I interferon in pDCs through mTOR. Nature Immunol. 9: 1097-1099).

[0715] TLR-9

[0716] TLR9 recognizes unmethylated CpG sequences in DNA molecules. CpG sites are relatively rare (.about.1%) on vertebrate genomes in comparison to bacterial genomes or viral DNA. TLR9 is expressed by numerous cells of the immune system such as B lymphocytes, monocytes, natural killer (NK) cells, and plasmacytoid dendritic cells. TLR9 is expressed intracellularly, within the endosomal compartments and functions to alert the immune system of viral and bacterial infections by binding to DNA rich in CpG motifs. TLR9 signals leads to activation of the cells initiating pro-inflammatory reactions that result in the production of cytokines such as type-I interferon and IL-12.

[0717] TLR Agonists

[0718] A TLR agonist can agonize one or more TLR, e.g., one or more of human TLR-1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, an adjunctive agent described herein is a TLR agonist. In some embodiments, the TLR agonist specifically agonizes human TLR-9. In some embodiments, the TLR-9 agonist is a CpG moiety. As used herein, a CpG moiety, is a linear dinucleotide having the sequence: 5'-C-phosphate-G-3', that is, cytosine and guanine separated by only one phosphate.

[0719] In some embodiments, the CpG moiety comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more CpG dinucleotides. In some embodiments, the CpG moiety consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 CpG dinucleotides. In some embodiments, the CpG moiety has 1-5, 1-10, 1-20, 1-30, 1-40, 1-50, 5-10, 5-20, 5-30, 10-20, 10-30, 10-40, or 10-50 CpG dinucleotides.

[0720] In some embodiments, the TLR-9 agonist is a synthetic ODN (oligodeoxynucleotides). CpG ODNs are short synthetic single-stranded DNA molecules containing unmethylated CpG dinucleotides in particular sequence contexts (CpG motifs). CpG ODNs possess a partially or completely phosphorothioated (PS) backbone, as opposed to the natural phosphodiester (PO) backbone found in genomic bacterial DNA. There are three major classes of CpG ODNs: classes A, B and C, which differ in their immunostimulatory activities. CpG-A ODNs are characterized by a PO central CpG-containing palindromic motif and a PS-modified 3' poly-G string. They induce high IFN-.alpha. production from pDCs but are weak stimulators of TLR9-dependent NF-.kappa.B signaling and pro-inflammatory cytokine (e.g. IL-6) production. CpG-B ODNs contain a full PS backbone with one or more CpG dinucleotides. They strongly activate B cells and TLR9-dependent NF-.kappa.B signaling but weakly stimulate IFN-.alpha. secretion. CpG-C ODNs combine features of both classes A and B. They contain a complete PS backbone and a CpG-containing palindromic motif. C-Class CpG ODNs induce strong IFN-.alpha. production from pDC as well as B cell stimulation.

Stromal Modifying Moieties

[0721] Solid tumors have a distinct structure that mimics that of normal tissues and comprises two distinct but interdependent compartments: the parenchyma (neoplastic cells) and the stroma that the neoplastic cells induce and in which they are dispersed. All tumors have stroma and require stroma for nutritional support and for the removal of waste products. In the case of tumors which grow as cell suspensions (e.g., leukemias, ascites tumors), the blood plasma serves as stroma (Connolly J L et al. Tumor Structure and Tumor Stroma Generation. In: Kufe D W et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton: BC Decker; 2003). The stroma includes a variety of cell types, including fibroblasts/myofibroblasts, glial, epithelial, fat, vascular, smooth muscle, and immune cells along with extracellular matrix (ECM) and extracellular molecules (Li Hanchen et al. Tumor Microenvironment: The Role of the Tumor Stroma in Cancer. J of Cellular Biochemistry 101: 805-815 (2007)).

[0722] Stromal modifying moieties described herein include moieties (e.g., proteins, e.g., enzymes) capable of degrading a component of the stroma, e.g., an ECM component, e.g., a glycosaminoglycan, e.g., hyaluronan (also known as hyaluronic acid or HA), chondroitin sulfate, chondroitin, dermatan sulfate, heparin sulfate, heparin, entactin, tenascin, aggrecan and keratin sulfate; or an extracellular protein, e.g., collagen, laminin, elastin, fibrinogen, fibronectin, and vitronectin.

Stromal Modifying Enzymes

[0723] In some embodiments, the stromal modifying moiety is an enzyme. For example, the stromal modifying moiety can include, but is not limited to a hyaluronidase, a collagenase, a chondroitinase, a matrix metalloproteinase (e.g., macrophage metalloelastase).

[0724] Hyaluronidases

[0725] Hyaluronidases are a group of neutral- and acid-active enzymes found throughout the animal kingdom. Hyaluronidases vary with respect to substrate specificity, and mechanism of action. There are three general classes of hyaluronidases: (1) Mammalian-type hyaluronidases, (EC 3.2.1.35) which are endo-beta-N-acetylhexosaminidases with tetrasaccharides and hexasaccharides as the major end products. They have both hydrolytic and transglycosidase activities, and can degrade hyaluronan and chondroitin sulfates; (2) Bacterial hyaluronidases (EC 4.2.99.1) degrade hyaluronan and, and to various extents, chondroitin sulfate and dermatan sulfate. They are endo-beta-N-acetylhexosaminidases that operate by a beta elimination reaction that yields primarily disaccharide end products; (3) Hyaluronidases (EC 3.2.1.36) from leeches, other parasites, and crustaceans are endo-beta-glucuronidases that generate tetrasaccharide and hexasaccharide end products through hydrolysis of the beta 1-3 linkage.

[0726] Mammalian hyaluronidases can be further divided into two groups: (1) neutral active and (2) acid active enzymes. There are six hyaluronidase-like genes in the human genome, HYAL1, HYAL2, HYAL3 HYAL4 HYALPI and PH20/SPAM1. HYALPI is a pseudogene, and HYAL3 has not been shown to possess enzyme activity toward any known substrates. HYAL4 is a chondroitinase and lacks activity towards hyaluronan. HYAL1 is the prototypical acid-active enzyme and PH20 is the prototypical neutral-active enzyme. Acid active hyaluronidases, such as HYAL1 and HYAL2 lack catalytic activity at neutral pH. For example, HYAL1 has no catalytic activity in vitro over pH 4.5 (Frost and Stern, "A Microtiter-Based Assay for Hyaluronidase Activity Not Requiring Specialized Reagents", Analytical Biochemistry, vol. 251, pp. 263-269 (1997). HYAL2 is an acid active enzyme with a very low specific activity in vitro.

[0727] In some embodiments the hyaluronidase is a mammalian hyaluronidase. In some embodiments the hyaluronidase is a recombinant human hyaluronidase. In some embodiments, the hyaluronidase is a neutral active hyaluronidase. In some embodiments, the hyaluronidase is a neutral active soluble hyaluronidase. In some embodiments, the hyaluronidase is a recombinant PH20 neutral-active enzyme. In some embodiments, the hyaluronidase is a recombinant PH20 neutral-active soluble enzyme. In some embodiments the hyaluronidase is glycosylated. In some embodiments, the hyaluronidase possesses at least one N-linked glycan. A recombinant hyaluronidase can be produced using conventional methods known to those of skill in the art, e.g., U.S. Pat. No. 7,767,429, the entire contents of which are incorporated by reference herein.

[0728] In some embodiments the hyaluronidase is rHuPH20 (also referred to as Hylenex.RTM.; presently manufactured by Halozyme; approved by the FDA in 2005 (see e.g., Scodeller P (2014) Hyaluronidase and other Extracellular Matrix Degrading Enzymes for Cancer Therapy: New Uses and Nano-Formulations. J Carcinog Mutage 5:178; U.S. Pat. Nos. 7,767,429; 8,202,517; 7,431,380; 8,450,470; 8,772,246; 8,580,252, the entire contents of each of which is incorporated by reference herein). rHuPH20 is produced by genetically engineered CHO cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase PH20. In some embodiments the hyaluronidase is glycosylated. In some embodiments, the hyaluronidase possesses at least one N-linked glycan. A recombinant hyaluronidase can be produced using conventional methods known to those of skill in the art, e.g., U.S. Pat. No. 7,767,429, the entire contents of which are incorporated by reference herein. In some embodiments, rHuPH20 has a sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, 100%) identical to the amino acid sequence of LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDRL GYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTW ARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRP NHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQS PVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVA LGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRK NWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADV KDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLS (SEQ ID NO: 39).

[0729] In any of the methods provided herein, the anti-hyaluronan agent can be an agent that degrades hyaluronan or can be an agent that inhibits the synthesis of hyaluronan. For example, the anti-hyaluronan agent can be a hyaluronan degrading enzyme. In another example, the anti-hyaluronan agent or is an agent that inhibits hyaluronan synthesis. For example, the anti-hyaluronan agent is an agent that inhibits hyaluronan synthesis such as a sense or antisense nucleic acid molecule against an HA synthase or is a small molecule drug. For example, an anti-hyaluronan agent is 4-methylumbelliferone (MU) or a derivative thereof, or leflunomide or a derivative thereof. Such derivatives include, for example, a derivative of 4-methylumbelliferone (MU) that is 6,7-dihydroxy-4-methyl coumarin or 5,7-dihydroxy-4-methyl coumarin.

[0730] In further examples of the methods provided herein, the hyaluronan degrading enzyme is a hyaluronidase. In some examples, the hyaluronan-degrading enzyme is a PH20 hyaluronidase or truncated form thereof to lacking a C-terminal glycosylphosphatidylinositol (GPI) attachment site or a portion of the GPI attachment site. In specific examples, the hyaluronidase is a PH20 selected from a human, monkey, bovine, ovine, rat, mouse or guinea pig PH20. For example, the hyaluronan-degrading enzyme is a human PH20 hyaluronidase that is neutral active and N-glycosylated and is selected from among (a) a hyaluronidase polypeptide that is a full-length PH20 or is a C-terminal truncated form of the PH20, wherein the truncated form includes at least amino acid residues 36-464 of SEQ ID NO: 39, such as 36-481, 36-482, 36-483, where the full-length PH20 has the sequence of amino acids set forth in SEQ ID NO: 39; or (b) a hyaluronidase polypeptide comprising a sequence of amino acids having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more sequence identity with the polypeptide or truncated form of sequence of amino acids set forth in SEQ ID NO: 39; or (c) a hyaluronidase polypeptide of (a) or (b) comprising amino acid substitutions, whereby the hyaluronidase polypeptide has a sequence of amino acids having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the polypeptide set forth in SEQ ID NO: 39 or the with the corresponding truncated forms thereof. In exemplary examples, the hyaluronan-degrading enzyme is a PH20 that comprises a composition designated rHuPH20.

[0731] In other examples, the anti-hyaluronan agent is a hyaluronan degrading enzyme that is modified by conjugation to a polymer. The polymer can be a PEG and the anti-hyaluronan agent a PEGylated hyaluronan degrading enzyme. Hence, in some examples of the methods provided herein the hyaluronan-degrading enzyme is modified by conjugation to a polymer. For example, the hyaluronan-degrading enzyme is conjugated to a PEG, thus the hyaluronan degrading enzyme is PEGylated. In an exemplary example, the hyaluronan-degrading enzyme is a PEGylated PH20 enzyme (PEGPH20). In the methods provided herein, the corticosteroid can be a glucocorticoid that is selected from among cortisones, dexamethasones, hydrocortisones, methylprednisolones, prednisolones and prednisones.

[0732] Chondroitinases

[0733] Chondroitinases are enzymes found throughout the animal kingdom which degrade glycosaminoglycans, specifically chondroitins and chondroitin sulfates, through an endoglycosidase reaction. In some embodiments the chondroitinase is a mammalian chondroitinase. In some embodiments the chondroitinase is a recombinant human chondroitinase. In some embodiments the chondroitinase is HYAL4. Other exemplary chondroitinases include chondroitinase ABC (derived from Proteus vulgaris; Japanese Patent Application Laid-open No 6-153947, T. Yamagata et al. J. Biol. Chem., 243, 1523 (1968), S. Suzuki et al, J. Biol. Chem., 243, 1543 (1968)), chondroitinase AC (derived from Flavobacterium heparinum; T. Yamagata et al., J. Biol. Chem., 243, 1523 (1968)), chondroitinase AC II (derived from Arthrobacter aurescens; K. Hiyama, and S. Okada, J. Biol. Chem., 250, 1824 (1975), K. Hiyama and S. Okada, J. Biochem. (Tokyo), 80, 1201 (1976)), Hyaluronidase ACIII (derived from Flavobacterium sp. Hp102; Hirofumi Miyazono et al., Seikagaku, 61, 1023 (1989)), chondroitinase B (derived from Flavobacterium heparinum; Y. M. Michelacci and C. P. Dietrich, Biochem. Biophys. Res. Commun., 56, 973 (1974), Y. M. Michelacci and C. P. Dietrich, Biochem. J., 151, 121 (1975), Kenichi Maeyama et al, Seikagaku, 57, 1189 (1985)), chondroitinase C (derived from Flavobacterium sp. Hp102; Hirofumi Miyazono et al, Seikagaku, 61, 1023 (1939)), and the like.

[0734] Matrix Metalloproteinases

[0735] Matrix metalloproteases (MMPs) are zinc-dependent endopeptidases that are the major proteases involved in extracellular matrix (ECM) degradation. MMPs are capable of degrading a wide range of extracellular molecules and a number of bioactive molecules. Twenty-four MMP genes have been identified in humans, which can be organized into six groups based on domain organization and substrate preference: Collagenases (MMP-1, -8 and -13), Gelatinases (MMP-2 and MMP-9), Stromelysins (MMP-3, -10 and -11), Matrilysin (MMP-7 and MMP-26), Membrane-type (MT)-MMPs (MMP-14, -15, -16, -17, -24 and -25) and others (MMP-12, -19, -20, -21, -23, -27 and -28). In some embodiments, the stromal modifying moiety is a human recombinant MMP (e.g., MMP-1, -2, -3, -4, -5, -6, -7, -8, -9, 10, -11, -12, -13, -14, 15, -15, -17, -18, -19, 20, -21, -22, -23, or -24).

[0736] Collagenases

[0737] The three mammalian collagenases (MMP-1, -8, and -13) are the principal secreted endopeptidases capable of cleaving collagenous extracellular matrix. In addition to fibrillar collagens, collagenases can cleave several other matrix and non-matrix proteins including growth factors. Collagenases are synthesized as inactive pro-forms, and once activated, their activity is inhibited by specific tissue inhibitors of metalloproteinases, TIMPs, as well as by non-specific proteinase inhibitors (Ala-aho R et al. Biochimie. Collagenases in cancer. 2005 March-April; 87(3-4):273-86). In some embodiments, the stromal modifying moiety is a collagenase. In some embodiments, the collagenase is a human recombinant collagenase. In some embodiments, the collagenase is MMP-1. In some embodiments, the collagenase is MMP-8. In some embodiments, the collagenase is MMP-13.

[0738] Macrophage Metalloelastase

[0739] Macrophage metalloelastase (MME), also known as MMP-12, is a member of the stromelysin subgroup of MMPs and catalyzes the hydrolysis of soluble and insoluble elastin and a broad selection of matrix and nonmatrix substrates including type IV collagen, fibronectin, laminin, vitronectin, entactin, heparan, and chondroitin sulfates (Erja Kerkela et al. Journal of Investigative Dermatology (2000) 114, 1113-1119; doi:10.1046/j.1523-1747.2000.00993). In some embodiments, the stromal modifying moiety is a MME. In some embodiments, the MME is a human recombinant MME. In some embodiments, the MME is MMP-12.

Exemplary Multispecific Molecules

[0740] The disclosure relates, inter alia, to novel multispecific molecules that include (i) a tumor-targeting moiety; and one or both of: (ii) an immune cell engager (e.g., chosen from one, two, three, or all of an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); and/or (iii) a cytokine molecule. Without being bound by theory, the multispecific molecules disclosed herein are expected to target (e.g., localize, bridge and/or activate) an immune cell (e.g., an immune effector cell chosen from an NK cell, a B cell, a dendritic cell or a macrophage), at a cancer cell. Increasing the proximity and/or activity of the immune cell using the multispecific molecules described herein is expected to enhance an immune response against the cancer cell, thereby providing a more effective cancer therapy. Accordingly, provided herein are, inter alia, multispecific molecules (e.g., multispecific antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

[0741] Accordingly, in one aspect, the disclosure features a multispecific molecule that includes:

[0742] (i) a tumor-targeting moiety, e.g., that binds to a cancer antigen (e.g., a solid tumor antigen, a stromal antigen, or a hematological antigen); and

[0743] one or two of the following:

[0744] (ii) an immune cell engager, e.g., chosen from one, two, three, or all of an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager; or

[0745] (iii) a cytokine molecule.

[0746] In one embodiment, the multispecific molecule includes two binding specificities or functions, e.g., it is a bispecific or a bifunctional molecule, e.g., which includes:

[0747] i) the tumor-targeting moiety and the cytokine molecule; or

[0748] ii) the tumor-targeting moiety and the immune cell engager.

[0749] In other embodiments, the multispecific molecule includes three or four binding specificities or functions, e.g., it is a trispecific or a tetraspecific molecule. Exemplary trispecific and tetraspecific molecules include:

[0750] (i) one tumor-targeting moiety, one immune cell engager, and one cytokine molecule;

[0751] (ii) one tumor-targeting moiety and two immune cell engagers (e.g., same or different immune cell engagers);

[0752] (iii) one tumor-targeting moiety and two cytokines (e.g., same or different cytokines);

[0753] (iv) one tumor-targeting moiety, two immune cell engagers (e.g., same or different immune cell engagers), and one cytokine molecule;

[0754] (v) one tumor-targeting moiety, one immune cell engager, and two cytokine molecules (e.g., same or different cytokine molecules);

[0755] (vi) one tumor-targeting moiety and three immune cell engagers (e.g., same or different immune cell engagers);

[0756] (vii) one tumor-targeting moiety and three cytokine molecules (e.g., same or different cytokine molecules);

[0757] (viii) two tumor-targeting moieties (e.g., same or different targeting moieties) and one immune cell engager;

[0758] (ix) two tumor-targeting moieties (e.g., same or different targeting moieties) and one cytokine molecule; and

[0759] (ix) two tumor-targeting moieties (e.g., same or different targeting moieties), one immune cell engager, and one cytokine molecule.

[0760] In some embodiments, the multispecific molecule includes a single chain antibody molecule, e.g., a single domain antibody, a scFv, a camelid, or a shark antibody, and a second moiety. In some embodiments, the multispecific molecule comprises a VH to VL from N to C orientation, of the scFv connected, optionally via a linker, to the second moiety (e.g., as shown in FIGS. 1A and 1B); the scFv can form the first binding specificity (depicted as binding moiety "1" in FIGS. 1A-1B). In some embodiments, the second moiety (depicted as partner A in FIGS. 1A-1B) is located before the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1A), or after the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1B); the second moiety can form the second binding specificity (depicted as binding moiety "2" in FIGS. 1A-1B). In other embodiments, the multispecific molecule comprises a VL to VH from N to C orientation, of the scFv connected, optionally via a linker, to the second moiety (e.g., as shown in FIGS. 2A and 2B); the scFv can form the first binding specificity (depicted as binding moiety "1" in FIGS. 2A-2B). In some embodiments, the second moiety (depicted as partner A in FIGS. 2A-2B) is located before the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2A), or after the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2B); the second moiety can form the second binding specificity (depicted as binding moiety "2" in FIGS. 2A-2B). In embodiments, the scFv can be a tumor targeting moiety (e.g., binds to a cancer antigen, e.g., a solid tumor, stromal, or hematological antigen), or can be an immune cell engager (e.g., binds to an immune cell antigen). In other embodiments, the second moiety (e.g., depicted as partner A in FIGS. 1A-1B or 2A-2B) is a tumor targeting moiety (e.g., in embodiments where the scFv is not the tumor targeting moiety), an immune cell engager (e.g., in embodiments where the scFv is not the immune cell engager), or a cytokine molecule (e.g., as described herein). In embodiments, partner A can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the tumor-targeting moiety is a scFv to a cancer cell antigen, and the second moiety is chosen from a cytokine molecule or an immune cell engager. In some embodiments, the second moiety is a second antibody molecule (e.g., a second scFv or Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule).

[0761] In other embodiments, the multispecific molecule is a trispecific or trifunctional that includes, or consists of, a single chain polypeptide, e.g., a contiguous single polypeptide chain. For example, the multispecific molecule can include a tumor targeting moiety (e.g., a first binding specificity to a cancer antigen, e.g., a solid tumor, stromal, or hematological antigen as described herein), a cytokine molecule as described herein, and an immune cell engager (e.g., a second binding specificity to an immune cell antigen as described herein), or any combination of at least 2 of any of the aforesaid.

[0762] In some embodiments, the multispecific molecule includes a single chain antibody molecule, e.g., a single domain antibody, a scFv, a camelid, or a shark antibody, and a second moiety. In some embodiments, the multispecific molecule comprises a VH to VL from N to C orientation, of the scFv connected, optionally via a linker, to a second moiety and/or a third moiety (e.g., as shown in FIG. 1C); the scFv can form the first binding specificity (depicted as binding moiety "1" in FIG. 1C). In some embodiments, the second or third moieties (depicted as partners A and B in FIG. 1C) is located before the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1C) and the third moiety (partner B) after the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1C), respectively; the second and third moieties can form the second and third binding specificities (depicted as binding moiety "2" and binding moiety "3," respectively, in FIG. 1C). In other embodiments, the multispecific molecule comprises a VL to VH from N to C orientation, of the scFv connected, optionally via a linker, to a second moiety and/or a third moiety (e.g., as shown in FIG. 2C). In some embodiments, the second moiety (depicted as partner A in FIG. 2C) is located before the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2C), and the third moiety (partner B) after the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2C); the second and third moieties can form the second and third binding specificities (depicted as binding moiety "2" and binding moiety "3," respectively, in FIG. 2C). In embodiments, the scFv of any of the aforesaid multispecific molecules can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a solid tumor, stromal or hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety and third moiety (e.g., depicted as partner A and partner B in FIG. 1C or 2C) is independently chosen from a tumor targeting moiety, an immune cell engager, or a cytokine molecule (e.g., as described herein). In embodiments, partner A and/or partner B can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv or a Fab), a receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the tumor-targeting moiety is a scFv to a cancer cell antigen, and the second moiety and third moiety is independently chosen from a cytokine molecule or an immune cell engager. In some embodiments, the second and third moiety is independently chosen from a second antibody molecule (e.g., a second scFv or Fab), a receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule).

[0763] In some embodiments, the multispecific molecule does not consist of a single chain polypeptide of an NK cell engager (i.e., a scFv) that binds to CD16 (FcTRIII), and a tumor targeting moiety, i.e., a scFv targeting CD33. In other embodiments, the multispecific molecule does not consist of a single chain polypeptide of the scFv that binds to CD16, an IL-15 cytokine, and the scFv targeting CD33.

[0764] In embodiments, the multispecific molecule is a bispecific or bifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In embodiments, the first and second polypeptides have a configuration as shown in FIGS. 3A-3B or FIGS. 4A-4B. In embodiments, the first and second polypeptides form a first binding specificity, e.g., an antigen binding domain (e.g., depicted as binding moiety "1" in FIGS. 3A-3B and FIGS. 4A-4B). In embodiments, a second moiety (depicted as partner A) is connected, e.g., via a linker, to either the first polypeptide or the second polypeptide. In embodiments, the second moiety forms a second binding specificity (e.g., depicted as binding moiety "2" in FIGS. 3A-3B and FIGS. 4A-4B).

[0765] In one embodiment depicted in FIGS. 3A-3B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the C-terminus of the second polypeptide (e.g., the C-terminus of the CL region of the second polypeptide) (e.g., as shown in FIG. 3A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the C-terminus of the first polypeptide (e.g., C-terminus of the CH1 region of the first polypeptide) (e.g., as shown in FIG. 3B).

[0766] In another embodiment depicted in FIGS. 4A-4B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the N-terminus of the second polypeptide (e.g., the N-terminus of the VL region of the second polypeptide) (e.g., as shown in FIG. 4A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the N-terminus of the first polypeptide (e.g., the N-terminus of the VH region of the first polypeptide) (e.g., as shown in FIG. 4B).

[0767] In embodiments, the first and second polypeptide (e.g., the VH and VL regions) can form a binding moiety (e.g., binding moiety 1 in FIGS. 3A-3B and 4A-4B); for example, the first and second polypeptide can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a solid tumor, a stromal or hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety (e.g., depicted as partner A in FIGS. 3A-3B and 4A-4B) forms a second binding moiety, e.g., it is chosen from a tumor targeting moiety, an immune cell engager, or a cytokine molecule (e.g., as described herein). In embodiments, the second moiety, e.g., partner A, can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the multispecific molecule includes a Fab molecule and the second moiety is chosen from a second antibody molecule (e.g., a scFv or a second Fab), a receptor molecule, or a receptor ligand molecule, or a cytokine molecule. In one embodiment, the tumor-targeting moiety is a Fab to a cancer cell antigen, and the second moiety is chosen from a cytokine molecule or an immune cell engager. In some embodiments, the second moiety is a second antibody molecule (e.g., a second scFv or Fab), a receptor molecule, or a receptor ligand molecule, or a cytokine molecule.

[0768] In embodiments, the multispecific molecule is a bispecific or bifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In embodiments, the first and second polypeptides have a configuration as shown in FIGS. 3A-3B or FIGS. 4A-4B. In embodiments, a second moiety (depicted as partner A) is connected, e.g., via a linker, to either the first polypeptide or the second polypeptide (e.g., either the N-terminus or the C-terminus of the first polypeptide or the second polypeptide).

[0769] In one embodiment of the bispecific or bifunctional molecule depicted in FIGS. 3A-3B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the CL region (e.g., C-terminus of the CL region) of the second polypeptide (e.g., as shown in FIG. 3A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the CH1 region (e.g., C-terminus of the CH1 region) of the first polypeptide (e.g., as shown in FIG. 3B).

[0770] In another embodiment of the bispecific or bifunctional molecule depicted in FIGS. 4A-4B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the VL region (e.g., N-terminus of the VL region) of the second polypeptide (e.g., as shown in FIG. 4A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the VH region (e.g., N-terminus of the VH region) of the first polypeptide (e.g., as shown in FIG. 4B).

[0771] In embodiments of the bispecific or bifunctional molecule, the first and second polypeptide (e.g., the VH and VL regions) can form a binding moiety (e.g., binding moiety 1 in FIGS. 3A-3B and 4A-4B); for example, the first and second polypeptide can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a tumor, a stromal or a hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety (e.g., depicted as partner A in FIGS. 3A-3B and 4A-4B) forms a second binding moiety, e.g., it is chosen from a tumor targeting moiety, an immune cell engager, or a cytokine molecule (e.g., as described herein). In embodiments, the second moiety, e.g., partner A, can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the multispecific molecule includes a Fab molecule and the second moiety is chosen from a second antibody molecule (e.g., a scFv or a second Fab), a receptor molecule, or a ligand molecule (e.g., a cytokine molecule). In one embodiment, the tumor-targeting moiety is a Fab to a cancer cell antigen, and the second moiety is chosen from a cytokine molecule or an immune cell engager. In some embodiments, the second moiety is a second antibody molecule (e.g., a second scFv or Fab), a receptor molecule, a receptor ligand molecule, or a cytokine molecule.

[0772] In other embodiments, the multispecific molecule is a trispecific or a trifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In embodiments, the first and second polypeptides have a configuration as shown in FIGS. 3C and 4C. In embodiments, a second moiety and a third moiety (depicted as partners A and B, respectively) are connected, e.g., via a linker, to the C-terminus, the N-terminus, or both of the first polypeptide and the second polypeptide, respectively. In one embodiment, the second moiety and third moieties are connected to C-terminus of the second and first polypeptides (or the first and second polypeptides), respectively. In another embodiment, the second moiety and third moieties are connected to N-terminus of the second and first polypeptides (or the first and second polypeptides), respectively. In one embodiment, the second moiety and third moiety are connected to N- and C-terminus of the second and first polypeptides (or the first and second polypeptides), respectively. Any configuration is intended by the present disclosure, including those exemplified in FIGS. 3C and 4C.

[0773] In one embodiment of the trispecific or trifunctional molecule depicted in FIGS. 3C-4C, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the C-terminus of the second polypeptide (e.g., the C-terminus of the CL region of the second polypeptide) (e.g., as shown in FIG. 3C), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the C-terminus of the first polypeptide (e.g., the C-terminus of the CH1 region of the first polypeptide) (e.g., as shown in FIG. 3C).

[0774] In another embodiment of the trispecific or trifunctional molecule depicted in FIGS. 3C-4C, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the N-terminus of the second polypeptide (e.g., the N-terminus of the VL region of the second polypeptide) (e.g., as shown in FIG. 4C), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the N-terminus of the first polypeptide (e.g., the N-terminus of the VH region of the first polypeptide) (e.g., as shown in FIG. 4C).

[0775] In another embodiment of the trispecific or trifunctional molecule, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the N-terminus of the second polypeptide (e.g., the N-terminus of the VL region of the second polypeptide), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the C-terminus of the first polypeptide (e.g., the C-terminus of the CH1 region of the first polypeptide).

[0776] In another embodiment of the trispecific or trifunctional molecule, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the C-terminus of the second polypeptide (e.g., the N-terminus of the CL region of the second polypeptide), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the N-terminus of the first polypeptide (e.g., the N-terminus of the VH region of the first polypeptide).

[0777] In embodiments of the trispecific or trifunctional molecule, the first and second polypeptides (e.g., the VH and VL regions) can form a first binding specificity (e.g., binding moiety "1" in FIGS. 3C and 4C); for example, the first and second polypeptide can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a solid tumor, a stromal or a hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety and the third moiety (e.g., depicted as partners A and B in FIGS. 3C and 4C) form a second and a third binding specificity, e.g., it is independently chosen from a tumor targeting moiety, an immune cell engager, or a cytokine molecule (e.g., as described herein). In embodiments, the second and a third binding specificity, e.g., partners A and B, can be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the multispecific molecule includes a Fab molecule and the second moiety and third moiety is, independently, chosen from a second antibody molecule (e.g., a scFv or a second Fab), a receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule). In some embodiments, the first binding specificity, the second binding specificity and the third binding specificity can each be independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In one embodiment, the tumor-targeting moiety is a Fab to a cancer cell antigen, and the second and third moiety is independently chosen from a cytokine molecule or an immune cell engager. In one embodiment, the tumor-targeting moiety is a Fab to a cancer cell antigen; the second moiety is a cytokine molecule; and the third moiety is an immune cell engager.

[0778] In one embodiment, the multispecific molecule includes at least two or at least three or at least four non-contiguous polypeptides, wherein:

[0779] (i) the first polypeptide includes from N- to C-orientation a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region); and

[0780] (ii) the second polypeptide includes from N- to C-orientation a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region).

[0781] In embodiments, the multispecific molecule is a bispecific or bifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In some embodiments, the first and second polypeptides (i) and (ii) include a paired amino acid substitution at a position chosen from one or more of 347, 349, 350, 351, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407, or 409, e.g., of the Fc region of human IgG1 For example, the first immunoglobulin chain constant region (e.g., the first Fc region) can include an amino acid substitution chosen from: T366S, L368A, or Y407V (e.g., corresponding to a cavity or hole), and the second immunoglobulin chain constant region (e.g., the second Fc region) includes a T366W (e.g., corresponding to a protuberance or knob). In some embodiments, the first and second polypeptides are a first and second member of a heterodimeric first and second Fc region.

[0782] In embodiments, the first and second polypeptides form a bispecific molecule. In some embodiments, the first polypeptide includes a first binding specificity (e.g., partner A or binding specificity 1 in FIG. 5A), and the second polypeptide includes a second binding specificity (e.g., partner B or binding specificity 2 in FIG. 5A). In embodiments, the first and second binding specificities (partner A and partner B, respectively) is each independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In embodiments, the first and second binding specificities are connected to either the first or the second polypeptide, or each of the polypeptides, (e.g., one or both members of a heterodimeric Fc molecule). In one embodiment, the first binding specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule), and the second binding specificity (e.g., partner B) is connected to the N-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). Alternatively, the first binding specificity (e.g., partner A) is connected to the C-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule), and the second binding specificity (e.g., partner B) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). Alternatively, the first binding specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule), and the second binding specificity (e.g., partner B) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). In other embodiments, the second binding specificity (e.g., partner B) is connected to N-terminus of the first polypeptide (e.g., the --CH2-CH3- region of the first Fc molecule), and the first binding specificity (e.g., partner A) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). In one embodiment, the first --CH2-CH3 region includes a protuberance or knob, and the second --CH2-CH3 region includes a cavity or hole, e.g., as depicted in FIG. 5A).

[0783] In some embodiments, the first and second binding specificities (binding moiety 1 and binding moiety 2) of the bispecific molecule can each be independently chosen from a tumor targeting moiety, a cytokine molecule, a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the first binding specificity is a tumor targeting moiety and the second binding specificity is chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0784] In some embodiments shown in FIG. 5A, the bispecific molecule can have partner A and B, which are depicted as first and second binding specificities (binding moieties 1 and 2), respectively (FIG. 5A). The first and second binding specificities can be, each independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In some embodiments, the first binding specificity is a tumor targeting moiety and the second binding specificity is chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0785] In embodiments, the first and second polypeptides form a trispecific or tetraspecific molecule (e.g., as depicted in FIGS. 5B-5C, respectively).

[0786] In some embodiments of the trispecific molecule, the first polypeptide includes a first binding specificity (e.g., partner A or binding moiety 1 in FIG. 5B), and the second polypeptide includes a second binding specificity (e.g., partner B or binding specificity 2 in FIG. 5B), wherein either the first or the second polypeptide further includes a third binding specificity (e.g., partner C or binding moiety 3 in FIG. 5B). In embodiments, the first and second binding specificities are connected to either the first or the second polypeptide, or each of the polypeptides, (e.g., one or both members of a heterodimeric Fc molecule). In one embodiment, the first and second binding specificities are connected, e.g., via a linker, to the N-terminus of the first and the second polypeptide, respectively, and the third binding specificity is connected, e.g., via a linker, to the C-terminal end of either the first or the second polypeptide. In one embodiment, the third binding specificity is connected, e.g., via a linker, to the C-terminal end of the first polypeptide (e.g., the C-terminal end of the first --CH2-CH3 region depicted in FIG. 5B). In one embodiment, the third binding specificity is connected, e.g., via a linker, to the C-terminal end of the second polypeptide (e.g., the C-terminal end of the second --CH2-CH3 region). In one embodiment, the first --CH2-CH3 region includes a protuberance or knob, and the second --CH2-CH3 region includes a hole or cavity, e.g., as depicted in FIG. 5B).

[0787] In embodiments, the first, second and third binding specificities (partner A, partner B, and partner C respectively) is each independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the first binding specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule); the second binding specificity (e.g., partner B) is connected to the N-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule); and the third binding specificity (e.g., partner C) is connected to the C-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). In other embodiments, the first binding specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule); the second binding specificity (e.g., partner B) is connected to the N-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule); and the third binding specificity (e.g., partner C) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). The first, second and third binding specificities can each be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second and third binding specificities (partners A-C, corresponding to binding moieties 1-3, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In embodiments, the first binding specificity is a tumor targeting moiety and the second and third binding specificity are each independently chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0788] In some embodiments of the tetraspecific molecule, the first polypeptide includes a first binding specificity (e.g., partner A or binding moiety 1 in FIG. 5C) and a third binding specificity (e.g., partner C or binding moiety 3 in FIG. 5C), and the second polypeptide includes a second binding specificity (e.g., partner B or binding specificity 2 in FIG. 5C) and a fourth binding specificity (e.g., partner D or binding moiety 4 in FIG. 5C). In one embodiment, the first and second binding specificities are connected, e.g., via a linker, to the N-terminus of the first and the second polypeptide, respectively, and the third and fourth binding specificities are connected, e.g., via a linker, to the C-terminal end of the first and the second polypeptide, respectively. Any permutation of binding specificity to the N- or C-terminus of the first or second polypeptide is encompassed by the present disclosure. In one embodiment, the first binding specificity (e.g., partner A) is connected, e.g., via a linker, to the N-terminal end of the first polypeptide (e.g., the N-terminal end of the first --CH2-CH3 region depicted in FIG. 5C); the second binding specificity (e.g., partner B) is connected, e.g., via a linker, to the N-terminal end of the second polypeptide (e.g., the N-terminal end of the second --CH2-CH3 region depicted in FIG. 5C); the third binding specificity (e.g., partner C) is connected, e.g., via a linker, to the C-terminal end of the first polypeptide (e.g., the C-terminal end of the first --CH2-CH3 region depicted in FIG. 5C); and the fourth binding specificity (e.g., partner D) is connected, e.g., via a linker, to the C-terminal end of the second polypeptide (e.g., the C-terminal end of the second -CH2-CH3 region). In one embodiment, the first --CH2-CH3 region includes a protuberance or knob, and the second --CH2-CH3 region includes a cavity or hole, e.g., as depicted in FIG. 5C). In embodiments, the first, second, third and fourth binding specificities (partner A, partner B, partner C and partner D, respectively) is each independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. The first, second, third and fourth binding specificities can each be, independently, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second, third and fourth binding specificities (partners A-D, corresponding to binding moieties 1-4, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In embodiments, the first binding specificity is a tumor targeting moiety and the second, third and fourth binding specificities are each independently chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[0789] In one embodiment, the multispecific molecule is a bispecific molecule that includes two non-contiguous first and second polypeptides. In embodiments, the first and second polypeptides, include, respectively, a first and a second binding sites, which are independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first and second binding specificities (binding sites 1-2, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In some embodiments, the first polypeptide has the following configuration from N-to-C: a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a tumor or stromal antigen (e.g., binding site #1), connected, optionally, via a linker to, a second binding specificity (e.g., a binding site #2); and the second polypeptide has the following configuration from N-to-C: a second portion of a first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a cancer antigen (e.g., the same cancer antigen bound by the first VH-CH1, e.g., binding site #1) (e.g., an example of this configuration is depicted in FIG. 6). In one embodiment, the bispecific molecule that includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the second binding specificity (e.g., binding site #2). In some embodiments, the first binding specificity (e.g., binding site #1 in FIG. 6) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; and the second binding specificity (e.g., binding site #2 in FIG. 6) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a receptor ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0790] In another embodiment, the multispecific molecule is a bispecific molecule that includes two or at least three non-contiguous first and second polypeptides, wherein:

[0791] (i) the first polypeptide includes from N- to C-orientation a first binding specificity, e.g., a first antibody molecule, connected, optionally via a linker, to a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region);

[0792] (ii) the second polypeptide includes from N- to C-orientation a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region); and

[0793] (optionally) (iii) a third polypeptide comprising a portion of the first antibody molecule or a second antibody molecule.

[0794] In embodiments, the first and second polypeptides, include, respectively, a first and a second binding specificities (e.g., sites), which are independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first and second binding specificities (binding sites 1-2, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0795] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[0796] (a) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a cancer antigen, e.g., a solid tumor, stromal or hematological antigen (e.g., binding site #1), connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., a first Fc region);

[0797] (b) a second binding specificity (e.g., a second binding site), which is chosen from a cytokine molecule, or an immune cell engager, connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and

[0798] (c) the third polypeptide has the following configuration from N-to-C: a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a cancer antigen, e.g., a solid tumor, stromal or hematological antigen (e.g., the same cancer antigen bound by the first VH-CH1, e.g., binding site #1) (e.g., an example of this configuration is depicted in FIG. 7).

[0799] In one embodiment, the bispecific molecule that includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the first Fc region, and the second binding specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region. In some embodiments, the first binding specificity (e.g., binding site #1 in FIG. 7) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; and the second binding specificity (e.g., binding site #2 in FIG. 7) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0800] In embodiments, the first immunoglobulin constant region (e.g., the first CH2-CH3 region) includes a protuberance or knob, e.g., as described herein.

[0801] In embodiments, the second immunoglobulin constant region (e.g., the second CH2-CH3 region) includes a cavity or hole. In embodiments, the first and second immunoglobulin constant region promote heterodimerization of the bispecific molecule.

[0802] In one embodiment, the multispecific molecule is a trispecific molecule that includes two non-contiguous first and second polypeptides. In embodiments, the first and second polypeptides, include, respectively, a first, a second and a third binding specificities, which are independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second and third binding specificities (binding sites 1-3, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0803] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[0804] (i) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a tumor or stromal antigen (e.g., binding site #1), connected, optionally, via a linker to, a second binding specificity (e.g., a binding site #3, e.g., a cytokine, a ligand or a second antibody molecule, e.g., a scFv); and

[0805] (ii) the second polypeptide has the following configuration from N-to-C: a second portion of a first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1, e.g., binding site #1), connected, optionally, via a linker to, a third binding specificity (e.g., a binding site #2, e.g., a cytokine, a ligand or a second antibody molecule, e.g., a scFv) (e.g., an example of this configuration is depicted in FIGS. 8A-8C).

[0806] In one embodiment, the bispecific molecule that includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the second and third binding specificities (e.g., binding sites #2 and #3). In some embodiments, the first binding specificity (e.g., binding site #1 in FIGS. 8A-8C) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; and the second and third binding specificity (e.g., binding sites #2 and #3 in FIGS. 8A-8C) are independently chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In one embodiment, the first binding specificity (e.g., binding site #1 in FIG. 8A) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; the second binding specificity (e.g., binding site #3 in FIG. 8A) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and the third binding specificity (e.g., binding site #2 in FIG. 8A) is an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In other embodiments, the first binding specificity (e.g., binding site #1 in FIG. 8B) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; the second binding specificity (e.g., binding site #3 in FIG. 8B) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and the third binding specificity (e.g., binding site #2 in FIG. 8B) is a ligand or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In other embodiments, the first binding specificity (e.g., binding site #1 in FIG. 8C) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; the second binding specificity (e.g., binding site #3 in FIG. 8C) is an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and the third binding specificity (e.g., binding site #2 in FIG. 8C) is a ligand or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0807] In another embodiment, the multispecific molecule is a trispecific molecule that includes two or at least three non-contiguous first and second polypeptides, wherein:

[0808] (i) the first polypeptide includes from N- to C-orientation a first binding specificity, e.g., a first antibody molecule, connected, optionally via a linker, to a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region);

[0809] (ii) the second polypeptide includes from N- to C-orientation a second binding specificity connected, optionally via a linker, to a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region); and

[0810] (optionally) (iii) a third polypeptide comprising a portion of the first antibody molecule or a second antibody molecule,

[0811] wherein either the first or the second polypeptide further includes a third binding specificity.

[0812] In embodiments, the first and second polypeptides, include, respectively, a first, a second, and a third binding specificities (e.g., sites), which are independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second and third binding specificities (binding sites 1-3, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0813] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[0814] (a) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a tumor or stromal antigen (e.g., binding site #1), connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., a first Fc region);

[0815] (b) a second binding specificity (e.g., a second binding site), which is chosen from a cytokine molecule, or an immune cell engager, connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and

[0816] (c) the third polypeptide has the following configuration from N-to-C: a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1, e.g., binding site #1),

[0817] wherein either the first or the second polypeptide further includes a third binding specificity, which is connected, optionally, via a linker to, the first or second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first or second Fc region).

[0818] In one embodiment, the third binding specificity is connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first Fc region). In another embodiment, the third binding specificity is connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region). Examples of these configurations are depicted in FIGS. 9A-9B.

[0819] In one embodiment, the trispecific molecule includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the first Fc region; and the second binding specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region, which further includes the third binding specificity (e.g., binding site #3) (e.g., as depicted in FIG. 9A). In other embodiments, the trispecific molecule includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the first Fc region, which further includes the third binding specificity (e.g., binding site #3); and the second binding specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region (e.g., as depicted in FIG. 9B).

[0820] In some embodiments, (a) the first binding specificity (e.g., binding site #1 in FIGS. 9A-9B) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; (b) the second binding specificity (e.g., binding site #2 in FIGS. 9A-9B) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and (c) the third binding specificity (e.g., binding site #3 in FIGS. 9A-9B) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0821] In embodiments, the first immunoglobulin constant region (e.g., the first CH2-CH3 region) includes a protuberance or knob, e.g., as described herein.

[0822] In embodiments, the second immunoglobulin constant region (e.g., the second CH2-CH3 region) includes a cavity or hole. In embodiments, the first and second immunoglobulin constant region promote heterodimerization of the bispecific molecule.

[0823] In another embodiment, the multispecific molecule is a tetraspecific molecule that includes two or at least three non-contiguous first and second polypeptides, wherein:

[0824] (i) the first polypeptide includes from N- to C-orientation a first binding specificity, e.g., a first antibody molecule, connected, optionally via a linker, to a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region);

[0825] (ii) the second polypeptide includes from N- to C-orientation a second binding specificity connected, optionally via a linker, to a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region); and

[0826] (optionally) (iii) a third polypeptide comprising a portion of the first antibody molecule or a second antibody molecule,

[0827] wherein the first or the second polypeptide further includes a third and a fourth binding specificities.

[0828] In embodiments, the first and second polypeptides, include, respectively, a first, a second, a third and a fourth binding specificities (e.g., sites), which are independently chosen from an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second, third and fourth binding specificities (binding sites 1-4, respectively) are each independently chosen from a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[0829] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[0830] (a) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a tumor or stromal antigen (e.g., binding site #1), connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., a first Fc region);

[0831] (b) a second binding specificity (e.g., a second binding site), which is chosen from a cytokine molecule, or an immune cell engager, connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and

[0832] (c) the third polypeptide has the following configuration from N-to-C: a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1, e.g., binding site #1),

[0833] wherein the first and the second polypeptide further includes a third and a fourth binding specificity, respectively, each of which is connected, optionally, via a linker to, the first and second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first and second Fc region). In one embodiment, the third binding specificity is connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and the fourth binding specificity is connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first Fc region). Examples of these configurations are depicted in FIGS. 10A-10C.

[0834] In one embodiment, the tetraspecific molecule includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the first Fc region, which further includes a fourth binding specificity (e.g., binding site #4); and the second binding specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region, which further includes the third binding specificity (e.g., binding site #3) (e.g., as depicted in FIG. 10A). In other embodiments, the tetraspecific molecule includes a Fab corresponding to the first binding specificity (binding site #1) connected, optionally via a linker, to the first Fc region, which further includes a third binding specificity (e.g., binding site #3); and the second binding specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region, which further includes the fourth binding specificity (e.g., binding site #4).

[0835] In some embodiments, (a) the first binding specificity (e.g., binding site #1 in FIGS. 10A-10C) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; and the second, third and fourth binding specificities (e.g., binding sites #2-4 in FIG. 10A) are each independently chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0836] In one embodiment, (a) the first binding specificity (e.g., binding site #1 in FIG. 10B) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; (b) the second binding specificity (e.g., binding site #2 in FIG. 10B) is an immune cell engager (e.g., an NK cell engager) chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; (c) the third binding specificity (e.g., binding site #3 in FIG. 10B) is a cytokine molecule or an immune cell engager; and (d) the fourth binding specificity (e.g., binding site #4 in FIG. 10B) is an immune cell engager (e.g., a macrophage or a dendritic cell engager) chosen from a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0837] In one embodiment, (a) the first binding specificity (e.g., binding site #1 in FIG. 10C) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen;

[0838] (b) the second binding specificity (e.g., binding site #2 in FIG. 10C) is an immune cell engager (e.g., an NK cell engager) chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; (c) the third binding specificity (e.g., binding site #3 in FIG. 10C) is an immune cell engager (e.g., a macrophage or a dendritic cell engager) chosen from a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and (d) the fourth binding specificity (e.g., binding site #4 in FIG. 10C) is an immune cell engager (e.g., a macrophage or a dendritic cell engager) chosen from a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[0839] In embodiments, the first immunoglobulin constant region (e.g., the first CH2-CH3 region) includes a protuberance or knob, e.g., as described herein.

[0840] In embodiments, the second immunoglobulin constant region (e.g., the second CH2-CH3 region) includes a cavity or hole. In embodiments, the first and second immunoglobulin constant region promote heterodimerization of the bispecific molecule.

Tumor-Targeting Moieties

[0841] In one embodiment, the tumor-targeting moiety includes an antibody molecule (e.g., Fab or scFv) that binds to mesothelin. In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from the heavy chain variable domain sequence of: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSS (SEQ ID NO: 1), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 1.

[0842] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs selected from GYSFTGYTMN (SEQ ID NO: 2); LITPYNGASSYNQKFRG (SEQ ID NO: 3); and GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0843] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 comprises GYSFTGYTMN (SEQ ID NO: 2); CDR2 comprises: LITPYNGASSYNQKFRG (SEQ ID NO: 3); and CDR3 comprises GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0844] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 consists of GYSFTGYTMN (SEQ ID NO: 2); CDR2 consists of LITPYNGASSYNQKFRG (SEQ ID NO: 3); and CDR3 consists of GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0845] In embodiments, the antibody molecule to mesothelin includes the heavy chain variable domain sequence of: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSS (SEQ ID NO: 1), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 1. In embodiments, the antibody molecule to mesothelin is a Fab and further comprises a heavy chain constant region (CH1) having the amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT (SEQ ID NO: 5), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence:

TABLE-US-00002 (SEQ ID NO: 6) MEFGLSWVFLVALFRGVQC.

[0846] Alternatively, or in combination with the heavy chain to mesothelin disclosed herein, the antibody molecule to mesothelin comprises one, two, three CDRs from the light chain variable domain sequence of: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIK (SEQ ID NO: 7), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 7.

[0847] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from SASSSVSYMH (SEQ ID NO: 8); DTSKLAS (SEQ ID NO: 9); and QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0848] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 comprises SASSSVSYMH (SEQ ID NO: 8); CDR2 comprises: DTSKLAS (SEQ ID NO: 9); and CDR3 comprises QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0849] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 consists of SASSSVSYMH (SEQ ID NO: 8); CDR2 consists of DTSKLAS (SEQ ID NO: 9); and CDR3 consists of QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0850] In some embodiments, the antibody molecule to mesothelin comprises the light chain variable domain sequence of: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIK (SEQ ID NO: 7), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 7.

[0851] In some embodiments, the antibody molecule to mesothelin is a Fab and further comprises a light chain constant region (CL1) having the amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 11. In embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12).

[0852] In other embodiments, the multispecific molecule, e.g., the tumor-targeting moiety, binds to a stromal antigen. In embodiments, the stromal antigen is chosen from one or more of: fibroblast activating protease (FAP), TGF-beta, hyaluronic acid, collagen, e.g., collagen IV, tenascin C, or tenascin W.

[0853] In one embodiment, the tumor-targeting moiety includes an antibody molecule (e.g., Fab or scFv) that binds to FAP, e.g., human FAP. In some embodiments, the antibody molecule to FAP comprises one, two, three CDRs from the heavy chain variable domain sequence depicted in underline in FIG. 12C (SEQ ID NO: 13), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 13. In some embodiments, the antibody molecule to FAP includes the heavy chain variable domain sequence depicted in underline in FIG. 12C (SEQ ID NO: 13), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 13.

[0854] In embodiments, the antibody molecule to FAP is a Fab and further comprises a heavy chain constant region (CH1) having the amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC (SEQ ID NO: 14), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 14. In embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MEFGLSWVFLVALFRGVQCEV (SEQ ID NO: 15).

[0855] Alternatively, or in combination with the heavy chain to FAP disclosed herein, the antibody molecule to FAP comprises one, two, three CDRs from the light chain variable domain sequence depicted in underline in FIG. 12D (SEQ ID NO: 16), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 16. In some embodiments, the antibody molecule to FAP includes the light chain variable domain sequence depicted in underline in FIG. 12D (SEQ ID NO: 16), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 16.

[0856] In embodiments, the antibody molecule to FAP is a Fab and further comprises a light chain constant region (CL1) having the amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence:

TABLE-US-00003 (SEQ ID NO: 12) MKYLLPTAAAGLLLLAAQPAMA.

Immune Cell Engagers

[0857] In one embodiment, the NK cell engager is a ligand of NKp30 is a B7-6, e.g., comprises the amino acid sequence of: DLKVEMMAGGTQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFDKEVKVFEFFGD HQEAFRPGAIVSPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQGTVQLEVVASP ASRLLLDQVGMKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISEDVITGPTIKNM DGTFNVTSCLKLNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSLSETEKTDNFS (SEQ ID NO: 24), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 24.

[0858] In other embodiments, the NK cell engager is a ligand of NKG2D chosen from MICA, MICB, or ULBP1, e.g., wherein:

(i) MICA comprises the amino acid sequence: EPHSLRYNLTVL SWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNK TWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGEL FLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLK SGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSSHDTQQWG DVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW (SEQ ID NO: 25), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 25; (ii) MICB comprises the amino acid sequence: AEPHSLRYNLMVLSQDESVQSGFLAEGHLDGQPFLRYDRQKRRAKPQGQWAEDVLGA KTWDTETEDLTENGQDLRRTLTHIKDQKGGLHSLQEIRVCEIHEDSSTRGSRHFYYDGEL FLSQNLETQESTVPQSSRAQTLAMNVTNFWKEDAMKTKTHYRAMQADCLQKLQRYLK SGVAIRRTVPPMVNVTCSEVSEGNITVTCRASSFYPRNITLTWRQDGVSLSHNTQQWGD VLPDGNGTYQTWVATRIRQGEEQRFTCYMEHSGNHGTHPVPSGKVLVLQSQRTD (SEQ ID NO: 26), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 26; or (iii) ULBP1 comprises the amino acid sequence: GWVDTHCLCYDFIITPKSRPEPQWCEVQGLVDERPFLHYDCVNHKAKAFASLGKKVNV TKTWEEQTETLRDVVDFLKGQLLDIQVENLIPIEPLTLQARMSCEHEAHGHGRGSWQFL FNGQKFLLFDSNNRKWTALHPGAKKMTEKWEKNRDVTMFFQKISLGDCKMWLEEFL MYWEQMLDPTKPPSLAPG (SEQ ID NO: 27), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 27.

[0859] In other embodiments, the NK cell engager is a ligand of DNAM1 chosen from NECTIN2 or NECL5, e.g., wherein:

(i) NECTIN2 comprises the amino acid sequence: QDVRVQVLPEVRGQLGGTVELPCHLLPPVPGLYISLVTWQRPDAPANHQNVAAFHPKM GPSFPSPKPGSERL SFVSAKQSTGQDTEAELQDATLALHGLTVEDEGNYTCEFATFPKGS VRGMTWLRVIAKPKNQAEAQKVTFSQDPTTVALCISKEGRPPARISWLSSLDWEAKETQ VSGTLAGTVTVTSRFTLVPSGRADGVTVTCKVEHESFEEPALIPVTLSVRYPPEVSISGYD DNWYLGRTDATLSCDVRSNPEPTGYDWSTTSGTFPTSAVAQGSQLVIHAVDSLFNTTFV CTVTNAVGMGRAEQVIFVRETPNTAGAGATGG (SEQ ID NO: 28), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 28; or (ii) NECL5 comprises the amino acid sequence: WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAV FHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVD IWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPG FLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNN WYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICN VTNALGARQAELTVQVKEGPPSEHSGISRN (SEQ ID NO: 29), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 29.

[0860] In yet other embodiments, the NK cell engager is a ligand of DAP10, which is an adapter for NKG2D (see e.g., Proc Natl Acad Sci USA. 2005 May 24; 102(21): 7641-7646; and Blood, 15 Sep. 2011 Volume 118, Number 11, the full contents of each of which is incorporated by reference herein).

[0861] In other embodiments, the NK cell engager is a ligand of CD16, which is a CD16a/b ligand, e.g., a CD16a/b ligand further comprising an antibody Fc region (see e.g., Front Immunol. 2013; 4: 76 discusses how antibodies use the Fc to trigger NK cells through CD16, the full contents of which are incorporated herein).

[0862] In other embodiments, the NK cell engager is a ligand of CRTAM, which is NECL2, e.g., wherein NECL2 comprises the amino acid sequence: QNLFTKDVTVIEGEVATISCQVNKSDDSVIQLLNPNRQTIYFRDFRPLKDSRFQLLNFSSS ELKVSLTNVSISDEGRYFCQLYTDPPQESYTTITVLVPPRNLMIDIQKDTAVEGEEIEVNC TAMASKPATTIRWFKGNTELKGKSEVEEWSDMYTVTSQLMLKVHKEDDGVPVICQVE HPAVTGNLQTQRYLEVQYKPQVHIQMTYPLQGLTREGDALELTCEAIGKPQPVMVTWV RVDDEMPQHAVLSGPNLFINNLNKTDNGTYRCEASNIVGKAHSDYMLYVYDPPTTIPPP TTTTTTTTTTTTTILTIITDSRAGEEGSIRAVDH (SEQ ID NO: 30), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 30.

[0863] In other embodiments, the NK cell engager is a ligand of CD27, which is CD70, e.g., wherein CD70 comprises the amino acid sequence: QRFAQAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALGRSFLHGPELDKGQ LRIIHRDGIYMVHIQVTLAICSSTTASRHHPTTLAVGICSPASRSISLLRLSFHQGCTIASQR LTPLARGDTLCTNLTGTLLPSRNTDETFFGVQWVRP (SEQ ID NO: 31), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 31.

[0864] In other embodiments, the NK cell engager is a ligand of PSGL1, which is L-selectin (CD62L), e.g., wherein L-selectin comprises the amino acid sequence:

[0865] WTYHYSEKPMNWQRARRFCRDNYTDLVAIQNKAEIEYLEKTLPFSRSYYWI GIRKIGGIWTWVGTNKSLTEEAENWGDGEPNNKKNKEDCVEIYIKRNKDAGKWNDDA CHKLKAALCYTASCQPWSCSGHGECVEIINNYTCNCDVGYYGPQCQFVIQCEPLEAPEL GTMDCTHPLGNFSFSSQCAFSCSEGTNLTGIEETTCGPFGNWSSPEPTCQVIQCEPLSAPD LGIMNCSHPLASFSFTSACTFICSEGTELIGKKKTICESSGIWSNPSPICQKLDKSFSMIKEG DYN (SEQ ID NO: 32), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 32.

[0866] In other embodiments, the NK cell engager is a ligand of CD96, which is NECL5, e.g., wherein NECL5 comprises the amino acid sequence: WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAV FHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVD IWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPG FLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNN WYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICN VTNALGARQAELTVQVKEGPPSEHSGISRN (SEQ ID NO: 29), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 29.

[0867] In other embodiments, the NK cell engager is a ligand of CD100 (SEMA4D), which is CD72, e.g., wherein CD72 comprises the amino acid sequence: RYLQVSQQLQQTNRVLEVTNSSLRQQLRLKITQLGQSAEDLQGSRRELAQSQEALQVEQ RAHQAAEGQLQACQADRQKTKETLQSEEQQRRALEQKLSNMENRLKPFFTCGSADTCC PSGWIMHQKSCFYISLTSKNWQESQKQCETLSSKLATFSEIYPQSHSYYFLNSLLPNGGS GNSYWTGLSSNKDWKLTDDTQRTRTYAQSSKCNKVHKTWSWWTLESESCRSSLPYICE MTAFRFPD (SEQ ID NO: 33), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 33.

[0868] In other embodiments, the NK cell engager is a ligand of NKp80, which is CLEC2B (AICL), e.g., wherein CLEC2B (AICL) comprises the amino acid sequence:

[0869] KLTRDSQSLCPYDWIGFQNKCYYFSKEEGDWNSSKYNCSTQHADLTIIDNIEE MNFLRRYKCSSDHWIGLKMAKNRTGQWVDGATFTKSFGMRGSEGCAYLSDDGAATA RCYTERKWICRKRIH (SEQ ID NO: 34), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 34.

[0870] In other embodiments, the NK cell engager is a ligand of CD244, which is CD48, e.g., wherein CD48 comprises the amino acid sequence: QGHLVHMTVVSGSNVTLNISESLPENYKQLTWFYTFDQKIVEWDSRKSKYFESKFKGR VRLDPQSGALYISKVQKEDNSTYIMRVLKKTGNEQEWKIKLQVLDPVPKPVIKIEKIEDM DDNCYLKLSCVIPGESVNYTWYGDKRPFPKELQNSVLETTLMPHNYSRCYTCQVSNSVS SKNGTVCLSPPCTLARS (SEQ ID NO: 35), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 35.

[0871] In other embodiments, the dendritic cell engager is chosen from one or more of a CD2 agonist, an OX40 antibody, an OX40L, 41BB agonist, a Toll-like receptor agonist or a fragment thereof (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4)), CD47 agonist, or a STING agonist.

[0872] In one embodiment, the OX40L comprises the amino acid sequence: QVSHRYPRIQSIKVQF TEYKKEKGFLTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQ EVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGE LILIHQNPGEFCVL (SEQ ID NO: 36), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 36.

[0873] In another embodiment, the CD40L comprises the amino acid sequence: MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLY YIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFE LQPGASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 37), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 37.

[0874] In yet other embodiments, the STING agonist comprises a cyclic dinucleotide, e.g., a cyclic di-GMP (cdGMP), a cyclic di-AMP (cdAMP), or a combination thereof, optionally with 2',5' or 3',5' phosphate linkages.

[0875] In one embodiment, the immune cell engager includes 41BB ligand, e.g., comprising the amino acid sequence: ACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPL S WYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALH LQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHL SAGQRLGVHLHTEARARH AWQLTQGATVLGLFRVTPEIPAGLPSPRSE (SEQ ID NO: 38), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 38.

Cytokine Molecules

[0876] In some embodiments, the multispecific molecules disclosed herein include a cytokine molecule. In embodiments, the cytokine molecule includes a full length, a fragment or a variant of a cytokine; a cytokine receptor domain, e.g., a cytokine receptor dimerizing domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor. In some embodiments, the cytokine is a single chain. In some embodiments, the cytokine comprises 2 or 2 or more polypeptide chains. An exemplary multichain cytokine molecule is IL12.

[0877] In some embodiments the cytokine molecule is chosen from interleukin-2 (IL-2), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-21 (IL-21), interleukin-7 (IL-7), or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforesaid cytokines. The cytokine molecule can be a monomer or a dimer. In embodiments, the cytokine molecule can further include a cytokine receptor dimerizing domain.

[0878] In other embodiments, the cytokine molecule is an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor chosen from an IL-15Ra or IL-21R.

[0879] In one embodiment, the cytokine molecule is IL-15, e.g., human IL-15 (e.g., comprising the amino acid sequence: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 17), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 17.

[0880] In some embodiments, the cytokine molecule comprises a receptor dimerizing domain, e.g., an IL15Ralpha dimerizing domain. In one embodiment, the IL15Ralpha dimerizing domain comprises the amino acid sequence: MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHADIWVKSYSLYSRERYICN SGFKRKAGTSSLTECVL (SEQ ID NO: 40), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 40. In some embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) of the multispecific molecule are covalently linked, e.g., via a linker (e.g., a Gly-Ser linker, e.g., a linker comprising the amino acid sequence SGGSGGGGSGGGSGGGGSLQ (SEQ ID NO: 19). In other embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) of the multispecific molecule are not covalently linked, e.g., are non-covalently associated.

[0881] In other embodiments, the cytokine molecule is IL-2, e.g., human IL-2 (e.g., comprising the amino acid sequence: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCL EEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFCQSIISTLT (SEQ ID NO: 20), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 20).

[0882] In other embodiments, the cytokine molecule is IL-18, e.g., human IL-18 (e.g., comprising the amino acid sequence: YFGKLESKL SVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGM AVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEG YFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 41), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 41).

[0883] In other embodiments, the cytokine molecule is IL-21, e.g., human IL-21 (e.g., comprising the amino acid sequence: QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSA NTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMI HQHLSSRTHGSEDS (SEQ ID NO: 22), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 22).

[0884] In yet other embodiments, the cytokine molecule is interferon gamma, e.g., human interferon gamma (e.g., comprising the amino acid sequence: QDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFK NFKDDQSIQKSVETIKEDMNVKFFNSNKKKRDDFEKLTNYSVTDLNVQRKAIHELIQVM AELSPAAKTGKRKRSQMLFRG (SEQ ID NO: 23), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 23).

Linkers

[0885] The multispecific molecule disclosed herein can further include a linker, e.g., a linker between one or more of: the targeting moiety and the cytokine molecule, the targeting moiety and the immune cell engager, the cytokine molecule and the immune cell engager, the cytokine molecule and the immunoglobulin chain constant region (e.g., the Fc region), the targeting moiety and the immunoglobulin chain constant region, or the immune cell engager and the immunoglobulin chain constant region. In embodiments, the linker chosen from: a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker, or a combination thereof.

[0886] In one embodiment, the multispecific molecule can include one, two, three or four linkers, e.g., a peptide linker. In one embodiment, the peptide linker includes Gly and Ser. Exemplary peptide linkers are depicted in the figures disclosed herein (e.g., FIGS. 11B-11C, 12B, 13B-C, 14A-B), e.g., a peptide linker chosen from: GGGGS (SEQ ID NO: 42); GGGGSGGGGS (SEQ ID NO: 43); GGGGSGGGGSGGGGS (SEQ ID NO: 44); or DVPSGPGGGGGSGGGGS (SEQ ID NO: 45).

Exemplary Multispecific Configurations:

[0887] In some embodiments, any of the multispecific molecules disclosed herein can include:

[0888] (I) a tumor-targeting moiety that comprises:

[0889] (a) an antibody molecule against a solid tumor antigen chosen from: Mesothelin, GD2, PMSA, CEA, Ron Kinase, or c-Met; and/or

[0890] (b) an antibody molecule against a stromal antigen is chosen from: FAP, hyaluronic acid, collagen IV, tenascin C, or tenascin W; or

[0891] (c) a combination of the antibody molecule against the solid tumor antigen and the antibody molecule against the stromal antigen; and

[0892] (II) one or both of:

[0893] (a) an immune cell engager chosen from one, two, three, or all of a CD40L or a CD70 ligand; an antibody molecule that binds to CD40 or CD70; an antibody molecule to OX40; an OX40L; B7H6, 41BB ligand (41BBL), or a STING agonist, or a combination thereof, or

[0894] (b) the cytokine molecule chosen from IL-2, IL-12, IL-15, IL-18, IL-7, or IL-21, fragment or variant thereof, or an antibody molecule to a cytokine receptor (e.g., an antibody (e.g., an agonistic antibody) to IL-15Ra, or IL-21R), or a combination of any of the aforesaid.

[0895] In some embodiments, the tumor targeting moiety is an antibody molecule that binds to mesothelin, PSCA or FAP. In some embodiments, the immune cell engager is an antibody molecule that binds to NKp30 or CD16. In other embodiments, the immune cell engager is chosen from a CD40 ligand (CD40L), B7H6 or 41BB ligand (41BBL). In other embodiments, the cytokine molecule is chosen from IL-15 or IL-21, or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to an IL-15Ra or IL-21R.

[0896] In some embodiments, the bispecific molecule is chosen from: (i) an antibody molecule to mesothelin and an antibody molecule to NKp30; (ii) an antibody molecule to mesothelin and an antibody molecule to CD16; (iii) an antibody molecule to PSCA and an antibody molecule to NKp30; (iv) an antibody molecule to PSCA and an antibody molecule to CD16; (v) an antibody molecule to FAP and an antibody molecule to NKp30; (vi) an antibody molecule to FAP and an antibody molecule to CD16; (vii) an antibody molecule to FAP and an IL-15 molecule; (viii) an antibody molecule to FAP and an antibody molecule (e.g., an agonistic antibody) to an IL-15Ra; (ix) an antibody molecule to FAP and an antibody molecule (e.g., an agonistic antibody) to an IL-21; or (x) an antibody molecule to FAP and an antibody molecule (e.g., an agonistic antibody) to an IL-21R.

[0897] In other embodiments, the trispecific molecule includes a tumor targeting moiety chosen from an antibody molecule to mesothelin, antibody molecule to PSCA or an antibody molecule to FAP; an immune cell engager, e.g., an NK cell engager, chosen from an antibody molecule to NKp30 or an antibody molecule to CD16; or a macrophage cell engager chosen from a CD40L, OX40L, or an antibody molecule to CD40 or an antibody molecule to OX40; and a cytokine molecule chosen from an IL-15, IL-21, an antibody to IL-15Ra or an antibody to IL-21R. Exemplary combinations include but are not limited to: (i) an antibody molecule to mesothelin; a CD40L polypeptide; and an IL-15 molecule; (ii) an antibody molecule to mesothelin; a CD40L polypeptide; and an IL-15 molecule; (iii) an antibody molecule to mesothelin; an antibody molecule that binds to NKp30; and an IL-15 molecule; (iv) an antibody molecule to mesothelin; an antibody molecule that binds to CD16; and an IL-15 molecule; (v) an antibody molecule to PSCA; an antibody molecule that binds to NKp30; and an IL-15 molecule; (vi) an antibody molecule to PSCA; an antibody molecule that binds to CD16; and an IL-15 molecule; (vii) an antibody molecule to PSCA; an antibody molecule that binds to CD16; and an IL-21 molecule; or (viii) an antibody molecule to mesothelin; an antibody molecule that binds to CD16; and an IL-21 molecule.

[0898] In other embodiments, the tetraspecific molecule includes (i) an antibody molecule to mesothelin, e.g., human mesothelin; a CD40L polypeptide; an IL-15 molecule; and B7H6; (ii) an antibody molecule to FAP, e.g., human mesothelin; a CD40L polypeptide; an IL-15 molecule; and B7H6; or (iii) an antibody molecule to mesothelin, e.g., human mesothelin; a CD40L polypeptide; an IL-21 molecule; and 41BBL.

[0899] In some embodiments, the multispecific molecule includes an antibody molecule to mesothelin, e.g., human mesothelin; a CD40L polypeptide; and an IL-15 molecule. In one embodiment, the antibody molecule includes a Fab against mesothelin having a light and a heavy chain. In embodiments, the heavy chain of the Fab against mesothelin further comprises the IL-15 molecule, e.g., human IL-15 molecule, optionally, wherein the Fab and the IL-15 molecule are linked, e.g., via a linker comprising Gly and Ser. In some embodiments, the multispecific molecule has the following configuration: Heavy chain of the Fab (e.g., VH-CH1) against mesothelin to IL-15, from N- to C-terminus, optionally, comprising a Gly-Ser linker between the Fab and the IL-15. In some embodiments, the multispecific molecule includes the amino acid sequence: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTGGGGSGGG GSGGGGSNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS, (SEQ ID NO: 46), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 46.

[0900] In embodiments, the light chain of the Fab to mesothelin further comprises a CD40L, optionally, wherein the Fab and the CD40L are linked, e.g., via a linker comprising Gly and Ser. In one embodiment, the multispecific molecule has the following configuration: Light chain of the Fab (e.g., VL-CL i) to mesothelin fused to CD40L, from N- to C-terminus, optionally, comprising a Gly-Ser linker between the Fab and the CD40L. In embodiments, the multispecific molecule includes the amino acid sequence: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDVPSGPGGGGGSGGGGSMQKGD QNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQV TFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGAS VFVNVTDPSQVSHGTGFTSFGLLKL, (SEQ ID NO: 47), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 47.

[0901] In other embodiments, the multispecific molecule includes an antibody molecule to FAP, e.g., human FAP, and an IL-15 molecule. In some embodiments, the antibody molecule includes a Fab against FAP having a light and a heavy chain. The heavy chain of the Fab to FAP can further include a first Fc region having a member of a paired cavity-protuberance (knob-in-a hole) in the Fc interface of the first Fc region. For example, the multispecific molecule can have the following configuration: Heavy chain of the Fab (e.g., VH-CH1) of FAP fused to First Fc region (e.g., CH2 to CH3), from N- to C-terminus, e.g., includes the amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSREEMTKNQVSL SCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL VSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK, (SEQ ID NO: 48), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 48.

[0902] In embodiments, the light chain of the Fab to FAP includes the amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, (SEQ ID NO: 49), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 49.

[0903] In embodiments, the IL-15 molecule, e.g., human IL-15 molecule, further includes a second Fc region having a second member of a paired cavity-protuberance (knob-in-a hole) in the Fc interface of the second Fc region, e.g., connected via a linker comprising Gly and Ser. In one embodiment, the multispecific molecule has the following configuration: IL-15 molecule-Second Fc region (e.g., CH2 to CH3), from N- to C-terminus, e.g., wherein the IL-15 molecule and the Second Fc region are connected via a linker comprising Gly and Ser, e.g., includes the amino acid sequence: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSL SSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTSGGGGSDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMIIEALHNHYTQKSLSLSPGK, (SEQ ID NO: 50), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 50.

[0904] In other embodiments, the multispecific molecule that includes the antibody molecule to FAP, e.g., human FAP, and the IL-15 molecule, further includes an immune cell engager, e.g., as described herein (e.g., a CD40 ligand). In some embodiments, the immune cell enhancer is linked, e.g., covalently linked, to the second Fc region having the second member of the paired cavity-protuberance (knob-in-a hole) and the IL-15 molecule, e.g., human IL-15 molecule, optionally comprising a linker comprising Gly and Ser between the IL-15 molecule and the second Fc region, and/or between the second Fc region and the immune cell enhancer. In embodiments, the multispecific molecule has the following configuration: IL-15 molecule-Second Fc region (e.g., CH2 to CH3)--Immune cell enhancer, from N- to C-terminus, optionally comprising a linker comprising Gly and Ser between the IL-15 molecule and the second Fc region, and/or between the second Fc region and the immune cell enhancer, e.g., it includes the amino acid sequence: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSL SSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTSGGGGSDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMIIEALHNHYTQKSLSLSPGKGGGGSMQ KGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIY AQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQP GASVFVNVTDPSQVSHGTGFTSFGLLKL, (SEQ ID NO: 51), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 51.

[0905] In other embodiments, the multispecific molecule that includes the antibody molecule to FAP, e.g., human FAP, the IL-15 molecule, and the CD40 ligand, further includes a second immune cell enhancer, e.g., a B7H6 molecule. In some embodiments, the second immune cell enhancer is linked, e.g., covalently linked, to the first Fc region having the first member of the paired cavity-protuberance (knob-in-a hole) in the Fe interface of the first Fc region and the heavy chain of the Fab, optionally comprising a linker comprising Gly and Ser between the B7H6 molecule and the first Fc region. In embodiments, the multispecific molecule has the following configuration: Heavy chain of the Fab (e.g., VH-CH1) to FAP fused to--First Fc region (e.g., CH2 to CH3) fused to--B7H6 molecule, from N- to C-terminus, optionally comprising a linker comprising Gly and Ser between the first Fc region and the B7H6 molecule, e.g., includes the amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKTSRYTF TEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSL SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL VSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKGGGGSDLKVEMMAGG TQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFDKEVKVFEFFGDHQEAFRPGAIV SPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQGTVQLEVVASPASRLLLDQVG MKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISEDVITGPTIKNMDGTFNVTSCLK LNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSLSETEKTDNFS, (SEQ ID NO: 52), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 52).

[0906] In another aspect, the invention features a multispecific molecule comprising:

[0907] a first amino acid sequence comprising: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTSGGGGSDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 50) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises an IL-15 polypeptide, a linker, and an immunoglobulin Fc;

[0908] a second amino acid sequence comprising: QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL VSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGS (SEQ ID NO: 53) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises an anti-FAP heavy chain of a Fab and an immunoglobulin Fc; and

[0909] a third amino acid sequence comprising: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 54) or an amino acid sequence substantially homologous thereto), wherein the amino acid sequence comprises a human kappa light chain of anti-FAP Fab.

[0910] In some embodiments, the first amino acid sequence further comprises: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6) or an amino acid sequence substantially homologous thereto. In some embodiments, the second amino acid sequence further comprises: MEFGLSWVFLVALFRGVQCEV (SEQ ID NO: 15) or an amino acid sequence substantially homologous thereto. In some embodiments, the third amino acid sequence further comprises: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12) or an amino acid sequence substantially homologous thereto.

[0911] In another aspect, the invention features a multispecific molecule comprising:

[0912] a first amino acid sequence comprising: MEFGLSWVFLVALFRGVQCNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAM KCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQS FVHIVQMFINTTSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO: 233) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide, IL-15, a linker, and immunoglobulin Fc;

[0913] a second amino acid sequence comprising: MEFGLSWVFLVALFRGVQCEVQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWV RQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYC ARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK (SEQ ID NO: 55) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide, an anti-FAP heavy chain of a Fab and immunoglobulin Fc; and

[0914] a third amino acid sequence comprising: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 49) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide and human kappa light chain of anti-FAP Fab.

[0915] In another aspect, the invention features a multispecific molecule comprising:

[0916] a first amino acid sequence comprising: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLL SLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSL SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTGGGGSGGG GSGGGGSNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIIIDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 46) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises an anti-mesothelin heavy chain of a Fab, a linker, and an IL-15; and

[0917] a second amino acid sequence comprising: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDVPSGPGGGGGSGGGGSMQKGD QNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQV TFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHiLGGVFELQPGAS VFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 56) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a human kappa light chain of anti-mesothelin Fab, a linker, and a CD40L.

[0918] In some embodiments, the first amino acid sequence further comprises: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6) or an amino acid sequence substantially homologous thereto. In some embodiments, the second amino acid sequence further comprises: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12) or an amino acid sequence substantially homologous thereto.

[0919] In another aspect, the invention features a multispecific molecule comprising:

[0920] a first amino acid sequence comprising: MEFGLSWVFLVALFRGVQCQVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVK QSHGKSLEWIGLITPYNGASSYNQKFRGKATLTVDKSSSTAYMDLL SLTSEDSAVYFCA RGGYDGRGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKTHTGGGGSGGGGSGGGGSNWVNVISDLKKIEDLIQSMHIDATLYTESDVH PSCKVTAMKCFLLELQVISLESGDASIIHDTVENLIILANNSLSSNGNVTESGCKECEELEE KNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 234) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide, an anti-mesothelin heavy chain of a Fab, a linker, and an IL-15; and

[0921] a second amino acid sequence comprising: MKYLLPTAAAGLLLLAAQPAMADIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQ QKSGTSPKRWIYDTSKLASGVPGRFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPL TFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DVPSGPGGGGGSGGGGSMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNL VTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTH SSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 235) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide, a human kappa light chain of anti-mesothelin Fab, a linker, and a CD40L.

[0922] In another aspect, the invention features a multispecific molecule comprising:

[0923] a first amino acid sequence comprising: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTSGGGGSDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMIIEALHNHYTQKSLSLSPGKGGGGSMQ KGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIY AQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQP GASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 51) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises IL-15, a linker, and immunoglobulin Fc, a linker, and CD40L;

[0924] a second amino acid sequence comprising: QVQLVQSGAEVKKPGASVKVSCKTSRYTF TEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL VSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSDLKVEMMAGG TQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFDKEVKVFEFFGDHQEAFRPGAIV SPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQGTVQLEVVASPASRLLLDQVG MKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISEDVITGPTIKNMDGTFNVTSCLK LNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSLSETEKTDNFS (SEQ ID NO: 52) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises an anti-B7H6 heavy chain of a Fab and immunoglobulin Fc, a linker, and B7H6; and

[0925] a third amino acid sequence comprising: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 57) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a human kappa light chain of anti-FAP Fab.

[0926] In some embodiments, the first amino acid sequence further comprises: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6) or an amino acid sequence substantially homologous thereto. In some embodiments, the second amino acid sequence further comprises: MEFGLSWVFLVALFRGVQCEV (SEQ ID NO: 15) or an amino acid sequence substantially homologous thereto. In some embodiments, the third amino acid sequence further comprises: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12) or an amino acid sequence substantially homologous thereto.

[0927] In another aspect, the invention features a multispecific molecule comprising:

[0928] a first amino acid sequence comprising: MEFGLSWVFLVALFRGVQCNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAM KCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQS FVHIVQMFINTTSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGKGGGGSMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTL ENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSA KPCGQQSIHILGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 58) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide, IL-15, a linker, and immunoglobulin Fc, a linker, and CD40L;

[0929] a second amino acid sequence comprising (or substantially homologous thereto): MEFGLSWVFLVALFRGVQCEVQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWV RQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMEL SSLRSEDTAVYYC ARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSL SCAVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SL SPGKGGGGSDLKVEMMAGGTQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFD KEVKVFEFFGDHQEAFRPGAIVSPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQ GTVQLEVVASPASRLLLDQVGMKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISE DVITGPTIKNMDGTFNVTSCLKLNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSL SETEKTDNFS (SEQ ID NO: 59) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide, anti-FAP heavy chain of a Fab and immunoglobulin Fc, a linker, and B7H6; and

[0930] a third amino acid sequence comprising: MKYLLPTAAAGLLLLAAQPAMADIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKN YLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQ YFSYPL TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (SEQ ID NO: 60) or an amino acid sequence substantially homologous thereto, wherein the amino acid sequence comprises a leader peptide and human kappa light chain of anti-FAP Fab.

[0931] An exemplary trispecific molecule includes a Fab molecule directed to the mesothelin tumor antigen, wherein first polypeptide includes the heavy chain VH-CH1 of the Fab connected via a linker to an IL-15 cytokine, and the second polypeptide of the Fab includes the light chain VL-CL connected via a linker to CD40 ligand (CD40L) (FIG. 11A-C). FIG. 11B provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the heavy chain VH-CH1 of the Fab (shown in underline and bold for VH and CH1, respectively), connected via a Gly-Ser linker (shown in italics), to a human IL-15 cytokine (shown in regular font). FIG. 11C provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the kappa light chain VL-CL of the Fab (shown in underline and bold for VL and CL, respectively), connected via a Gly-Ser linker (shown in italics), to a human CD40L (shown in orange).

[0932] An exemplary bispecific molecule includes a Fab molecule directed to the stromal antigen, wherein the first polypeptide includes the heavy chain VH-CH1 of the Fab to the stromal antigen connected to the first Fc molecule having a cavity; the second polypeptide includes the IL-15 cytokine connected to the second Fc molecule having a protuberance; and the third polypeptide includes a light chain VL-CL of the Fab to the stromal antigen (FIG. 12A). FIG. 12B provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the human IL-15 cytokine (shown in regular font), and further including an optional Gly-Ser linker (shown in italics) connected to the second Fc molecule having a protuberance (shown in italics). FIG. 12C provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the followed by the heavy chain VH-CH1 of the Fab to the stromal antigen FAP (shown in underline and bold for VH and CH1, respectively), connected to the first Fc molecule having a cavity (shown in regular font). FIG. 12D provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the kappa light chain VL-CL of the Fab to the stromal antigen FAP (shown in underline and bold for VL and CL, respectively).

[0933] An exemplary tetraspecific molecule includes a Fab molecule directed to the mesothelin antigen, wherein the first polypeptide includes the heavy chain VH-CH1 of the Fab to the mesothelin antigen connected to the first Fc molecule having a protuberance (knob) in the CH3 region, and further includes a first immune cell engager, e.g., 41BB-ligand; the second polypeptide includes the IL-21 cytokine connected, optionally via a Gly-Ser linker, to the second Fc molecule having a cavity (hole), and further includes, e.g., via a Gly-Ser linker, a second immune cell engager, e.g., CD40L; and the third polypeptide includes a light chain VL-CL of the Fab to the mesothelin antigen (molecule A) (FIG. 14A-14B). The following amino acid sequences are included: (i) Molecule A corresponding to the heavy chain and light chain, respectively, of the mesothelin Fab (hMeso_SS1_Fab); (ii) Molecule B corresponding to human IL-21; (iii) Linker between the Molecule B and second Fc region (Molecule B to KiH_Fc linker);

[0934] (iv) Linker between the first Fc region and Molecule C (KiH_Fc to Molecule C linker); (v) Molecule C corresponding to human 41BB ligand; (vi) Linker between the second Fc region and Molecule D (KiH_Fc to Molecule D linker); (vii) Molecule C corresponding to human CD40L;

[0935] (viii) first member Fc region (Fc Knob), including from N to C orientation, the VH of the mesothelin Fab, the CH2-CH3 amino acid sequence including a substitution of T for W at position 366, followed by a Gly-Ser linker and the human 41BB ligand; and (ix) second member Fc region (Fc Hole), including from N to C orientation, the human IL-21, a Gly-Ser linker, the CH2-CH3 amino acid sequence including a substitution of T for S at position 366, L for A at position 368, Y for V at position 407, followed by a Gly-Ser linker and the human CD40L

[0936] An exemplary tetraspecific molecule includes a Fab molecule directed to the stromal antigen, wherein the first polypeptide includes the heavy chain VH-CH1 of the Fab to the stromal antigen connected to the first Fc molecule having a cavity, and further includes a first immune cell engager, B7H6; the second polypeptide includes the IL-15 cytokine connected, optionally via a Gly-Ser linker, to the second Fc molecule having a protuberance, and further includes, e.g., via a Gly-Ser linker, a second immune cell engager, CD40L; and the third polypeptide includes a light chain VL-CL of the Fab to the stromal antigen (FIG. 13A). FIG. 13B provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the human IL-15 cytokine (shown in regular font), further including an optional Gly-Ser linker (shown in italics) connected to the second Fc molecule having a protuberance (shown in regular font), which further includes, e.g., an optional Gly-Ser linker (shown in italics, connected to the human CD40L amino acid sequence (shown in italics). FIG. 13C provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the followed by the heavy chain VH-CH1 of the Fab to the stromal antigen FAP (shown in underline and bold for VH and CH1, respectively), connected to the first Fc molecule having a cavity (shown in regular font), which further includes, e.g., an optional Gly-Ser linker (shown in italics, connected to the human B7H6 amino acid sequence (shown in blue). FIG. 13D provides, from N- to C-orientation, the amino acid sequence of an optional signal peptide (shown in italics), followed by the kappa light chain VL-CL of the Fab to the stromal antigen FAP (shown in underline and bold for VL and CL, respectively).

Exemplary Multispecific Molecules Comprising Stromal Modifying Moiety

[0937] The disclosure relates, inter alia, to novel multifunctional, e.g., multispecific, molecules that include (i) a stromal modifying moiety and (ii) a tumor-targeting moiety (e.g., an antibody molecule, a ligand molecule, or a receptor molecule) that binds to a tumor antigen or a stromal antigen. Without being bound by theory, the multifunctional molecules disclosed herein are believed to inter alia target (e.g., localize to) a cancer site, and alter the tumor stroma, e.g., alter the tumor microenvironment near the cancer site. The multifunctional molecules can further include one or both of: an immune cell engager (e.g., chosen from one, two, three, or all of an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); and/or a cytokine molecule. Accordingly, provided herein are, inter alia, multifunctional, e.g., multispecific molecules, that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.

[0938] Accordingly, in one aspect, the disclosure features a multifunctional (e.g., bifunctional) molecule that includes a stromal modifying moiety and a tumor-targeting moiety (e.g., an antibody molecule, a ligand molecule, or a receptor molecule), e.g., that binds to a cancer antigen (e.g., a solid tumor antigen, a stromal antigen, or a hematological antigen).

[0939] In some embodiments, the multifunctional molecule further includes one or two of the following:

[0940] (i) an immune cell engager, e.g., chosen from one, two, three, or all of an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager; or

[0941] (ii) a cytokine molecule.

[0942] In other embodiments, the multifunctional molecule includes three or four binding specificities or functions, e.g., it is a trispecific or a tetraspecific molecule. Exemplary trispecific and tetraspecific molecules include:

[0943] (i) one tumor-targeting moiety, one stromal modifying moiety and one immune cell engager;

[0944] (ii) one tumor-targeting moiety, one stromal modifying moiety and one cytokine molecule;

[0945] (iii) one tumor-targeting moiety, one stromal modifying moiety and two immune cell engagers (e.g., same or different immune cell engagers);

[0946] (iv) one tumor-targeting moiety, one stromal modifying moiety and two cytokines (e.g., same or different cytokines);

[0947] (v) one tumor-targeting moiety, one stromal modifying moiety, one immune cell engager, and one cytokine molecule;

[0948] (vi) two tumor-targeting moieties (e.g., same or different targeting moieties) and one stromal modifying moiety;

[0949] (vii) one tumor-targeting moiety and two stromal modifying moieties (e.g., same or different stromal modifying moieties);

[0950] (viii) two tumor-targeting moieties (e.g., same or different targeting moieties), one stromal modifying moiety and one immune cell engager;

[0951] (ix) two tumor-targeting moieties (e.g., same or different targeting moieties), one stromal modifying moiety and one cytokine molecule;

[0952] (x) one tumor-targeting moiety, two stromal modifying moieties (e.g., same or different stromal modifying moieties) and one immune cell engager; and

[0953] (xi) one tumor-targeting moiety, two stromal modifying moieties (e.g., same or different stromal modifying moieties) and one cytokine molecule.

Stromal Modifying Moieties

[0954] In some embodiments, the stromal modifying moiety causes one or more of: decreases the level or production of a stromal or extracellular matrix (ECM) component; decreases tumor fibrosis; increases interstitial tumor transport; improves tumor perfusion; expands the tumor microvasculature; decreases interstitial fluid pressure (IFP) in a tumor; or decreases or enhances penetration or diffusion of an agent, e.g., a cancer therapeutic or a cellular therapy, into a tumor or tumor vasculature.

[0955] In some embodiments, the stromal or ECM component decreased is chosen from a glycosaminoglycan or an extracellular protein, or a combination thereof. In some embodiments, the glycosaminoglycan is chosen from hyaluronan (also known as hyaluronic acid or HA), chondroitin sulfate, chondroitin, dermatan sulfate, heparin, heparin sulfate, entactin, tenascin, aggrecan and keratin sulfate. In some embodiments, the extracellular protein is chosen from collagen, laminin, elastin, fibrinogen, fibronectin, or vitronectin. In some embodiments, the stromal modifying moiety includes an enzyme molecule that degrades a tumor stroma or extracellular matrix (ECM). In some embodiments, the enzyme molecule is chosen from a hyaluronidase molecule, a collagenase molecule, a chondroitinase molecule, a matrix metalloproteinase molecule (e.g., macrophage metalloelastase), or a variant (e.g., a fragment) of any of the aforesaid. The term "enzyme molecule" includes a full length, a fragment or a variant of the enzyme, e.g., an enzyme variant that retains at least one functional property of the naturally-occurring enzyme.

[0956] In some embodiments, the stromal modifying moiety decreases the level or production of hyaluronic acid. In other embodiments, the stromal modifying moiety comprises a hyaluronan degrading enzyme, an agent that inhibits hyaluronan synthesis, or an antibody molecule against hyaluronic acid.

[0957] In some embodiments, the hyaluronan degrading enzyme is a hyaluronidase molecule, e.g., a full length or a variant (e.g., fragment thereof) thereof. In some embodiments, the hyaluronan degrading enzyme is active in neutral or acidic pH, e.g., pH of about 4-5. In some embodiments, the hyaluronidase molecule is a mammalian hyaluronidase molecule, e.g., a recombinant human hyaluronidase molecule, e.g., a full length or a variant (e.g., fragment thereof, e.g., a truncated form) thereof. In some embodiments, the hyaluronidase molecule is chosen from HYAL1, HYAL2, or PH-20/SPAM1, or a variant thereof (e.g., a truncated form thereof). In some embodiments, the truncated form lacks a C-terminal glycosylphosphatidylinositol (GPI) attachment site or a portion of the GPI attachment site. In some embodiments, the hyaluronidase molecule is glycosylated, e.g., comprises at least one N-linked glycan.

[0958] In some embodiments, the hyaluronidase molecule comprises the amino acid sequence: LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDRL GYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTW ARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRP NHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQS PVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFL SQDELVYTFGETVA LGASGIVIWGTL SIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRK NWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADV KDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLS (SEQ ID NO: 61), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 61.

[0959] In some embodiments, the hyaluronidase molecule comprises:

[0960] (i) the amino acid sequence of 36-464 of SEQ ID NO: 61;

[0961] (ii) the amino acid sequence of 36-481, 36-482, or 36-483 of PH20, wherein PH20 has the sequence of amino acids set forth in SEQ ID NO: 61; or

[0962] (iii) an amino acid sequence having at least 95% to 100% sequence identity to the polypeptide or truncated form of sequence of amino acids set forth in SEQ ID NO: 61; or

[0963] (iv) an amino acid sequence having 30, 20, 10, 5 or fewer amino acid substitutions to the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the hyaluronidase molecule comprises an amino acid sequence at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 100%) identical to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the hyaluronidase molecule is encoded by a nucleotide sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, 100%) identical to the nucleotide sequence of SEQ ID NO: 61.

[0964] In some embodiments, the hyaluronidase molecule is PH20, e.g., rHuPH20. In some embodiments, the hyaluronidase molecule is HYAL1 and comprises the amino acid sequence: FRGPLLPNRPFTTVWNANTQWCLERHGVDVDVSVFDVVANPGQTFRGPDMTIFYSSQG TYPYYTPTGEPVFGGLPQNASLIAHLARTFQDILAAIPAPDFSGLAVIDWEAWRPRWAFN WDTKDIYRQRSRALVQAQHPDWPAPQVEAVAQDQFQGAARAWMAGTLQLGRALRPR GLWGFYGFPDCYNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSRALYPSIYMPAVLEG TGKSQMYVQHRVAEAFRVAVAAGDPNLPVLPYVQIFYDTTNHFLPLDELEHSLGESAA QGAAGVVLWVSWENTRTKESCQAIKEYMDTTLGPFILNVTSGALLCSQALCSGHGRCV RRTSHPKALLLLNPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRCYPGWQAPWC ERKSMW (SEQ ID NO: 62), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 62.

[0965] In some embodiments, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule, further comprises a polymer, e.g., is conjugated to a polymer, e.g., PEG. In some embodiments, the hyaluronan-degrading enzyme is a PEGylated PH20 enzyme (PEGPH20). In some embodiments, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule, further comprises an immunoglobulin chain constant region (e.g., Fc region) chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4. In some embodiments, the immunoglobulin constant region (e.g., the Fc region) is linked, e.g., covalently linked to, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule. In some embodiments, the immunoglobulin chain constant region (e.g., Fc region) is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function. In some embodiments, the hyaluronan degrading enzyme, e.g., the hyaluronidase molecule forms a dimer.

[0966] In some embodiments, the stromal modifying moiety comprises an inhibitor of the synthesis of hyaluronan, e.g., an HA synthase. In some embodiments, the inhibitor comprises a sense or an antisense nucleic acid molecule against an HA synthase or is a small molecule drug. In some embodiments, the inhibitor is 4-methylumbelliferone (MU) or a derivative thereof (e.g., 6,7-dihydroxy-4-methyl coumarin or 5,7-dihydroxy-4-methyl coumarin), or leflunomide or a derivative thereof.

[0967] In some embodiments, the stromal modifying moiety comprises antibody molecule against hyaluronic acid.

[0968] In some embodiments, the stromal modifying moiety comprises a collagenase molecule, e.g., a mammalian collagenase molecule, or a variant (e.g., fragment) thereof. In some embodiments, the collagenase molecule is collagenase molecule IV, e.g., comprising the amino acid sequence of: YNFFPRKPKWDKNQITYRIIGYTPDLDPETVDDAFARAFQVWSDVTPLRFSRIHDGEADI MINFGRWEHGDGYPFDGKDGLLAHAFAPGTGVGGDSSHFDDDELWTLGEGQVVRVKY GNADGEYCKFPFLFNGKEYNSCTDTGRSDGFLWCSTTYNFEKDGKYGFCPHEALFTMG GNAEGQPCKFPFRFQGTSYDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPETAMSTVG GNSEGAPCVFPFTFLGNKYESCTSAGRSDGKMWCATTANYDDDRKWGFCPDQGYSLF LVAAHEFGHAMGLEHSQDPGALMAPIYTYTKNFRL SQDDIKGIQELYGASPDIDLGTGP TPTLGPVTPEICKQDIVFDGIAQIRGEIFFFKDRFIWRTVTPRDKPMGPLLVATFWPELPEK IDAVYEAPQEEKAVFFAGNEYWIYSASTLERGYPKPLTSLGLPPDVQRVDAAFNWSKNK KTYIFAGDKFWRYNEVKKKMDPGFPKLIADAWNAIPDNLDAVVDLQGGGHSYFFKGA YYLKLENQSLKSVKFGSIKSDWLGC (SEQ ID NO: 63), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 63.

Tumor-Targeting Moieties

[0969] In some embodiments, the tumor-targeting moiety comprises an antibody molecule (e.g., Fab or scFv) that binds to mesothelin. In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from the heavy chain variable domain sequence of: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSS (SEQ ID NO: 1), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 1.

[0970] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from GYSFTGYTMN (SEQ ID NO: 2); LITPYNGASSYNQKFRG (SEQ ID NO: 3); and GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0971] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 comprises GYSFTGYTMN (SEQ ID NO: 2); CDR2 comprises: LITPYNGASSYNQKFRG (SEQ ID NO: 3); and CDR3 comprises GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0972] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 consists of GYSFTGYTMN (SEQ ID NO: 2); CDR2 consists of LITPYNGASSYNQKFRG (SEQ ID NO: 3); and CDR3 consists of GGYDGRGFDY (SEQ ID NO: 4), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0973] In some embodiments, the antibody molecule to mesothelin comprises the heavy chain variable domain sequence of: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVT VSS (SEQ ID NO: 1), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 1.

[0974] In some embodiments, the antibody molecule to mesothelin is a Fab and further comprises a heavy chain constant region (CH1) having the amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT (SEQ ID NO: 5), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 5.

[0975] In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6).

[0976] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from the light chain variable domain sequence of: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIK (SEQ ID NO: 7), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 7.

[0977] In some embodiments, the antibody molecule to mesothelin comprises one, two, three CDRs from SASSSVSYMH (SEQ ID NO: 8); DTSKLAS (SEQ ID NO: 9); and QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0978] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 comprises SASSSVSYMH (SEQ ID NO: 8); CDR2 comprises: DTSKLAS (SEQ ID NO: 9); and CDR3 comprises QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0979] In some embodiments, the antibody molecule to mesothelin consists of three CDRs, wherein CDR1 consists of SASSSVSYMH (SEQ ID NO: 8); CDR2 consists of DTSKLAS (SEQ ID NO: 9); and CDR3 consists of QQWSGYPLT (SEQ ID NO: 10), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0980] In some embodiments, the antibody molecule to mesothelin comprises the light chain variable domain sequence of: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIK (SEQ ID NO: 7), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 7.

[0981] In some embodiments, the antibody molecule to mesothelin is a Fab and further comprises a light chain constant region (CL1) having the amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 11.

[0982] In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12). In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence: METDTLLLWVLLLWVPGSTG (SEQ ID NO: 64). In some embodiments, the signal peptide comprises the amino acid sequence: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6).

[0983] In some embodiments, the tumor-targeting moiety comprises an antibody molecule (e.g., Fab or scFv) that binds to FAP.

[0984] In some embodiments, the antibody molecule to FAP comprises one, two, three CDRs from the heavy chain variable domain sequence of: QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSS (SEQ ID NO: 65), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 65.

[0985] In some embodiments, the antibody molecule to FAP comprises one, two, three CDRs selected from SRYTFTEYTIH (SEQ ID NO: 66); GINPNNGIPNYNQKFKG (SEQ ID NO: 67); and RRIAYGYDEGHAMDY (SEQ ID NO: 68), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0986] In some embodiments, the antibody molecule to FAP consists of three CDRs, wherein CDR1 comprises SRYTFTEYTIH (SEQ ID NO: 66); CDR2 comprises: GINPNNGIPNYNQKFKG (SEQ ID NO: 67); and CDR3 comprises RRIAYGYDEGHAMDY (SEQ ID NO: 68), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0987] In some embodiments, the antibody molecule to FAP consists of three CDRs, wherein CDR1 consists of SRYTFTEYTIH (SEQ ID NO: 66); CDR2 consists of GINPNNGIPNYNQKFKG (SEQ ID NO: 67); and CDR3 consists of RRIAYGYDEGHAMDY (SEQ ID NO: 68), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0988] In some embodiments, the antibody molecule to FAP comprises the heavy chain variable domain sequence of: QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSS (SEQ ID NO: 65), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 65.

[0989] In some embodiments, the antibody molecule to FAP is a Fab and further comprises a heavy chain constant region (CH1) having the amino acid sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC (SEQ ID NO: 14), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 14.

[0990] In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12). In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence: METDTLLLWVLLLWVPGSTG (SEQ ID NO: 64). In some embodiments, the signal peptide comprises the amino acid sequence: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6). In some embodiments, the antibody molecule to FAP comprises one, two, three CDRs from the light chain variable domain sequence of: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK (SEQ ID NO: 69), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) from the CDR sequence of SEQ ID NO: 69.

[0991] In some embodiments, the antibody molecule to FAP comprises one, two, three CDRs selected from KSSQSLLYSRNQKNYLA (SEQ ID NO: 70); WASTRES (SEQ ID NO: 71); and QQYFSYPLT (SEQ ID NO: 72), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0992] In some embodiments, the antibody molecule to FAP consists of three CDRs, wherein CDR1 comprises KSSQSLLYSRNQKNYLA (SEQ ID NO: 70); CDR2 comprises: WASTRES (SEQ ID NO: 71); and CDR3 comprises QQYFSYPLT (SEQ ID NO: 72), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0993] In some embodiments, the antibody molecule to FAP consists of three CDRs, wherein CDR1 consists of KSSQSLLYSRNQKNYLA (SEQ ID NO: 70); CDR2 consists of WASTRES (SEQ ID NO: 71); and CDR3 consists of QQYFSYPLT (SEQ ID NO: 72), or a closely related CDR, e.g., CDRs which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions).

[0994] In some embodiments, the antibody molecule to FAP comprises the light chain variable domain sequence of: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK (SEQ ID NO: 69, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 69.

[0995] In some embodiments, the antibody molecule to FAP is a Fab and further comprises a light chain constant region (CL1) having the amino acid sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 11), or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 11.

[0996] In some embodiments, the antibody molecule further comprises a signal peptide, e.g., a signal peptide comprising the amino acid sequence: MKYLLPTAAAGLLLLAAQPAMA (SEQ ID NO: 12). In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence: METDTLLLWVLLLWVPGSTG (SEQ ID NO: 16). In some embodiments, the signal peptide comprises the amino acid sequence: MEFGLSWVFLVALFRGVQC (SEQ ID NO: 6).

Immune Cell Engagers

[0997] In some embodiments, the ligand of NKp30 is a B7-6, e.g., comprises the amino acid sequence of: DLKVEMMAGGTQITPLNDNVTIFCNIFYSQPLNITSMGITWFWKSLTFDKEVKVFEFFGD HQEAFRPGAIVSPWRLKSGDASLRLPGIQLEEAGEYRCEVVVTPLKAQGTVQLEVVASP ASRLLLDQVGMKENEDKYMCESSGFYPEAINITWEKQTQKFPHPIEISEDVITGPTIKNM DGTFNVTSCLKLNSSQEDPGTVYQCVVRHASLHTPLRSNFTLTAARHSLSETEKTDNFS (SEQ ID NO: 24), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 24.

[0998] In some embodiments, the ligand of NKp44 or NKp46 is a viral HA.

[0999] In some embodiments, the ligand of DAP10 is a coreceptor for NKG2D.

[1000] In some embodiments, the ligand of CD16 is a CD16a/b ligand, e.g., a CD16a/b ligand further comprising an antibody Fc region.

[1001] In some embodiments, the ligand of NKG2D is chosen from MICA, MICB, or ULBP1, e.g., wherein:

(i) MICA includes the amino acid sequence: EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNK TWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGEL FLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLK SGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWG DVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW (SEQ ID NO: 25), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 25; (ii) MICB includes the amino acid sequence: AEPHSLRYNLMVL SQDESVQSGFLAEGHLDGQPFLRYDRQKRRAKPQGQWAEDVLGA KTWDTETEDLTENGQDLRRTLTHIKDQKGGLHSLQEIRVCEIHEDSSTRGSRHFYYDGEL FLSQNLETQESTVPQSSRAQTLAMNVTNFWKEDAMKTKTHYRAMQADCLQKLQRYLK SGVAIRRTVPPMVNVTCSEVSEGNITVTCRASSFYPRNITLTWRQDGVSLSHNTQQWGD VLPDGNGTYQTWVATRIRQGEEQRFTCYMEHSGNHGTHPVPSGKVLVLQSQRTD (SEQ ID NO: 26), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 26; or (iii) ULBP1 includes the amino acid sequence: GWVDTHCLCYDFIITPKSRPEPQWCEVQGLVDERPFLHYDCVNHKAKAFASLGKKVNV TKTWEEQTETLRDVVDFLKGQLLDIQVENLIPIEPL TLQARMSCEHEAHGHGRGSWQFL FNGQKFLLFDSNNRKWTALHPGAKKMTEKWEKNRDVTMFFQKISLGDCKMWLEEFL MYWEQMLDPTKPPSLAPG (SEQ ID NO: 27), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 27.

[1002] In some embodiments, the ligand of DNAM1 is chosen from NECTIN2 or NECL5, e.g., wherein:

(i) NECTIN2 includes the amino acid sequence: QDVRVQVLPEVRGQLGGTVELPCHLLPPVPGLYISLVTWQRPDAPANHQNVAAFHPKM GPSFPSPKPGSERL SFVSAKQSTGQDTEAELQDATLALHGLTVEDEGNYTCEFATFPKGS VRGMTWLRVIAKPKNQAEAQKVTFSQDPTTVALCISKEGRPPARISWL SSLDWEAKETQ VSGTLAGTVTVTSRFTLVPSGRADGVTVTCKVEHESFEEPALIPVTLSVRYPPEVSISGYD DNWYLGRTDATLSCDVRSNPEPTGYDWSTTSGTFPTSAVAQGSQLVIHAVDSLFNTTFV CTVTNAVGMGRAEQVIFVRETPNTAGAGATGG (SEQ ID NO: 28), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 28; or (ii) NECL5 includes the amino acid sequence: WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAV FHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVD IWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPG FLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNN WYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICN VTNALGARQAELTVQVKEGPPSEHSGISRN (SEQ ID NO: 29), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 29.

[1003] In some embodiments, the ligand of CRTAM is NECL2, e.g., wherein NECL2 includes the amino acid sequence: QNLFTKDVTVIEGEVATISCQVNKSDDSVIQLLNPNRQTIYFRDFRPLKDSRFQLLNFSSS ELKVSLTNVSISDEGRYFCQLYTDPPQESYTTITVLVPPRNLMIDIQKDTAVEGEEIEVNC TAMASKPATTIRWFKGNTELKGKSEVEEWSDMYTVTSQLMLKVHKEDDGVPVICQVE HPAVTGNLQTQRYLEVQYKPQVHIQMTYPLQGLTREGDALELTCEAIGKPQPVMVTWV RVDDEMPQHAVLSGPNLFINNLNKTDNGTYRCEASNIVGKAHSDYMLYVYDPPTTIPPP TTTTTTTTTTTTTILTIITDSRAGEEGSIRAVDH (SEQ ID NO: 30), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 30.

[1004] In some embodiments, the ligand of CD27 is CD70, e.g., wherein CD70 includes the amino acid sequence: QRFAQAQQQLPLESLGWDVAELQLNHTGPQQDPRLYWQGGPALGRSFLHGPELDKGQ LRIIHRDGIYMVHIQVTLAICSSTTASRHHPTTLAVGICSPASRSISLLRLSFHQGCTIASQR LTPLARGDTLCTNLTGTLLPSRNTDETFFGVQWVRP (SEQ ID NO: 31), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 31.

[1005] In some embodiments, the ligand of PSGL1 is L-selectin (CD62L), e.g., wherein L-selectin includes the amino acid sequence: WTYHYSEKPMNWQRARRFCRDNYTDLVAIQNKAEIEYLEKTLPFSRSYYWIGIRKIGGI WTWVGTNKSLTEEAENWGDGEPNNKKNKEDCVEIYIKRNKDAGKWNDDACHKLKAA LCYTASCQPWSCSGHGECVEIINNYTCNCDVGYYGPQCQFVIQCEPLEAPELGTMDCTH PLGNFSFSSQCAFSCSEGTNLTGIEETTCGPFGNWSSPEPTCQVIQCEPLSAPDLGIMNCSH PLASFSFTSACTFICSEGTELIGKKKTICESSGIWSNPSPICQKLDKSFSMIKEGDYN (SEQ ID NO: 32), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 32.

[1006] In some embodiments, the ligand of CD96 is NECL5, e.g., wherein NECL5 includes the amino acid sequence: WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAV FHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVD IWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPG FLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEVSISGYDNN WYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPVDKPINTTLICN VTNALGARQAELTVQVKEGPPSEHSGISRN (SEQ ID NO: 29), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 29.

[1007] In some embodiments, the ligand of CD100 (SEMA4D) is CD72, e.g., wherein CD72 includes the amino acid sequence: RYLQVSQQLQQTNRVLEVTNSSLRQQLRLKITQLGQSAEDLQGSRRELAQSQEALQVEQ RAHQAAEGQLQACQADRQKTKETLQSEEQQRRALEQKLSNMENRLKPFFTCGSADTCC PSGWIMHQKSCFYISLTSKNWQESQKQCETLSSKLATFSEIYPQSHSYYFLNSLLPNGGS GNSYWTGLSSNKDWKLTDDTQRTRTYAQSSKCNKVHKTWSWWTLESESCRSSLPYICE MTAFRFPD (SEQ ID NO: 33), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 33.

[1008] In some embodiments, the ligand of NKp80 is CLEC2B (AICL), e.g., wherein CLEC2B (AICL) includes the amino acid sequence: KLTRDSQSLCPYDWIGFQNKCYYFSKEEGDWNSSKYNCSTQHADLTIIDNIEEMNFLRR YKCSSDHWIGLKMAKNRTGQWVDGATFTKSFGMRGSEGCAYLSDDGAATARCYTER KWICRKRIH (SEQ ID NO: 34), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 34.

[1009] In some embodiments, the ligand of CD244 is CD48, e.g., wherein CD48 includes the amino acid sequence: QGHLVHMTVVSGSNVTLNISESLPENYKQLTWFYTFDQKIVEWDSRKSKYFESKFKGR VRLDPQSGALYISKVQKEDNSTYIMRVLKKTGNEQEWKIKLQVLDPVPKPVIKIEKIEDM DDNCYLKLSCVIPGESVNYTWYGDKRPFPKELQNSVLETTLMPHNYSRCYTCQVSNSVS SKNGTVCLSPPCTLARS (SEQ ID NO: 35), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 35.

[1010] In some embodiments, the immune cell engager mediates binding to, or activation of, one or more of a B cell, a macrophage, and/or a dendritic cell. In some embodiments, the immune cell engager comprises a B cell, macrophage, and/or dendritic cell engager chosen from one or more of CD40 ligand (CD40L) or a CD70 ligand; an antibody molecule that binds to CD40 or CD70; an antibody molecule to OX40; an OX40 ligand (OX40L); a Toll-like receptor agonist (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4) or a TLR9 agonist); a 41BB agonist; a CD2 agonist; a CD47 agonist; or a STING agonist, or a combination thereof. In some embodiments, the B cell engager is a CD40L, an OX40L, or a CD70 ligand, or an antibody molecule that binds to OX40, CD40 or CD70. In some embodiments, the macrophage cell engager is a CD2 agonist; a CD40L; an OX40L; an antibody molecule that binds to OX40, CD40 or CD70; a Toll-like receptor agonist or a fragment thereof (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4) or TLR9); CD47; or a STING agonist. In some embodiments, the dendritic cell engager is a CD2 agonist, an OX40 antibody, an OX40L, 41BB agonist, a Toll-like receptor agonist (e.g., a TLR4, e.g., a constitutively active TLR4 (caTLR4) or a TLR9 agonist); a CD47 agonist, or a STING agonist.

[1011] In some embodiments, the OX40L comprises the amino acid sequence: QVSHRYPRIQSIKVQFTEYKKEKGFLTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQ EVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGE LILIHQNPGEFCVL (SEQ ID NO: 36), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 36.

[1012] In some embodiments, the CD40L comprises the amino acid sequence: MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLY YIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFE LQPGASVFVNVTDPSQVSHGTGFTSFGLLKL (SEQ ID NO: 37), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 37.

[1013] In some embodiments, the STING agonist comprises a cyclic dinucleotide, e.g., a cyclic di-GMP (cdGMP), a cyclic di-AMP (cdAMP), or a combination thereof, optionally with 2',5' or 3',5' phosphate linkages.

[1014] In one embodiment, the immune cell engager includes 41BB ligand, e.g., comprising the amino acid sequence: ACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPL S WYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALH LQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHL SAGQRLGVHLHTEARARH AWQLTQGATVLGLFRVTPETPAGLPSPRSE (SEQ ID NO: 38), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 38.

Cytokine Molecules

[1015] In one embodiment, the cytokine molecule is IL-15, e.g., human IL-15 (e.g., comprising the amino acid sequence: NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 17), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 17.

[1016] In some embodiments, the cytokine molecule comprises a receptor dimerizing domain, e.g., an IL15Ralpha dimerizing domain. In one embodiment, the IL15Ralpha dimerizing domain comprises the amino acid sequence: MAPRRARGCRTLGLPALLLLLLLRPPATRGITCPPPMSVEHADIWVKSYSLYSRERYICN SGFKRKAGTSSLTECVL (SEQ ID NO: 73), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) of the multispecific molecule are covalently linked, e.g., via a linker (e.g., a Gly-Ser linker, e.g., a linker comprising the amino acid sequence SGGSGGGGSGGGSGGGGSLQ (SEQ ID NO: 19). In other embodiments, the cytokine molecule (e.g., IL-15) and the receptor dimerizing domain (e.g., an IL15Ralpha dimerizing domain) of the multispecific molecule are not covalently linked, e.g., are non-covalently associated.

[1017] In other embodiments, the cytokine molecule is IL-2, e.g., human IL-2 (e.g., comprising the amino acid sequence: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCL EEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFCQSIISTLT (SEQ ID NO: 20), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 20).

[1018] In other embodiments, the cytokine molecule is IL-18, e.g., human IL-18 (e.g., comprising the amino acid sequence: YFGKLESKL SVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGM AVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEG YFLACEKERDLFKLILKKEDELGDRSIMFTVQNED (SEQ ID NO: 74), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 74).

[1019] In other embodiments, the cytokine molecule is IL-21, e.g., human IL-21 (e.g., comprising the amino acid sequence: QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSA NTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMI HQHLSSRTHGSEDS (SEQ ID NO: 22), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 22).

[1020] In yet other embodiments, the cytokine molecule is interferon gamma, e.g., human interferon gamma (e.g., comprising the amino acid sequence: QDPYVKEAENLKKYFNAGHSDVADNGTLFLGILKNWKEESDRKIMQSQIVSFYFKLFK NFKDDQSIQKSVETIKEDMNVKFFNSNKKKRDDFEKLTNYSVTDLNVQRKAIHELIQVM AELSPAAKTGKRKRSQMLFRG (SEQ ID NO: 23), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 23).

Linkers

[1021] In some embodiments, the multifunctional molecule further comprises a linker, e.g., a linker between the tumor targeting moiety and the stromal modifying moiety, the cytokine molecule and the immunoglobulin chain constant region (e.g., the Fc region), the targeting moiety and the immunoglobulin chain constant region, or the immune cell engager and the immunoglobulin chain constant region.

[1022] In some embodiments, the linker is selected from: a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker. In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker comprises Gly and Ser. In some embodiments, the peptide linker is selected from GGGGS (SEQ ID NO: 42); GGGGSGGGGSGGGGS (SEQ ID NO: 44); and DVPSGPGGGGGSGGGGS (SEQ ID NO: 45). In some embodiments, the peptide linker is a A(EAAAK)nA family of linkers (e.g., as described in Protein Eng. (2001) 14 (8): 529-532). These are stiff helical linkers with n ranging from 2-5. In some embodiments, the peptide linker is selected from AEAAAKEAAAKAAA (SEQ ID NO: 75); AEAAAKEAAAKEAAAKAAA (SEQ ID NO: 76); AEAAAKEAAAKEAAAKEAAAKAAA (SEQ ID NO: 77); and AEAAAKEAAAKEAAAKEAAAKEAAAKAAA (SEQ ID NO: 78).

Configurations of the Multifunctional Molecules

[1023] In some embodiments, the multifunctional molecule includes a single chain antibody molecule, e.g., a single domain antibody, a scFv, a camelid, or a shark antibody, and a second moiety. In some embodiments, the multifunctional molecule comprises a VH to VL from N to C orientation, of the scFv connected, optionally via a linker, to the second moiety (e.g., as shown in FIGS. 1A and 1B); the scFv can form the first binding specificity (depicted as binding moiety "1" in FIGS. 1A-1B). In some embodiments, the second moiety (depicted as partner A in FIGS. 1A-1B) is located before the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1A), or after the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1B); the second moiety can form the second binding specificity (depicted as binding moiety "2" in FIGS. 1A-1B). In other embodiments, the multifunctional molecule comprises a VL to VH from N to C orientation, of the scFv connected, optionally via a linker, to the second moiety (e.g., as shown in FIGS. 2A and 2B); the scFv can form the first binding specificity (depicted as binding moiety "1" in FIGS. 2A-2B). In some embodiments, the second moiety (depicted as partner A in FIGS. 2A-2B) is located before the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2A), or after the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2B); the second moiety can form the second binding specificity (depicted as binding moiety "2" in FIGS. 2A-2B). In embodiments, the scFv can be a tumor targeting moiety (e.g., binds to a cancer antigen, e.g., a solid tumor, stromal, or hematological antigen), or can be an immune cell engager (e.g., binds to an immune cell antigen). In other embodiments, the second moiety (e.g., depicted as partner A in FIGS. 1A-1B or 2A-2B) is a stromal modifying, e.g., as described herein.

[1024] In other embodiments, the multifunctional molecule is a trispecific or trifunctional that includes, or consists of, a single chain polypeptide, e.g., a contiguous single polypeptide chain. For example, the multifunctional molecule can include a tumor targeting moiety (e.g., a first binding specificity to a cancer antigen, e.g., a solid tumor, stromal, or hematological antigen as described herein), a stromal modifying, e.g., as described herein, and one of: a cytokine molecule as described herein, and an immune cell engager (e.g., a second binding specificity to an immune cell antigen as described herein), or any combination of any of the aforesaid.

[1025] In some embodiments, the multifunctional molecule includes a single chain antibody molecule, e.g., a single domain antibody, a scFv, a camelid, or a shark antibody, and a second moiety. In some embodiments, the multifunctional molecule comprises a VH to VL from N to C orientation, of the scFv connected, optionally via a linker, to a second moiety and/or a third moiety (e.g., as shown in FIG. 1C); the scFv can form the first binding specificity (depicted as binding moiety "1" in FIG. 1C). In some embodiments, the second or third moieties (depicted as partners A and B in FIG. 1C) is located before the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1C) and the third moiety (partner B) after the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 1C), respectively; the second and third moieties can form the second and third binding specificities (depicted as binding moiety "2" and binding moiety "3," respectively, in FIG. 1C). In other embodiments, the multifunctional molecule comprises a VL to VH from N to C orientation, of the scFv connected, optionally via a linker, to a second moiety and/or a third moiety (e.g., as shown in FIG. 2C). In some embodiments, the second moiety (depicted as partner A in FIG. 2C) is located before the VL region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2C), and the third moiety (partner B) after the VH region of the scFv from an N- to C-orientation (e.g., as shown in FIG. 2C); the second and third moieties can form the second and third binding specificities (depicted as binding moiety "2" and binding moiety "3," respectively, in FIG. 2C). In embodiments, the scFv of any of the aforesaid multifunctional molecules can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a solid tumor, stromal or hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety or the third moiety (e.g., depicted as partner A and partner B in FIG. 1C or 2C) include a stromal modifying, e.g., as described herein, with the remaining moiety being chosen from a second tumor targeting moiety, an immune cell engager, or a cytokine molecule (e.g., as described herein). In embodiments, partner A and/or partner B can be an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv or a Fab), a stromal modifying moiety, receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the tumor-targeting moiety is a scFv to a cancer cell antigen, the second moiety is a stromal modifying, e.g., as described herein, and third moiety is independently chosen from a cytokine molecule or an immune cell engager. In some embodiments, the second and third moiety is independently chosen from a stromal modifying moiety, a second antibody molecule (e.g., a second scFv or Fab), a receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule).

[1026] In embodiments, the multifunctional molecule is a bispecific or bifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In embodiments, the first and second polypeptides have a configuration as shown in FIGS. 3A-3B or FIGS. 4A-4B. In embodiments, the first and second polypeptides form a first binding specificity, e.g., an antigen binding domain (e.g., depicted as binding moiety "1" in FIGS. 3A-3B and FIGS. 4A-4B). In embodiments, a second moiety (depicted as partner A) is connected, e.g., via a linker, to either the first polypeptide or the second polypeptide. In embodiments, the second moiety forms a second binding specificity (e.g., depicted as binding moiety "2" in FIGS. 3A-3B and FIGS. 4A-4B).

[1027] In one embodiment depicted in FIGS. 3A-3B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the C-terminus of the second polypeptide (e.g., the C-terminus of the CL region of the second polypeptide) (e.g., as shown in FIG. 3A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the C-terminus of the first polypeptide (e.g., C-terminus of the CH1 region of the first polypeptide) (e.g., as shown in FIG. 3B).

[1028] In another embodiment depicted in FIGS. 4A-4B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the N-terminus of the second polypeptide (e.g., the N-terminus of the VL region of the second polypeptide) (e.g., as shown in FIG. 4A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the N-terminus of the first polypeptide (e.g., the N-terminus of the VH region of the first polypeptide) (e.g., as shown in FIG. 4B).

[1029] In embodiments, the first and second polypeptide (e.g., the VH and VL regions) can form a binding moiety (e.g., binding moiety 1 in FIGS. 3A-3B and 4A-4B); for example, the first and second polypeptide can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a solid tumor, a stromal or hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety (e.g., depicted as partner A in FIGS. 3A-3B and 4A-4B) includes a stromal modifying moiety, e.g., a stromal modifying moiety as described herein.

[1030] In embodiments, the multispecific molecule is a bispecific or bifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In embodiments, the first and second polypeptides have a configuration as shown in FIGS. 3A-3B or FIGS. 4A-4B. In embodiments, a second moiety (depicted as partner A) is connected, e.g., via a linker, to either the first polypeptide or the second polypeptide (e.g., either the N-terminus or the C-terminus of the first polypeptide or the second polypeptide).

[1031] In one embodiment of the bispecific or bifunctional molecule depicted in FIGS. 3A-3B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the CL region (e.g., C-terminus of the CL region) of the second polypeptide (e.g., as shown in FIG. 3A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the CH1 region (e.g., C-terminus of the CH1 region) of the first polypeptide (e.g., as shown in FIG. 3B).

[1032] In another embodiment of the bispecific or bifunctional molecule depicted in FIGS. 4A-4B, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the VL region (e.g., N-terminus of the VL region) of the second polypeptide (e.g., as shown in FIG. 4A). In other embodiments, the second moiety (e.g., partner A) is connected, e.g., via a linker, to the VH region (e.g., N-terminus of the VH region) of the first polypeptide (e.g., as shown in FIG. 4B).

[1033] In embodiments of the bispecific or bifunctional molecule, the first and second polypeptide (e.g., the VH and VL regions) can form a binding moiety (e.g., binding moiety 1 in FIGS. 3A-3B and 4A-4B); for example, the first and second polypeptide can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a tumor, a stromal or a hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety (e.g., depicted as partner A in FIGS. 3A-3B and 4A-4B) includes a stromal modifying moiety, e.g., as described herein.

[1034] In one embodiment, the multispecific molecule includes a Fab molecule and the second moiety is chosen from a stromal modifying moiety, or a second antibody molecule (e.g., a scFv or a second Fab), a receptor molecule, or a ligand molecule (e.g., a cytokine molecule). In one embodiment, the tumor-targeting moiety is a Fab to a cancer cell antigen, and the second moiety includes a stromal modifying moiety, optionally further including a cytokine molecule or an immune cell engager. In some embodiments, the second moiety is a second antibody molecule (e.g., a second scFv or Fab), a stromal modifying moiety, a receptor molecule, a receptor ligand molecule, or a cytokine molecule.

[1035] In other embodiments, the multispecific molecule is a trispecific or a trifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In embodiments, the first and second polypeptides have a configuration as shown in FIGS. 3C and 4C. In embodiments, a second moiety and a third moiety (depicted as partners A and B, respectively) are connected, e.g., via a linker, to the C-terminus, the N-terminus, or both of the first polypeptide and the second polypeptide, respectively. In one embodiment, the second moiety and third moieties are connected to C-terminus of the second and first polypeptides (or the first and second polypeptides), respectively. In another embodiment, the second moiety and third moieties are connected to N-terminus of the second and first polypeptides (or the first and second polypeptides), respectively. In one embodiment, the second moiety and third moiety are connected to N- and C-terminus of the second and first polypeptides (or the first and second polypeptides), respectively. Any configuration is intended by the present disclosure, including those exemplified in FIGS. 3C and 4C.

[1036] In one embodiment of the trispecific or trifunctional molecule depicted in FIGS. 3C-4C, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the C-terminus of the second polypeptide (e.g., the C-terminus of the CL region of the second polypeptide) (e.g., as shown in FIG. 3C), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the C-terminus of the first polypeptide (e.g., the C-terminus of the CH1 region of the first polypeptide) (e.g., as shown in FIG. 3C).

[1037] In another embodiment of the trispecific or trifunctional molecule depicted in FIGS. 3C-4C, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the N-terminus of the second polypeptide (e.g., the N-terminus of the VL region of the second polypeptide) (e.g., as shown in FIG. 4C), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the N-terminus of the first polypeptide (e.g., the N-terminus of the VH region of the first polypeptide) (e.g., as shown in FIG. 4C).

[1038] In another embodiment of the trispecific or trifunctional molecule, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the N-terminus of the second polypeptide (e.g., the N-terminus of the VL region of the second polypeptide), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the C-terminus of the first polypeptide (e.g., the C-terminus of the CH1 region of the first polypeptide).

[1039] In another embodiment of the trispecific or trifunctional molecule, the second moiety (e.g., partner A corresponding to the second binding specificity "2") is connected, e.g., via a linker, to the C-terminus of the second polypeptide (e.g., the N-terminus of the CL region of the second polypeptide), and the third moiety (e.g., partner B corresponding to the third binding specificity "3") is connected, e.g., via a linker, to the N-terminus of the first polypeptide (e.g., the N-terminus of the VH region of the first polypeptide).

[1040] In embodiments of the trispecific or trifunctional molecule, the first and second polypeptides (e.g., the VH and VL regions) can form a first binding specificity (e.g., binding moiety "1" in FIGS. 3C and 4C); for example, the first and second polypeptide can be a tumor targeting moiety (e.g., bind to a cancer antigen, e.g., a solid tumor, a stromal or a hematological antigen) or can be an immune cell engager (e.g., bind to an immune cell antigen). In embodiments, the second moiety or the third moiety (e.g., depicted as partners A and B in FIGS. 3C and 4C) includes a stromal modifying moiety, e.g., a stromal modifying moiety as described herein, and the remaining moiety is chosen from a tumor targeting moiety, an immune cell engager, or a cytokine molecule (e.g., as described herein). In embodiments, the second and a third binding specificity, e.g., partners A and B, can be, independently, a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the multifunctional molecule includes a Fab molecule and the second moiety or third moiety includes a stromal modifying moiety, and the remaining moiety is chosen from a second antibody molecule (e.g., a scFv or a second Fab), a receptor molecule, or a ligand molecule (e.g., a receptor ligand or a cytokine molecule). In some embodiments, the first binding specificity, the second binding specificity and the third binding specificity can each be independently chosen from a tumor targeting moiety, a stromal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In one embodiment, the tumor-targeting moiety is a Fab to a cancer cell antigen, and the second or third moiety is a stromal modifying moiety, and the remaining moiety is chosen from a cytokine molecule or an immune cell engager.

[1041] In one embodiment, the multifunctional molecule includes at least two, at least three, or at least four non-contiguous polypeptides, wherein:

[1042] (i) the first polypeptide includes from N- to C-orientation a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region); and

[1043] (ii) the second polypeptide includes from N- to C-orientation a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region).

[1044] In embodiments, the multifunctional molecule is a bispecific or bifunctional molecule, wherein the first and second polypeptides (i) and (ii) are non-contiguous, e.g., are two separate polypeptide chains. In some embodiments, the first and second polypeptides (i) and (ii) include a paired amino acid substitution at a position chosen from one or more of 347, 349, 350, 351, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407, or 409, e.g., of the Fc region of human IgG1 For example, the first immunoglobulin chain constant region (e.g., the first Fc region) can include an amino acid substitution chosen from: T366S, L368A, or Y407V (e.g., corresponding to a cavity or hole), and the second immunoglobulin chain constant region (e.g., the second Fc region) includes a T366W (e.g., corresponding to a protuberance or knob). In some embodiments, the first and second polypeptides are a first and second member of a heterodimeric first and second Fc region.

[1045] In embodiments, the first and second polypeptides form a bifunctional, e.g., a bispecific, molecule. In some embodiments, the first polypeptide includes a first binding and/or functional specificity (e.g., partner A or binding specificity 1 in FIG. 5A), and the second polypeptide includes a second binding and/or functional specificity (e.g., partner B or binding specificity 2 in FIG. 5A). In embodiments, the first and second binding and/or functional specificities (partner A and partner B, respectively) is each independently chosen from a stromal modified moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In embodiments, the first and second binding specificities are connected to either the first or the second polypeptide, or each of the polypeptides, (e.g., one or both members of a heterodimeric Fc molecule). In one embodiment, the first binding specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule), and the second binding specificity (e.g., partner B) is connected to the N-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). Alternatively, the first binding and/or functional specificity (e.g., partner A) is connected to the C-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule), and the second binding and/or functional specificity (e.g., partner B) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). Alternatively, the first binding specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule), and the second binding specificity (e.g., partner B) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). In other embodiments, the second binding and/or functional specificity (e.g., partner B) is connected to N-terminus of the first polypeptide (e.g., the --CH2-CH3- region of the first Fc molecule), and the first binding and/or functional specificity (e.g., partner A) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). In one embodiment, the first --CH2-CH3 region includes a protuberance or knob, and the second --CH2-CH3 region includes a cavity or hole, e.g., as depicted in FIG. 5A).

[1046] In some embodiments, the first and second binding and/or functional specificities (binding moiety 1 and binding moiety 2) of the bifunctional molecule can each be independently chosen from a stromal modifying moiety, a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the first binding and/or functional specificity is a tumor targeting moiety and the second binding and/or functional specificity is a stromal modifying moiety. In other embodiments, the first binding and/or functional specificity is an immune cell engager and the second binding and/or functional specificity is a stromal modifying moiety, e.g., wherein the immune cell engager is chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[1047] In some embodiments shown in FIG. 5A, the bispecific molecule can have partner A and B, which are depicted as first and second binding and/or functional specificities (binding moieties 1 and 2), respectively (FIG. 5A). The first and second binding and/or functional specificities can be, each independently, a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In some embodiments, the first binding and/or functional specificity is a tumor targeting moiety and the second binding and/or functional specificity is a stromal modifying moiety. In other embodiments, the first binding and/or functional specificity is an immune cell engager and the second binding and/or functional specificity is a stromal modifying moiety, e.g., wherein the immune cell engager is chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[1048] In embodiments, the first and second polypeptides form a trifunctional, e.g., a trispecific, or a tetrafunctional, e.g., a tetraspecific, molecule (e.g., as depicted in FIGS. 5B-5C, respectively).

[1049] In some embodiments of the trifunctional, e.g., the trispecific, molecule, the first polypeptide includes a first binding and/or functional specificity (e.g., partner A or binding moiety 1 in FIG. 5B), and the second polypeptide includes a second binding and/or functional specificity (e.g., partner B or binding specificity 2 in FIG. 5B), wherein either the first or the second polypeptide further includes a third binding and/or functional specificity (e.g., partner C or binding moiety 3 in FIG. 5B). In embodiments, the first and second binding and/or functional specificities are connected to either the first or the second polypeptide, or each of the polypeptides, (e.g., one or both members of a heterodimeric Fc molecule). In one embodiment, the first and second binding and/or functional specificities are connected, e.g., via a linker, to the N-terminus of the first and the second polypeptide, respectively, and the third binding and/or functional specificity is connected, e.g., via a linker, to the C-terminal end of either the first or the second polypeptide. In one embodiment, the third binding and/or functional specificity is connected, e.g., via a linker, to the C-terminal end of the first polypeptide (e.g., the C-terminal end of the first --CH2-CH3 region depicted in FIG. 5B). In one embodiment, the third binding and/or functional specificity is connected, e.g., via a linker, to the C-terminal end of the second polypeptide (e.g., the C-terminal end of the second --CH2-CH3 region). In one embodiment, the first --CH2-CH3 region includes a protuberance or knob, and the second --CH2-CH3 region includes a hole or cavity, e.g., as depicted in FIG. 5B).

[1050] In embodiments, the first, second and third binding and/or functional specificities (partner A, partner B, and partner C respectively) is each independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. In one embodiment, the first binding and/or functional specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule); the second binding and/or functional specificity (e.g., partner B) is connected to the N-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule); and the third binding and/or functional specificity (e.g., partner C) is connected to the C-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). In other embodiments, the first binding and/or functional specificity (e.g., partner A) is connected to the N-terminal end of the first polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule); the second binding and/or functional specificity (e.g., partner B) is connected to the N-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the first Fc molecule); and the third binding and/or functional specificity (e.g., partner C) is connected to the C-terminal end of the second polypeptide (e.g., a --CH2-CH3- region of the second Fc molecule). The first, second and third binding and/or functional specificities can each be, independently, a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second and third binding and/or functional specificities (partners A-C, corresponding to binding moieties 1-3, respectively) are each independently chosen from a tumor targeting moiety, a stomal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In embodiments, the first binding and/or functional specificity is a tumor targeting moiety, the second binding and/or functional specificity is a stromal modifying moiety, and the third binding and/or functional specificity is chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[1051] In some embodiments of the tetrafunctional, e.g., the tetraspecific, molecule, the first polypeptide includes a first binding and/or functional specificity (e.g., partner A or binding moiety 1 in FIG. 5C) and a third binding and/or functional specificity (e.g., partner C or binding moiety 3 in FIG. 5C), and the second polypeptide includes a second binding and/or functional specificity (e.g., partner B or binding specificity 2 in FIG. 5C) and a fourth binding and/or functional specificity (e.g., partner D or binding moiety 4 in FIG. 5C). In one embodiment, the first and second binding specificities are connected, e.g., via a linker, to the N-terminus of the first and the second polypeptide, respectively, and the third and fourth binding specificities are connected, e.g., via a linker, to the C-terminal end of the first and the second polypeptide, respectively. Any permutation of binding and/or functional specificity to the N- or C-terminus of the first or second polypeptide is encompassed by the present disclosure. In one embodiment, the first binding and/or functional specificity (e.g., partner A) is connected, e.g., via a linker, to the N-terminal end of the first polypeptide (e.g., the N-terminal end of the first --CH2-CH3 region depicted in FIG. 5C); the second binding and/or functional specificity (e.g., partner B) is connected, e.g., via a linker, to the N-terminal end of the second polypeptide (e.g., the N-terminal end of the second --CH2-CH3 region depicted in FIG. 5C); the third binding and/or functional specificity (e.g., partner C) is connected, e.g., via a linker, to the C-terminal end of the first polypeptide (e.g., the C-terminal end of the first --CH2-CH3 region depicted in FIG. 5C); and the fourth binding and/or functional specificity (e.g., partner D) is connected, e.g., via a linker, to the C-terminal end of the second polypeptide (e.g., the C-terminal end of the second -CH2-CH3 region). In one embodiment, the first --CH2-CH3 region includes a protuberance or knob, and the second --CH2-CH3 region includes a cavity or hole, e.g., as depicted in FIG. 5C). In embodiments, the first, second, third and fourth binding and/or functional specificities (partner A, partner B, partner C and partner D, respectively) is each independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand or a cytokine molecule), e.g., as described herein. The first, second, third and fourth binding and/or functional specificities can each be, independently, a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second, third and fourth binding and/or functional specificities (partners A-D, corresponding to binding moieties 1-4, respectively) are each independently chosen from a tumor targeting moiety, a stromal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In embodiments, the first binding and/or functional specificity is a tumor targeting moiety, the second binding and/or functional specificity is a stromal modifying moiety, and the third and fourth binding and/or functional specificities are each independently chosen from a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager.

[1052] In one embodiment, the multifunctional molecule is a bispecific molecule that includes two non-contiguous first and second polypeptides. In embodiments, the first and second polypeptides, include, respectively, a first and a second binding sites, which are independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first and second binding and/or functional specificities (binding sites 1-2, respectively) are each independently chosen from a stromal modifying moiety, a tumor targeting moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In some embodiments, the first polypeptide has the following configuration from N-to-C: a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a cancer antigen (e.g., binding site #1), connected, optionally, via a linker to, a second binding and/or functional specificity (e.g., a binding site #2, e.g., a stromal modifying moiety, e.g., as described herein); and the second polypeptide has the following configuration from N-to-C: a second portion of a first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a cancer antigen (e.g., the same cancer antigen bound by the first VH-CH1, e.g., binding site #1) (e.g., an example of this configuration is depicted in FIG. 16). In one embodiment, the bispecific molecule that includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the second binding and/or functional specificity (e.g., binding site #2, e.g., a stromal modifying moiety, e.g., as described herein). In some embodiments, the first binding and/or functional specificity (e.g., binding site #1 in FIG. 16) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; and the second binding and/or functional specificity (e.g., binding site #2 in FIG. 16) is a stromal modifying moiety, e.g., as described herein.

[1053] In another embodiment, the multifunctional molecule is a bifunctional, e.g., a bispecific, molecule that includes two or at least three non-contiguous first and second polypeptides, wherein:

[1054] (i) the first polypeptide includes from N- to C-orientation a first binding and/or functional specificity, e.g., a first antibody molecule, connected, optionally via a linker, to a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region);

[1055] (ii) the second polypeptide includes from N- to C-orientation a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region); and

[1056] (optionally) (iii) a third polypeptide comprising a portion of the first antibody molecule or a second antibody molecule.

[1057] In embodiments, the first and second polypeptides, include, respectively, a first and a second binding and/or functional specificities (e.g., sites), which are independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first and second binding and/or functional specificities (binding sites 1-2, respectively) are a tumor targeting moiety and a stromal modifying moiety, e.g., as described herein.

[1058] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[1059] (a) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a cancer antigen, e.g., a solid tumor, stromal or hematological antigen (e.g., binding site #1), connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., a first Fc region);

[1060] (b) a second binding and/or functional specificity (e.g., a second binding site), which is a stromal modifying moiety, connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and

[1061] (c) the third polypeptide has the following configuration from N-to-C: a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a cancer antigen, e.g., a solid tumor, stromal or hematological antigen (e.g., the same cancer antigen bound by the first VH-CH1, e.g., binding site #1) (e.g., an example of this configuration is depicted in FIG. 7).

[1062] In one embodiment, the bifunctional, e.g., bispecific, molecule that includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the first Fc region, and the second binding and/or functional specificity (e.g., binding site #2, e.g., a stromal modifying moiety, e.g., as described herein) connected, optionally via a linker, to the second Fc region.

[1063] In some embodiments, the first binding and/or functional specificity (e.g., binding site #1 in FIG. 17) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; and the second binding and/or functional specificity (e.g., binding site #2 in FIG. 17) is a stromal modifying moiety, e.g., as described herein.

[1064] In embodiments, the first immunoglobulin constant region (e.g., the first CH2-CH3 region) includes a protuberance or knob, e.g., as described herein.

[1065] In embodiments, the second immunoglobulin constant region (e.g., the second CH2-CH3 region) includes a cavity or hole. In embodiments, the first and second immunoglobulin constant region promote heterodimerization of the bispecific molecule.

[1066] In one embodiment, the multifunctional molecule is a trifunctional, e.g., a trispecific, molecule that includes two non-contiguous first and second polypeptides. In embodiments, the first and second polypeptides, include, respectively, a first, a second and a third binding and/or functional specificities, which are independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second and third binding and/or functional specificities (binding sites 1-3, respectively) are each independently chosen from a tumor targeting moiety, a stromal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In some embodiments, the first binding and/or functional specificity (binding site 1) is a tumor targeting moiety, the second binding and/or functional specificity (binding site 2) is a stromal modifying moiety, and the third binding and/or functional specificities (binding site 3) is chosen from a tumor targeting moiety, a stromal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[1067] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[1068] (i) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a cancer antigen (e.g., binding site #1), connected, optionally, via a linker to, a second binding and/or functional specificity (e.g., a binding site #3, e.g., a cytokine, a ligand or a second antibody molecule, e.g., a scFv); and

[1069] (ii) the second polypeptide has the following configuration from N-to-C: a second portion of a first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1, e.g., binding site #1), connected, optionally, via a linker to, a third binding and/or functional specificity (e.g., a binding site #2, e.g., a stromal modifying moiety) (e.g., an example of this configuration is depicted in FIG. 18.

[1070] In one embodiment, the bifunctional, e.g., bispecific, molecule includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the second and third binding and/or functional specificities (e.g., binding sites #2 and #3). In some embodiments, the first binding and/or functional specificity (e.g., binding site #1 in FIG. 18) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; the second binding and/or functional specificity (e.g., binding site #2 in FIG. 18) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and the third binding and/or functional specificity (e.g., binding site #3) is a stromal modifying moiety. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[1071] In another embodiment, the multifunctional molecule is a trifunctional, e.g., a trispecific, molecule that includes two or at least three non-contiguous first and second polypeptides, wherein:

[1072] (i) the first polypeptide includes from N- to C-orientation a first binding specificity, e.g., a first antibody molecule, connected, optionally via a linker, to a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region);

[1073] (ii) the second polypeptide includes from N- to C-orientation a second binding specificity connected, optionally via a linker, to a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region); and

[1074] (optionally) (iii) a third polypeptide comprising a portion of the first antibody molecule or a second antibody molecule, wherein either the first or the second polypeptide further includes a third binding and/or functional specificity.

[1075] In embodiments, the first and second polypeptides, include, respectively, a first, a second, and a third binding and/or functional specificities (e.g., sites), which are independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second and third binding and/or functional specificities (binding sites 1-3, respectively) are each independently chosen from a tumor targeting moiety, a stromal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein. In one embodiment, the first binding and/or functional specificity (binding site #1) is a tumor targeting moiety, the second binding and/or functional specificity (binding site #2) is an immune cell engager or a cytokine molecule, and the third binding and/or functional specificity (binding site #3) is a stromal modifying moiety, e.g., as shown in FIG. 19A or 19B.

[1076] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[1077] (a) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a tumor or stromal antigen (e.g., binding site #1), connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., a first Fc region);

[1078] (b) a second binding and/or functional specificity (e.g., a second binding site), which is chosen from a cytokine molecule, or an immune cell engager, connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and

[1079] (c) the third polypeptide has the following configuration from N-to-C: a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1, e.g., binding site #1),

[1080] wherein either the first or the second polypeptide further includes a third binding and/or functional specificity, which is connected, optionally, via a linker to, the first or second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first or second Fc region). In one embodiment, the third binding specificity is connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first Fc region). In another embodiment, the third binding specificity is connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region). Examples of these configurations are depicted in FIGS. 19A-19B.

[1081] In one embodiment, the trifunctional, e.g., trispecific, molecule includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the first Fc region; and the second binding and/or functional specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region, which further includes the third binding and/or functional specificity (e.g., binding site #3) (e.g., as depicted in FIG. 19A). In other embodiments, the trifunctional, e.g., trispecific, molecule includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the first Fc region, which further includes the third binding and/or functional specificity (e.g., binding site #3); and the second binding and/or functional specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region (e.g., as depicted in FIG. 19B).

[1082] In some embodiments, (a) the first binding and/or functional specificity (e.g., binding site #1 in FIGS. 19A-19B) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; (b) the second binding and/or functional specificity (e.g., binding site #2 in FIGS. 19A-19B) is chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and (c) the third binding and/or functional specificity (e.g., binding site #3 in FIGS. 19A-19B) is a stromal modifying moiety. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[1083] In embodiments, the first immunoglobulin constant region (e.g., the first CH2-CH3 region) includes a protuberance or knob, e.g., as described herein.

[1084] In embodiments, the second immunoglobulin constant region (e.g., the second CH2-CH3 region) includes a cavity or hole. In embodiments, the first and second immunoglobulin constant region promote heterodimerization of the bispecific molecule.

[1085] In another embodiment, the multifunctional molecule is a tetrafunctional, e.g., tetraspecific, molecule that includes two or at least three non-contiguous first and second polypeptides, wherein:

[1086] (i) the first polypeptide includes from N- to C-orientation a first binding and/or functional specificity, e.g., a first antibody molecule, connected, optionally via a linker, to a first immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a first Fc region);

[1087] (ii) the second polypeptide includes from N- to C-orientation a second binding and/or functional specificity connected, optionally via a linker, to a second immunoglobulin constant region (e.g., a CH2 connected to a CH3 region) (e.g., a second Fc region); and

[1088] (optionally) (iii) a third polypeptide comprising a portion of the first antibody molecule or a second antibody molecule,

[1089] wherein the first or the second polypeptide further includes a third and a fourth binding and/or functional specificities.

[1090] In embodiments, the first and second polypeptides, include, respectively, a first, a second, a third and a fourth binding and/or functional specificities (e.g., sites), which are independently chosen from a stromal modifying moiety, an enzyme molecule, an antibody molecule (e.g., a single chain antibody molecule (e.g., a scFv) or a Fab), a receptor molecule, a ligand molecule (e.g., a receptor ligand, or a cytokine molecule), e.g., as described herein. In some embodiments, the first, second, third and fourth binding and/or functional specificities (binding sites 1-4, respectively) are each independently chosen from a tumor targeting moiety, a stromal modifying moiety, a cytokine molecule, an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager, e.g., as described herein.

[1091] In some embodiments, the first polypeptide has the following configuration from N-to-C:

[1092] (a) a first portion of a first antigen domain, e.g., a first VH-CH1 of a Fab molecule, that binds to, e.g., a tumor or stromal antigen (e.g., binding site #1), connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., a first Fc region);

[1093] (b) a second binding and/or functional specificity (e.g., a second binding site), which is chosen from a cytokine molecule, or an immune cell engager, connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and

[1094] (c) the third polypeptide has the following configuration from N-to-C: a second portion of the first antigen domain, e.g., a first VL-CL of the Fab, that binds to, e.g., a tumor or stromal antigen (e.g., the same tumor or stromal antigen bound by the first VH-CH1, e.g., binding site #1),

[1095] wherein the first and the second polypeptide further includes a third and a fourth binding and/or functional specificity, respectively, each of which is connected, optionally, via a linker to, the first and second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first and second Fc region). In one embodiment, the third binding and/or functional specificity is connected, optionally, via a linker to, the second immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the second Fc region); and the fourth binding and/or functional specificity is connected, optionally, via a linker to, the first immunoglobulin constant region (e.g., the CH2 connected to the CH3 region) (e.g., the first Fc region). Examples of these configurations are depicted in FIG. 20.

[1096] In one embodiment, the tetrafunctional, e.g., tetraspecific, molecule includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the first Fc region, which further includes a fourth binding and/or functional specificity (e.g., binding site #4); and the second binding and/or functional specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region, which further includes the third binding and/or functional specificity (e.g., binding site #3) (e.g., as depicted in FIG. 20). In other embodiments, the tetrafunctional, e.g., tetraspecific, molecule includes a Fab corresponding to the first binding and/or functional specificity (binding site #1) connected, optionally via a linker, to the first Fc region, which further includes a third binding and/or functional specificity (e.g., binding site #3); and the second binding and/or functional specificity (e.g., binding site #2) connected, optionally via a linker, to the second Fc region, which further includes the fourth binding and/or functional specificity (e.g., binding site #4).

[1097] In some embodiments, (a) the first binding and/or functional specificity (e.g., binding site #1 in FIG. 20) is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; the second and fourth binding and/or functional specificities (e.g., binding sites #2 and 4 in FIG. 20) are each independently chosen from a cytokine molecule, or an immune cell engager, e.g., chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and the third binding and/or functional specificity (e.g., binding site #3 in FIG. 20) is a stromal modifying moiety. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[1098] In another embodiment, (a) the first binding and/or functional specificity is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor, stromal or hematological antigen; (b) the second binding and/or functional specificity is an immune cell engager (e.g., an NK cell engager) chosen from a receptor, a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; (c) the third binding and/or functional specificity is a cytokine molecule or an immune cell engager; and (d) the fourth binding and/or functional specificity is a stromal modifying moiety. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[1099] In one embodiment, (a) the first binding and/or functional specificity is a tumor targeting moiety, e.g., binds to a cancer antigen, e.g., a tumor or stromal antigen; (b) the second binding and/or functional specificity is a stromal modifying moiety; (c) the third binding and/or functional specificity is an immune cell engager (e.g., a macrophage or a dendritic cell engager) chosen from a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen; and (d) the fourth binding and/or functional specificity is an immune cell engager (e.g., a macrophage or a dendritic cell engager) chosen from a ligand molecule or an antibody molecule (e.g., a scFv) that binds to an immune cell antigen. In embodiments where the antibody molecule is a scFv, the scFv may be connected to the C-terminus of the first polypeptide in a VH-VL or a VL-VH configuration.

[1100] In embodiments, the first immunoglobulin constant region (e.g., the first CH2-CH3 region) includes a protuberance or knob, e.g., as described herein.

[1101] In embodiments, the second immunoglobulin constant region (e.g., the second CH2-CH3 region) includes a cavity or hole. In embodiments, the first and second immunoglobulin constant region promote heterodimerization of the bispecific molecule.

[1102] In some embodiments, the multifunctional molecule comprises the following formula in an N terminal to C terminal orientation:

[1103] R1-(optionally L1)-R2;

[1104] R2-(optionally L1)-R1;

[1105] wherein:

[1106] (i) R1 comprises 1, 2 or more stromal modifying moieties, e.g., the same or different stromal modifying moieties as described herein;

[1107] (ii) R2 comprises 1, 2 or more tumor targeting moieties, e.g., the same or different tumor targeting moieties as described herein; and

[1108] (iii) optionally, L1 is the linker (e.g., a linker described herein).

[1109] In some embodiments, the multifunctional molecule further comprises R3, wherein R3 comprises 1, 2 or more cytokine molecules, e.g., a cytokine molecule described herein.

[1110] In some embodiments, the multifunctional molecule further comprises R4, wherein R4 comprises 1, 2 or more immune cell engagers (e.g., an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager described herein).

[1111] In some embodiments, the invention describes a multifunctional molecule comprising an R1, R2, R3, and R4 described herein.

[1112] In some embodiments, the multifunctional molecule comprises the following formula in an N terminal to C terminal orientation:

[1113] R1-(optionally L1)-R2-(optionally L2)-R3/R4;

[1114] R1-(optionally L1)-R3/R4-(optionally L2)-R2;

[1115] R2-(optionally L1)-R1-(optionally L2)-R3/R4;

[1116] R2-(optionally L1)-R3/R4-(optionally L2)-R1;

[1117] R3/R4-(optionally L1)-R1-(optionally L2)-R2; or

[1118] R3/R4-(optionally L1)-R2-(optionally L2)-R1;

[1119] wherein:

[1120] (i) R1 comprises 1, 2 or more of the stromal modifying moieties (e.g., a moiety described herein) (e.g., the same or different stromal modifying moieties);

[1121] (ii) R2 comprises 1, 2 or more of the tumor targeting moieties (e.g., a moiety described herein) (e.g., the same or different tumor targeting moieties);

[1122] (iii) R3 comprises 1, 2 or more cytokine molecules, e.g., a cytokine molecule (e.g., a cytokine molecule described herein) (e.g., the same or different cytokine molecules);

[1123] (iv) R4 comprises 1, 2 or more immune cell engagers (e.g., an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager (e.g., an immune cell engager described herein)); and

[1124] wherein:

[1125] R3 and R4 are both present;

[1126] R3 is present and R4 is absent;

[1127] R4 is present and R3 is absent; and

[1128] optionally, L1 and/or L2 is the linker (e.g., a linker described herein).

[1129] In some embodiments, the multifunctional molecule has the following configuration:

[1130] (i) Stromal modifying moiety connected to the heavy chain of the Fab that bind to tumor or stromal antigen (e.g., VH-CH1), from N- to C-terminus, optionally, comprising a Gly-Ser linker between the Fab and the stromal modifying moiety; and/or

[1131] (ii) Light chain of the Fab (e.g., VL-CL1), from N- to C-terminus.

[1132] In other embodiments, the Fab (e.g., VH-CH1) against mesothelin is coupled to a hyaluronidase molecule or collagenase molecule IV, e.g., comprising the Fab amino acid sequence: QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASS YNQKFRGKATLTVDKSSSTAYMDLL SLT SEDSAVYFCARGGYDGRGFDYWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT (SEQ ID NO: 79) a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 79; and

[1133] one or both of hyaluronidase molecule or collagenase molecule IV, e.g., comprising:

[1134] (i) the hyaluronidase molecule amino acid sequence of: FRGPLLPNRPFTTVWNANTQWCLERHGVDVDVSVFDVVANPGQTFRGPDMTIFYSSQG TYPYYTPTGEPVFGGLPQNASLIAHLARTFQDILAAIPAPDFSGLAVIDWEAWRPRWAFN WDTKDIYRQRSRALVQAQHPDWPAPQVEAVAQDQFQGAARAWMAGTLQLGRALRPR GLWGFYGFPDCYNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSRALYPSIYMPAVLEG TGKSQMYVQHRVAEAFRVAVAAGDPNLPVLPYVQIFYDTTNHFLPLDELEHSLGESAA QGAAGVVLWVSWENTRTKESCQAIKEYMDTTLGPFILNVTSGALLCSQALCSGHGRCV RRTSHPKALLLLNPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRCYPGWQAPWC ERKSMW (SEQ ID NO: 62), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 62; or

[1135] (ii) the collagenase molecule amino acid sequence of SEQ ID NO: 63, or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 63, optionally, comprising a Gly-Ser linker between the Fab and the hyaluronidase molecule or collagenase molecule IV.

[1136] In some embodiments, the second polypeptide comprises a light chain of the Fab (e.g., VL-CL1) to the tumor or stromal antigen. In some embodiments, the light chain of the Fab binds to mesothelin, e.g., comprises the amino acid sequence: DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPG RFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 80), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 80.

[1137] In other embodiments, the Fab (e.g., VH-CH1) against FAP coupled to a hyaluronidase molecule or collagenase molecule IV, e.g., comprising the Fab amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKTSRYTF TEYTIHWVRQAPGQRLEWIGGINPNNGIPN YNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC (SEQ ID NO: 81), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 81; and

[1138] one or both of hyaluronidase molecule or collagenase molecule IV, e.g., comprising:

[1139] (i) the hyaluronidase molecule amino acid sequence of: FRGPLLPNRPFTTVWNANTQWCLERHGVDVDVSVFDVVANPGQTFRGPDMTIFYSSQG TYPYYTPTGEPVFGGLPQNASLIAHLARTFQDILAAIPAPDFSGLAVIDWEAWRPRWAFN WDTKDIYRQRSRALVQAQHPDWPAPQVEAVAQDQFQGAARAWMAGTLQLGRALRPR GLWGFYGFPDCYNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSRALYPSIYMPAVLEG TGKSQMYVQHRVAEAFRVAVAAGDPNLPVLPYVQIFYDTTNHFLPLDELEHSLGESAA QGAAGVVLWVSWENTRTKESCQAIKEYMDTTLGPFILNVTSGALLCSQALCSGHGRCV RRTSHPKALLLLNPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRCYPGWQAPWC ERKSMW (SEQ ID NO: 62), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 62; or

[1140] (ii) the collagenase molecule amino acid sequence of SEQ ID NO: 63, or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 63, optionally, comprising a Gly-Ser linker between the Fab and the hyaluronidase molecule or collagenase IV molecule. The amino acid sequence for the VH is underlined and the amino acid sequence for CH1 is shown without the underline.

[1141] In some embodiments, the second polypeptide comprises a light chain of the Fab (e.g., VL-CL1) to FAP. In some embodiments, the light chain of the Fab binds to FAP, e.g., comprises the amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWAST RESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 49), or a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 49. The amino acid sequence for the VL is underlined and the amino acid sequence for CL1 is shown without the underline.

[1142] In some embodiments, the multifunctional molecule further comprises a first and second domain that promote association of the first and the second polypeptide, e.g., a first and second immunoglobulin chain constant regions (e.g., a first and second Fc regions).

[1143] In some embodiments, (i) the first polypeptide has the following configuration: Heavy chain of the Fab (e.g., VH-CH1) to first Fc region (e.g., CH2 to CH3), from N- to C-terminus; and (ii) the second polypeptide has the following configuration: Light chain of the Fab (e.g., VH-CH1) to second Fc region (e.g., CH2 to CH3), from N- to C-terminus.

[1144] In some embodiments, the first immunoglobulin chain constant regions (e.g., a first Fc region) comprises the amino acid sequence: DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS SHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 82), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 82.

[1145] In some embodiments, the second immunoglobulin chain constant regions (e.g., a second Fc region) comprises the amino acid sequence: DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK, (SEQ ID NO: 83), a fragment thereof, or an amino acid sequence substantially identical thereto (e.g., 95% to 99.9% identical thereto, or having at least one amino acid alteration, but not more than five, ten or fifteen alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) to the amino acid sequence of SEQ ID NO: 83.

[1146] In some embodiments, the multifunctional molecule further comprises at least one cytokine molecule (e.g., R3) and/or at least one immune cell engager (e.g., R4) (e.g., an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager). In some embodiments, the stromal modifying moiety (e.g., R1), the tumor-targeting moiety (e.g., R2), and one or both of the cytokine molecule (e.g., R3) and/or the immune cell engager (e.g., R4) are in the same polypeptide, e.g., wherein, e.g., in the N- to C-direction, the stromal modifying moiety is a first polypeptide, the tumor-targeting moiety is a second polypeptide, and one or both of the cytokine molecule and/or the immune cell engager, optionally connected via a linker.

[1147] In some embodiments, the stromal modifying moiety (e.g., R1), the tumor-targeting moiety (e.g., R2), and one or both of the cytokine molecule (e.g., R3) and/or the immune cell engager (e.g., R4) are in the same polypeptide, e.g., wherein, e.g., in the N- to C-direction, the tumor-targeting moiety is a first polypeptide, the stromal modifying moiety is a second polypeptide, and one or both of the cytokine molecule and/or the immune cell engager, optionally connected via a linker. In some embodiments, the stromal modifying moiety, the tumor-targeting moiety, and one or both of the cytokine molecule (e.g., R3) and/or the immune cell engager (e.g., R4) are in different polypeptides, e.g., a first and a second polypeptide not covalently linked.

[1148] In some embodiments, 1) the first polypeptide comprises, e.g., in the N- to C-direction, the first tumor-targeting moiety (e.g., R2), the stromal modifying moiety (e.g., R1), and optionally, a first domain that promotes association of the first and second polypeptide, e.g., a first immunoglobulin chain constant region (e.g., a first Fc region); 2) the second polypeptide comprises, e.g., in the N- to C-direction, the second tumor-targeting moiety (e.g., R2), and optionally, a second domain that promotes association of the first and second polypeptide, e.g., a second immunoglobulin chain constant region (e.g., a second Fc region); and 3) either or both the first and/or second polypeptide, e.g., in the N- to C-direction, further comprise the cytokine molecule (e.g., R3) and/or the immune cell engager (e.g., R4).

[1149] In some embodiments, the first tumor targeting moiety comprises a heavy chain variable domain of the tumor targeting antibody molecule (e.g., Fab); and the second tumor targeting moiety comprises a light chain variable domain of the tumor targeting antibody molecule (e.g., Fab). In some embodiments, the first tumor targeting moiety comprises a light chain variable domain of a tumor targeting antibody; and the tumor targeting moiety of the second polypeptide comprises a heavy chain variable domain of a tumor targeting antibody.

[1150] In some embodiments, the multifunctional molecule comprises a) a first polypeptide comprising: a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and two polypeptides, one comprising a tumor targeting moiety and the other comprising a stromal modifying moiety; b) a second polypeptide comprising: a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and two polypeptides selected from: a tumor targeting moiety; an immune cell engager; and a cytokine molecule, wherein the multifunctional molecule comprises the tumor targeting moiety and the stromal modifying moiety; and one or both of the immune cell engager or the cytokine molecule.

[1151] In some embodiments, the multifunctional molecule comprises: a tumor targeting moiety; a stromal modifying moiety; and an immune cell engager; a tumor targeting moiety; a stromal modifying moiety; and a cytokine molecule; a tumor targeting moiety; a stromal modifying moiety; an immune cell engager; and a cytokine molecule; a tumor targeting moiety; a stromal modifying moiety; and two immune cell engagers; a tumor targeting moiety; a stromal modifying moiety; and two cytokine molecules; two tumor targeting moieties; a stromal modifying moiety; and an immune cell engager; or a tumor targeting moiety; a stromal modifying moiety; and two immune cell engagers.

[1152] In some embodiments, the multifunctional molecule comprises: i) a first polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a stromal modifying moiety; ii) a first polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a cytokine molecule and/or an immune cell engager; or iii) a first polypeptide comprises, e.g., in the N--C or C-N direction a cytokine; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and an immune cell engager; and iv) a second polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a stromal modifying moiety; ii) a second polypeptide comprises, e.g., in the N--C or C-N direction, a tumor targeting moiety; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a cytokine molecule and/or an immune cell engager; or iii) a second polypeptide comprises, e.g., in the N--C or C-N direction a cytokine; a domain that promotes association of the first and second polypeptide, e.g., an Fc molecule; and a stromal modifying moiety.

[1153] In some embodiments, the tumor targeting moiety is specific for mesothelin or FAP; the stromal modifying moiety comprises hyaluronidase molecule or collagenase IV molecule, or a fragment or variant thereof, the cytokine molecule comprising an IL-15 molecule; the immune cell engager comprising a CD40L molecule; and the immune cell engager comprising a B7H6 molecule.

Exemplary Multispecific and Multifunctional Molecules and corresponding Nucleic Acid and Amino Acid Sequences

TABLE-US-00004 TABLE 1 Nucleic acid sequences. Sequence ID Description Nucleic Acid Sequence SEQ ID .alpha.Mesothelin CAGGTCCAGCTGCAGGAAAGCGGCC NO: 85 Ab237 VH CTGGACTGGTCAAGCCTAGCCAGAC CCTGAGCCTGACCTGTACCGTGTCC GGCGGCAGCATCAACAACAACAATT ACTACTGGACATGGATCCGGCAGCA CCCCGGCAAGGGCCTGGAATGGATC GGCTACATCTACTACAGCGGCTCCA CCTTCTACAACCCCAGCCTGAAGTC CAGAGTGACCATCAGCGTGGACACC AGCAAGACCCAGTTCTCCCTGAAGC TGAGCAGCGTGACAGCCGCCGACAC AGCCGTGTACTACTGCGCCAGAGAA GATACCATGACCGGCCTGGATGTGT GGGGCCAGGGCACCACAGTGACAGT GTCTAGC SEQ ID .alpha.Mesothelin GATATCCAGATGACACAGAGCCCTA NO: 86 Ab237 VL GCAGCCTGAGCGCCAGCGTGGGCGA TAGAGTGACCATCACCTGTCGGGCC AGCCAGAGCATCAACAACTACCTGA ACTGGTATCAGCAGAAGCCCGGCAA GGCCCCTACCCTGCTGATCTATGCC GCTTCTAGCCTGCAGAGCGGCGTGC CCAGCAGATTTTCTGGCAGCAGATC CGGCACCGACTTCACCCTGACAATC AGCAGCCTGCAGCCCGAGGACTTCG CCGCCTACTTCTGCCAGCAGACCTA CAGCAATCCCACCTTCGGCCAGGGC ACCAAGGTGGAAGTGAAG SEQ ID Human IL2 GCCCCTACCAGCAGCAGCACCAAGA NO: 87 AAACCCAGCTCCAGCTCGAGCACCT CCTGCTGGACCTGCAGATGATCCTG AACGGCATCAACAACTACAAGAACC CCAAGCTGACCCGGATGCTGACCTT CAAGTTCTACATGCCCAAGAAGGCC ACCGAGCTGAAGCACCTCCAGTGCC TGGAAGAGGAACTGAAGCCCCTGGA AGAAGTGCTGAACCTGGCCCAGAGC AAGAACTTCCACCTGAGGCCCAGGG ACCTGATCAGCAACATCAACGTGAT CGTGCTGGAACTGAAAGGCAGCGAG ACAACCTTCATGTGCGAGTACGCCG ACGAGACAGCCACCATCGTGGAATT TCTGAACCGGTGGATCACCTTCTGC CAGAGCATCATCAGCACCCTGACA SEQ ID 2x4GS GGCGGCGGAGGATCTGGCGGAGGCG NO: 88 linker GCAGC SEQ ID Human GATAAGACCCACACCTGTCCTCCAT NO: 89 CH2, CH3 GTCCTGCCCCTGAGCTGCTGGGCGG knob ACCTAGCGTGTTCCTGTTCCCTCCA AAGCCCAAGGACACCCTGATGATCA GCCGGACCCCTGAAGTGACCTGCGT GGTGGTGGATGTGTCCCACGAGGAT CCCGAAGTGAAGTTCAATTGGTACG TGGACGGCGTGGAAGTGCACAACGC CAAGACCAAGCCCAGAGAGGAACAG TACAACAGCACCTACCGGGTGGTGT CCGTGCTGACCGTGCTGCACCAGGA CTGGCTGAACGGCAAAGAGTACAAG TGCAAGGTGTCCAACAAGGCCCTGC CTGCCCCTATCGAGAAAACCATCAG CAAGGCCAAGGGCCAGCCCCGCGAA CCTCAGGTGTACACACTGCCTCCCT GCCGGGAAGAGATGACCAAGAACCA GGTGTCCCTGTGGTGCCTGGTCAAG GGCTTCTACCCCTCCGATATCGCCG TGGAATGGGAGAGCAACGGCCAGCC CGAGAACAACTACAAGACCACCCCT CCCGTGCTGGACAGCGACGGCAGCT TCTTCCTGTACTCCAAACTGACCGT GGACAAGAGCCGGTGGCAGCAGGGC AATGTGTTCAGCTGTAGCGTGATGC ACGAGGCCCTGCACAACCACTACAC CCAGAAGTCTCTGAGCCTGAGCCCC GGCAAGTAATGA SEQ ID Human GATAAGACCCACACCTGTCCTCCAT NO: 90 CH2, CH3 GTCCTGCCCCTGAGCTGCTGGGCGG hole ACCTAGCGTGTTCCTGTTCCCTCCA AAGCCCAAGGACACCCTGATGATCA GCCGGACCCCTGAAGTGACCTGCGT GGTGGTGGATGTGTCCCACGAGGAT CCCGAAGTGAAGTTCAATTGGTACG TGGACGGCGTGGAAGTGCACAACGC CAAGACCAAGCCCAGAGAGGAACAG TACAACAGCACCTACCGGGTGGTGT CCGTGCTGACCGTGCTGCACCAGGA CTGGCTGAACGGCAAAGAGTACAAG TGCAAGGTGTCCAACAAGGCCCTGC CTGCCCCTATCGAGAAAACCATCAG CAAGGCCAAGGGCCAGCCTAGAGAG CCTCAGGTCTGCACCCTGCCTCCCA GCCGGGAAGAGATGACCAAGAACCA GGTGTCCCTGTCCTGCGCCGTGAAG GGCTTCTACCCCTCCGATATCGCCG TGGAATGG GAGAGCAACGGCCAGCCCGAGAACA ACTACAAGACCACCCCTCCCGTGCT GGACAGCGACGGCAGCTTCTTCCTG GTGTCCAAACTGACCGTGGACAAGA GCCGGTGGCAGCAGGGCAATGTGTT CAGCTGTAGCGTGATGCACGAGGCC CTGCACAACCACTACACCCAGAAGT CTCTGAGCCTGAGCCCCGGCAAGTA ATGA SEQ ID CH1 GCCAGCACCAAGGGCCCTAGCGTGT NO: 91 TCCCTCTGGCCCCTAGCTCTAAGAG CACATCTGGCGGAACAGCCGCCCTG GGCTGCCTGGTCAAGGATTACTTTC CTGAGCCCGTGACCGTGTCCTGGAA CTCTGGTGCTCTGACCAGCGGCGTG CACACCTTTCCAGCTGTGCTGCAGA GCAGCGGCCTGTACAGCCTGTCTAG CGTGGTCACAGTGCCTAGCAGCAGC CTGGGCACACAGACCTACATCTGCA ACGTGAACCACAAGCCCAGCAACAC CAAGGTGGACAAGCGGGTGGAACCC AAGAGCTGC SEQ ID CL (kappa) AGAACAGTGGCCGCTCCCAGCGTGT NO: 92 TCATCTTCCCACCCAGCGACGAGCA GCTGAAGTCTGGCACAGCCAGCGTC GTGTGCCTGCTGAACAACTTCTACC CCAGAGAAGCCAAGGTGCAGTGGAA GGTGGACAACGCCCTGCAGTCCGGC AACAGCCAGGAAAGCGTCACCGAGC AGGACAGCAAGGACTCCACCTACAG CCTGTCCAGCACCCTGACCCTGAGC AAGGCCGACTACGAGAAGCACAAAG TGTACGCCTGCGAAGTGACCCACCA GGGCCTGAGCAGCCCCGTGACCAAG AGCTTCAATAGAGGCGAGTGCTAAT GA SEQ ID CL (lambda) GGCCAGCCCAAGGCCAACCCCACCG NO: 93 TGACCCTGTTCCCTCCATCCTCCGA GGAACTGCAGGCTAACAAGGCCACC CTCGTGTGCCTGATCTCCGACTTCT ACCCTGGCGCCGTGACCGTGGCTTG GAAGGCTGATGGCTCTCCTGTGAAG GCCGGCGTGGAAACCACCAAGCCCT CCAAGCAGTCCAACAACAAATACGC CGCCTCCAGCTACCTGTCCCTGACC CCTGAGCAGTGGAAGTCCCACCGGT CCTACAGCTGCCAGGTCACACATGA GGGCTCCACCGTGGAAAAGACCGTG GCCCCTACCGAGTGCTCCTAATGA SEQ ID .alpha.PD1L1 GAGGTGCAGCTGCTGGAATCTGGCG NO: 94 Avclumab GAGGACTGGTGCAGCCTGGCGGCTC VH TCTGAGACTGTCTTGTGCCGCCTCC GGCTTCACCTTCTCCAGCTATATCA TGATGTGGGTCCGACAGGCCCCTGG CAAGGGCCTGGAATGGGTGTCCTCT ATCTACCCCTCCGGCGGCATCACCT TTTACGCCGACACCGTGAAGGGCCG GTTCACCATCTCCCGGGACAACTCC AAGAACACCCTGTACCTGCAGATGA ACTCCCTGCGGGCCGAGGACACCGC CGTGTACTACTGCGCTAGAATCAAG CTGGGCACCGTGACCACCGTGGACT ATTGGGGCCAGGGCACCCTGGTCAC CGTGTCCTCT SEQ ID .alpha.PD1L1 CAGTCTGCTCTGACCCAGCCTGCCT NO: 95 Avelumab CTGTGTCTGGCTCCCCTGGCCAGTC VL CATCACCATCAGCTGTACCGGCACC TCCTCCGACGTGGGCGGCTACAACT ACGTGTCCTGGTATCAGCAGCATCC CGGCAAGGCCCCTAAGCTGATGATC TACGACGTGTCCAACCGGCCCTCCG GCGTGTCCAATCGGTTCTCTGGCTC CAAGTCCGGCAACACCGCCTCCCTG ACAATCAGCGGACTGCAGGCCGAGG ACGAGGCCGACTACTACTGCTCCTC CTACACCTCCAGCTCTACCCGGGTG TTCGGCACCGGCACCAAAGTGACAG TGCTG SEQ ID 3x4GS GGCGGCGGAGGATCTGGCGGAGGTG NO: 96 linker GAAGCGGAGGCGGTGGATCT SEQ ID .alpha.NKp46 CAGGTTCAGTTGCAGCAGTCCGGAC NO: 97 VH CTGAGCTGGTTAAGCCTGGCGCTTC CGTGAAGATGTCCTGCAAGGCTTCC GGCTACACCTTCAC CGACTACGTGATCAACTGGGGCAAG CAGAGATCTGGCCAGGGACTCGAGT GGATCGGCGAGATCTATCCTGGCTC CGGCACCAATTACTACAACGAGAAG TTCAAGGCTAAGGCTACCCTGACCG CCGACAAGTCCTCCAATATCGCCTA CATGCAGCTGTCCAGCCTGACCTCT GAGGACTCCGCTGTGTACTTCTGCG CTCGGAGAGGCAGATACGGCCTGTA TGCCATGGATTACTGGGGACAGGGA ACCAGTGTGACAGTGTCAAGT SEQ ID .alpha.NKp46 VL GATATTCAGATGACCCAGACCACCT NO: 98 CCAGCCTGTCCGCTTCTCTGGGCGA CAGAGTGACAATCAGCTGCAGAGCC AGCCAGGACATCAGCAACTACCTGA ACTGGTATCAACAGAAACCCGACGG CACCGTGAAGCTGCTGATCTACTAC ACCTCTCGGCTGCACTCTGGCGTGC CCTCTAGATTTTCTGGCAGCGGAAG CGGCACCGACTATTCCCTGACCATC AACAACCTGGAACAAGAGGATATCG CTACCTACTTCTGCCAGCAAGGCAA CACCCGGCCTTGGACATTTGGCGGC GGAACAAAGCTGGAAATCAAGTGAT GA SEQ ID 4x 4GS GGTGGCGGAGGAAGCGGCGGAGGCG NO: 99 linker GCTCTGGTGGTGGTGGTTCTGGTGG CGGTGGCTCC SEQ ID .alpha.Mesothelin CAGGTCCAGCTGCAGGAATCTGGCC NO: 100 M912 VH CTGGCCTGGTCAAGCCCTCCGAGAC ACTGTCTCTGACCTGCACCGTGTCC GGCGGCTCTGTGTCCTCCGGCTCCT ACTACTGGTCCTGGATCCGGCAGCC TCCAGGCAAGGGACTGGAATGGATC GGCTACATCTACTACTCCGGCAGCA CCAACTACAACCCCAGCCTGAAGTC CAGAGTGACCATCTCCGTGGACACC TCCAAGAACCAGTTCTCCCTGAAGC TGTCCTCCGTGACCGCCGCTGACAC CGCCGTGTACTACTGTGCCAGAGAG GGCAAGAACGGCGCCTTCGATATCT GGGGCCAGGGCACCATGGTCACCGT GTCTAGC SEQ ID .alpha.Mesothelin GACATCCAGATGACCCAGAGCCCTT NO: 101 M912 VL CCAGCCTGTCCGCCTCTGTGGGCGA CAGAGTGACCATCACCTGTCGGGCC TCCCAGTCCATCTCCTCCTACCTGA ACTGGTATCAGCAGAAGCCCGGCAA GGCCCCTAAGCTGCTGATCTACGCC GCCTCCAGTCTGCAGTCTGGCGTGC

CATCTGGCTTCTCCGGCTCTGGCTC TGGCACCGACTTCACCCTGACCATC TCCAGCCTGCAGCCCGAGGACTTCG CCACCTACTACTGCCAGCAGTCCTA CTCCACCCCTCTGACCTTCGGCGGA GGCACCAAGGTGGAAATCAAG SEQ ID 1x4GS GGCGGCGGAGGCTCC NO: 102 .alpha.NKp30 DNA sequence corresponding to BioLegend Catalog #325207 SEQ ID Human IL7 GACTGTGACATCGAAGGCAAGGACG NO: 104 GCAAGCAGTACGAGAGCGTGCTGAT GGTGTCCATCGACCAGCTGCTGGAC AGCATGAAGGAAATCGGCTCCAACT GCCTGAACAACGAGTTCAACTTCTT CAAGCGGCACATCTGCGACGCCAAC AAAGAAGGCATGTTCCTGTTCAGAG CCGCCAGAAAGCTGCGGCAGTTCCT GAAGATGAACTCCACCGGCGACTTC GACCTGCATCTGCTGAAAGTGTCTG AGGGCACCACCATCCTGCTGAACTG TACCGGCCAAGTGAAGGGCAGAAAG CCTGCTGCTCTGGGCGAAGCCCAGC CTACCAAGTCTCTGGAAGAGAACAA GAGCCTGAAAGAGCAGAAGAAGCTG AACGACCTCTGCTTCCTGAAGCGGC TGCTGCAAGAGATCAAGACCTGCTG GAACAAGATTCTGATGGGGACCAAA GAGCAC SEQ ID .alpha.IGFIR GAAGTGCAGCTGTTGCAGTCTGGCG NO: 105 heavy GAGGATTGGTTCAGCCTGGCGGATC CCTGAGACTGTCTTGTGCCGCCTCT GGCTTCATGTTCAGCAGATACCCCA TGCACTGGGTCCGACAGGCCCCTGG AAAAGGACTGGAATGGGTCGGATCC ATCTCCGGAAGTGGCGGCGCTACCC CTTACGCCGATTCTGTGAAGGGCAG ATTCACCATCAGCCGGGACAACTCC AAGAACACCCTGTACCTGCAGATGA ACTCCCTGAGAGCCGAGGACACCGC CGTGTACTACTGCGCCAAGGACTTC TACCAGATCCTGACCGGCAACGCCT TCGACTATTGGGGCCAGGGCACAAC CGTGACCGTGTCCTCT SEQ ID .alpha.IGFIR GACATCCAGATGACCCAGTCTCCAT NO: 106 light CCTCTCTGTCTGCCAGCCTGGGCGA CAGAGTGACCATCACCTGTAGAGCC TCTCAGGGCATCTCCTCCTACCTGG CCTGGTATCAGCAGAAGCCTGGCAA GGCTCCCAAGCTGCTGATCTACGCC AAGAGCACACTGCAGTCTGGCGTGC CCTCTAGATTCTCCGGCTCTGGCTC TGGCACCGACTTTACCCTGACAATC TCCAGCCTGCAGCCTGAGGACTCCG CCACCTACTACTGTCAGCAGTACTG GACCTTTCCACTGACCTTCGGCGGA GGCACCAAGGTGGAAATCAAG SEQ ID .alpha.HER3 CAGGTGCAGCTGGTTCAGTCTGGCG NO: 107 heavy GAGGATTGGTTCAGCCAGGCGGATC CCTGAGACTGTC TTGTGCCGCTTCTGGCTTCACCTTC GACGACTACGCTATGCACTGGGTCC GACAGGCCCCTGGCAAAGGATTGGA ATGGGTGGCCGGCATCTCTTGGGAC TCTGGCTCTACCGGCTACGCCGACT CTGTGAAGGGCAGATTCACCATCTC TCGGGACAACGCCAAGAACTCCCTG TACCTGCAGATGAACAGCCTGAGAG CCGAGGACACCGCTCTGTACTACTG CGCTAGAGATCTGGGCGCCTACCAG TGGGTGGAAGGCTTTG ATTATTGGGGCCAGGGCACCCTGGT CACCGTGTCTAGT SEQ ID .alpha.HER3 light TCTTACGAGCTGACCCAGGATCCAG NO: 108 CCGTGTCTGTTGCTCTGGGCCAGAC AGTGCGGATTACCTGCCAGGGCGAC TCCCTGAGATCCTACTACGCCTCCT GGTATCAGCAGAAGCCAGGCCAGGC TCCTGTGCTGGTCATCTACGGCAAG AACAACCGGCCTAGCGGCATCCCTG ACAGATTCTCCGGCTCTACCTCCGG CAACTCTGCCAGCCTGACAATTACT GGCGCCCAGGCTGAGGACGAGGCCG ACTACTACTGCAACTCCAGAGACAG CCCTGGCAATCAGTGGGTTTTCGGC GGAGGCACCAAAGTGACAGTTCTTG GT SEQ ID .alpha.CD3 heavy CAAGTTCAGTTGGTTCAAAGCGGTG NO: 109 GCGGCGTGGTGCAGCCTGGAAGATC TCTCAGACTGTCCTGCAAGGCCTCC GGCTACACCTTCACCAGATACACCA TGCATTGGGTTCGACAAGCACCAGG CAAGGGCCTCGAGTGGATCGGCTAC ATCAACCCTTCCAGAGGCTACACCA ACTACAACCAGAAAGTGAAGGACCG GTTCACCATCAGCAGAGACAACAGC AAGAATACCGCCTTTCTGCAGATGG ACTCCCTGCGGCCTGAAGATACCGG CGTGTACTTTTGCGCCCGGTACTAC GACGACCACTACTCCCTGGATTACT GGGGACAGGGAACACCCGTGACAGT GTCTAGC SEQ ID .alpha.CD3 light GATATTCAGATGACCCAGTCTCCTT NO: 110 CCAGCCTGTCCGCTTCTGTGGGCGA CAGAGTGACTATTACCTGCTCCGCC TCTTCCTCCGTGTCCTACATGAACT GGTATCAACAAACACCCGGCAAGGC CCCTAAGAGATGGATCTACGACACC AGCAAGCTGGCCTCTGGCGTGCCCT CTAGATTTTCTGGCTCTGGCTCCGG CACCGACTATACCTTTACAATCTCC AGCCTGCAGCCTGAGGATATCGCCA CCTACTACTGTCAGCAG TGGTCTAGCAACCCCTTCACCTTTG GACAGGGCACCAAGCTGCAGATCAC CTGATGA SEQ ID Human IL2 GCTCCTACCTCCTCCAGCACCAAGA NO: 111 F42A Y45A AAACCCAGCTGCAGTTGGAGCATCT GCTGCTGGACCTCCAGATGATCCTG AATGGCATCAACAATTACAAGAACC CCAAGCTCACCCGGATGCTGACCGC CAAGTTTGCCATGCCTAAGAAGGCC ACCGAGCTGAAACATCTGCAGTGCC TGGAAGAGGAACTGAAGCCCCTGGA AGAAGTGCTGAATCTGGCCCAGTCC AAGAACTTCCACCTGAGGCCTCGGG ACCTGATCTCCAACATCAACGTGAT CGTGCTCGAGCTGAAGGGCTCCGAG ACAACCTTCATGTGCGAGTACGCCG ACGAGACAGCTACCATCGTGGAATT TCTGAACCGGTGGATCACCTTCTGT CAGTCCATCATCAGCACCCTGACC SEQ ID .alpha.NKp46 2 GAAGTGCAGCTCCAAGAATCTGGAC NO: 112 heavy CCGGGCTCGTGAAGCCCAGCCAGTC TCTGAGTCTGACCTGTACAGTGACC GGCTACTCCATCACCTCCGACTACG CTTGGAACTGGATCCGGCAGTTCCC CGGCAACAAGTTGGAGTGGATGGGC TATATCACCTACAGCGGCAGCACCT CTTACAACCCTTCTCTGGAATCCCG GATCAGCATCACCCGGGACACCTCT ACCAATCAGTTCTTTCTGCAGCTGA ACAGCGTGACCACCGAGGACACCGC CACCTACTATTGTGCTAGAGGCGGC TACTACGGCTCCTCCTGGGGAGTGT TTGCTTACTGGGGACAGGGAACCCT CGTGACTGTTTCTGCT SEQ ID .alpha.NKp46 2 GACATCCAGATGACCCAGTCTCCAG NO: 113 light CCAGCCTGTCTGCTTCTGTGGGCGA GACAGTGACCATTACCTGCCGGGTG TCCGAGAACATCTACTCCTACCTGG CCTGGTATCAACAGAAACAGGGCAA GTCCCCTCAGCTGCTGGTGTACAAT GCTAAGACCCTGGCTGAGGGCGTGC CCTCTAGATTTTCTGGCTCTGGCAG CGGCACCCAGTTTAGCCTGAAGATC AACTCCCTGCAGCCTGAGGACTTCG GCAGCTACTACTGCCAGCACCACTA TGGCACCCCTTGGACATTTGGCGGA GGCACCAAGCTGGAAATCAAG SEQ ID .alpha.NKp46 4 CAGGTTCAGTTGCAGCAGTCTGCCG NO: 114 heavy TGGAACTGGCTAGACCTGGCGCTTC CGTGAAGATGTCCTGCAAGGCCTCC GGCTACACCTTCACCAGCTTCACCA TGCACTGGGTCAAGCAGAGGCCTGG ACAAGGCTTGGAGTGGATTGGATAT ATCAACCCTAGCTCTGGCTACACCG AGTACAACCAGAAGTTCAAGGACAA GACCACTCTGACCGCCGACAAGTCC TCCAGCACCGCTTACATGCAGCTCG ACTCCCTGACCTCTGACGACTCTGC TGTGTACTATTGCGTGCGGGGCTCC TCCAGAGGCTTCGATTATTGGGGAC AAGGCACACTCGTGACAGTGTCAGC T SEQ ID .alpha.NKp46 4 GATATCCAGATGATCCAGTCTCCTG NO: 115 light CCAGCCTGTCCGTGTCTGTGGGAGA GACTGTGACCATCACCTGTCGGGCC TCCGAGAACATCTACTCCAACCTGG CCTGGTTCCAGCAGAAGCAGGGAAA GTCTCCTCAGCTGCTGGTGTACGCC GCCACCAATTTGGCTGATGGCGTGC CCTCTCGGTTCTCCGGATCTGGATC TGGCACACAGTATTCCCTGAAGATC AACTCCCTGCAGTCCGAGGACTTCG GCATCTACTATTGCCAGCACTTCTG GGGCACCCCTAGAACCTTTGGCGGC GGAACAAAGCTGGAAATCAAG

TABLE-US-00005 TABLE 2 Sequences used to construct ORFS. Construct SEQ ID NO: N-term Linker Variable Constant Fc Linker C-term SEQ ID SEQ ID SEQ ID SEQ ID NO: 116 NO: 85 NO: 91 NO: 89 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 117 NO: 85 NO: 91 NO: 89 NO: 96 NO: 103 SEQ ID SEQ ID SEQ ID NO: 118 NO: 86 NO: 92 SEQ ID SEQ ID SEQ ID SEQ ID NO: 119 NO: 87 NO: 88 NO: 90 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 120 NO: 94 NO: 91 NO: 90 NO: 96 NO: 87 SEQ ID SEQ ID SEQ ID NO: 121 NO: 95 NO: 93 SEQ ID SEQ ID SEQ ID SEQ ID NO: 122 NO: 100 NO: 91 NO: 89 SEQ ID SEQ ID SEQ ID NO: 123 NO: 101 NO: 92 SEQ ID SEQ ID NO: 124 NO: 89 SEQ ID SEQ ID NO: 125 NO: 90 SEQ ID SEQ ID SEQ ID SEQ ID NO: 126 NO: 105 NO: 91 NO: 90 SEQ ID SEQ ID SEQ ID NO: 127 NO: 106 NO: 92 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 128 NO: 105 NO: 91 NO: 90 NO: 96 NO: 81 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 129 NO: 105 NO: 91 NO: 90 NO: 96 NO: 104 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 130 NO: 107 NO: 99 NO: 108 NO: 88 NO: 89 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 131 NO: 107 NO: 99 NO: 108 NO: 88 NO: 89 NO: 96 NO: 97, 98, 994 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 132 NO: 107 NO: 99 NO: 108 NO: 88 NO: 89 NO: 96 NO: 108, 99, 110 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 133 NO: 85 NO: 91 NO: 89 NO: 96 NO: 97, 98, 99 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 134 NO: 91 NO: 93 NO: 96 NO: 111 SEQ ID SEQ ID SEQ ID SEQ ID NO: 135 NO: 94 NO: 91 NO: 90 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 136 NO: 100 NO: 91 NO: 89 NO: 96 NO: 97, 98, 99 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 137 NO: 100 NO: 91 NO: 89 NO: 96 NO: 28, 15, 29 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 138 NO: 100 NO: 91 NO: 89 NO: 96 NO: 114, 99, 115

TABLE-US-00006 TABLE 3 Nucleic acid sequences of ORFs. Sequence ID Nucleic Acid Sequence SEQ ID ATGGAAACCGATACACTGCTGCTGT NO: 116 GGGTGCTGCTCCTCTGGGTGCCAGG ATCTACAGGCGCCCCTACCAGCAGC AGCACCAAGAAAACCCAGCTCCAGC TCGAGCACCTCCTGCTGGACCTGCA GATGATCCTGAACGGCATCAACAAC TACAAGAACCCCAAGCTGACCCGGA TGCTGACCTTCAAGTTCTACATGCC CAAGAAGGCCACCGAGCTGAAGCAC CTCCAGTGCCTGGAAGAGGAACTGA AGCCCCTGGAAGAAGTGCTGAACCT GGCCCAGAGCAAGAACTTCCACCTG AGGCCCAGGGACCTGATCAGCAACA TCAACGTGATCGTGCTGGAACTGAA AGGCAGCGAGACAACCTTCATGTGC GAGTACGCCGACGAGACAGCCACCA TCGTGGAATTTCTGAACCGGTGGAT CACCTTCTGCCAGAGCATCATCAGC ACCCTGACAGGCGGCGGAGGATCTG GCGGAGGCGGCAGCGATAAGACCCA CACCTGTCCTCCATGTCCCGCCCCT GAACTGCTGGGCGGACCTAGCGTGT TCCTGTTCCCTCCAAAGCCCAAGGA CACCCTGATGATCAGCCGGACCCCT GAAGTGACCTGCGTGGTGGTGGATG TGTCCCACGAGGATCCCGAAGTGAA GTTCAATTGGTACGTGGACGGCGTG GAAGTGCACAACGCCAAGACCAAGC CCAGAGAGGAACAGTACAACAGCAC CTACCGGGTGGTGTCCGTGCTGACC GTGCTGCACCAGGACTGGCTGAATG GCAAAGAGTACAAGTGCAAGGTGTC CAACAAGGCCCTGCCTGCCCCTATC GAGAAAACCATCAGCAAGGCCAAGG GCCAGCCTAGAGAGCCTCAGGTCTG CACCCTGCCTCCCAGCCGGGAAGAG ATGACCAAGAACCAGGTGTCCCTGA GCTGCGCCGTGAAGGGCTTCTACCC CTCCGATATCGCCGTGGAATGGGAG AGCAACGGCCAGCCCGAGAACAATT ACAAGACCACCCCTCCCGTGCTGGA CAGCGACGGCAGCTTCTTCCTGGTG TCCAAACTGACCGTGGACAAGAGCC GGTGGCAGCAGGGCAATGTGTTCAG CTGTAGCGTGATGCACGAGGCCCTG CACAACCACTACACCCAGAAGTCTC TGAGCCTGAGCCCCGGCAAGTAATG A SEQ ID ATGGAAACCGATACACTGCTGCTGT NO: 119 GGGTGCTGCTCCTCTGGGTGCCAGG ATCTACAGGCGCCCCTACCAGCAGC AGCACCAAGAAAACCCAGCTCCAGC TCGAGCACCTCCTGCTGGACCTGCA GATGATCCTGAACGGCATCAACAAC TACAAGAACCCCAAGCTGACCCGGA TGCTGACCTTCAAGTTCTACATGCC CAAGAAGGCCACCGAGCTGAAGCAC CTCCAGTGCCTGGAAGAGGAACTGA AGCCCCTGGAAGAAGTGCTGAACCT GGCCCAGAGCAAGAACTTCCACCTG AGGCCCAGGGACCTGATCAGCAACA TCAACGTGATCGTGCTGGAACTGAA AGGCAGCGAGACAACCTTCATGTGC GAGTACGCCGACGAGACAGCCACCA TCGTGGAATTTCTGAACCGGTGGAT CACCTTCTGCCAGAGCATCATCAGC ACCCTGACAGGCGGCGGAGGATCTG GCGGAGGCGGCAGCGATAAGACCCA CACCTGTCCTCCATGTCCCGCCCCT GAACTGCTGGGCGGACCTAGCGTGT TCCTGTTCCCTCCAAAGCCCAAGGA CACCCTGATGATCAGCCGGACCCCT GAAGTGACCTGCGTGGTGGTGGATG TGTCCCACGAGGATCCCGAAGTGAA GTTCAATTGGTACGTGGACGGCGTG GAAGTGCACAACGCCAAGACCAAGC CCAGAGAGGAACAGTACAACAGCAC CTACCGGGTGGTGTCCGTGCTGACC GTGCTGCACCAGGACTGGCTGAATG GCAAAGAGTACAAGTGCAAGGTGTC CAACAAGGCCCTGCCTGCCCCTATC GAGAAAACCATCAGCAAGGCCAAGG GCCAGCCTAGAGAGCCTCAGGTCTG CACCCTGCCTCCCAGCCGGGAAGAG ATGACCAAGAACCAGGTGTCCCTGA GCTGCGCCGTGAAGGGCTTCTACCC CTCCGATATCGCCGTGGAATGGGAG AGCAACGGCCAGCCCGAGAACAATT ACAAGACCACCCCTCCCGTGCTGGA CAGCGACGGCAGCTTCTTCCTGGTG TCCAAACTGACCGTGGACAAGAGCC GGTGGCAGCAGGGCAATGTGTTCAG CTGTAGCGTGATGCACGAGGCCCTG CACAACCACTACACCCAGAAGTCTC TGAGCCTGAGCCCCGGCAAGTAATG A SEQ ID ATGGAAACCGATACACTGCTGCTGT NO: 117 GGGTGCTGCTCCTCTGGGTGCCAGG (+ DNA ATCTACAGGCCAGGTCCAGCTGCAG sequence GAAAGCGGCCCTGGACTGGTCAAGC for CTAGCCAGACCCTGAGCCTGACCTG BioLegend TACCGTGTCCGGCGGCAGCATCAAC #325207) AACAA Catalog CAATTACTACTGGACATGGATCCGG CAGCACCCCGGCAAGGGCCTGGAAT GGATCGGCTACATCTACTACAGCGG CTCCACCTTCTACAACCCCAGCCTG AAGTCCAGAGTGACCATCAGCGTGG ACACCAGCAAGACCCAGTTCTCCCT GAAGCTGAGCAGCGTGACAGCCGCC GACACAGCCGTGTACTACTGCGCCA GAGAAGATACCATGACCGGCCTGGA TGTGTGGGGCCAGGGCACCACAGTG ACAGTGTCTAGCGCCAGCACCAAGG GCCCTAGCGTGTTCCCTCTGGCCCC TAGCTCTAAGAGCACATCTGGCGGA ACAGCCGCCCTGGGCTGCCTGGTCA AGGATTACTTTCCTGAGCCCGTGAC CGTGTCCTGGAACTCTGGTGCTCTG ACCAGCGGCGTGCACACCTTTCCAG CTGTGCTGCAGAGCAGCGGCCTGTA CAGCCTGTCTAGCGTGGTCACAGTG CCTAGCAGCAGCCTGGGCACACAGA CCTACATCTGCAACGTGAACCACAA GCCCAGCAACACCAAGGTGGACAAG CGGGTGGAACCCAAGAGCTGCGACA AGACCCACACCTGTCCTCCCTGTCC TGCCCCTGAACTGCTGGGCGGACCT TCCGTGTTCCTGTTCCCTCCAAAGC CCAAGGACACCCTGATGATCAGCCG GACCCCTGAAGTGACCTGCGTGGTG GTGGATGTGTCCCACGAGGATCCCG AAGTGAAGTTCAATTGGTACGTGGA CGGCGTGGAAGTGCACAACGCCAAG ACCAAGCCCAGAGAGGAACAGTACA ACAGCACCTACCGGGTGGTGTCCGT GCTGACCGTGCTGCACCAGGACTGG CTGAACGGCAAAGAGTACAAGTGCA AGGTGTCCAACAAGGCCCTGCCAGC CCCTATCGAGAAAACCATCAGCAAG GCCAAGGGCCAGCCCCGCGAACCTC AGGTGTACACACTGCCTCCCTGCCG GGAAGAGATGACCAAGAACCAGGTG TCCCTGTGGTGTCTCGTGAAGGGCT TCTACCCCTCCGATATCGCCGTGGA ATGGGAGAGCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCTCCCG TGCTGGACAGCGACGGCAGCTTCTT CCTGTACTCCAAACTGACCGTGGAC AAGAGCCGGTGGCAGCAGGGCAATG TGTTCAGCTGTAGCGTGATGCACGA GGCCCTGCACAACCACTACACCCAG AAGTCCCTGTCCCTGAGCCCTGGAA AAGGTGGCGGAGGAAGCGGAGGCGG AGGTTCTGGCGGCGGAGGATCT SEQ ID ATGGAAACCGATACACTGCTGCTGT NO: 125 GGGTGCTGCTCCTCTGGGTGCCAGG CAGCACCGGCGATAAGACCCACACC TGTCCTCCATGTCCTGCCCCTGAGC TGCTGGGCGGACCTAGCGTGTTCCT GTTCCCTCCAAAGCCCAAGGACACC CTGATGATCAGCCGGACCCCTGAAG TGACCTGCGTGGTGGTGGATGTGTC CCACGAGGATCCCGAAGTGAAGTTC AATTGGTACGTGGACGGCGTGGAAG TGCACAACGCCAAGACCAAGCCCAG AGAGGAACAGTACAACAGCACCTAC CGGGTGGTGTCCGTGCTGACCGTGC TGCACCAGGACTGGCTGAACGGCAA AGAGTACAAGTGCAAGGTGTCCAAC AAGGCCCTGCCTGCCCCTATCGAGA AAACCATCAGCAAGGCCAAGGGCCA GCCTAGAGAGCCTCAGGTCTGCACC CTGCCTCCCAGCCGGGAAGAGATGA CCAAGAACCAGGTGTCCCTGTCCTG CGCCGTGAAGGGCTTCTACCCCTCC GATATCGCCGTGGAATGGGAGAGCA ACGGCCAGCCCGAGAACAACTACAA GACCACCCCTCCCGTGCTGGACAGC GACGGCAGCTTCTTCCTGGTGTCCA AACTGACCGTGGACAAGAGCCGGTG GCAGCAGGGCAATGTGTTCAGCTGT AGCGTGATGCACGAGGCCCTGCACA ACCACTACACCCAGAAGTCTCTGAG CCTGAGCCCCGGCAAGTAATGA SEQ ID ATGGAAACCGATACACTGCTGCTGT NO: 124 GGGTGCTGCTCCTCTGGGTGCCAGG CAGCACCGGCGATAAGACCCACACC TGTCCTCCATGTCCTGCCCCTGAGC TGCTGGGCGGACCTAGCGTGTTCCT GTTCCCTCCAAAGCCCAAGGACACC CTGATGATCAGCCGGACCCCTGAAG TGACCTGCGTGGTGGTGGATGTGTC CCACGAGGATCCCGAAGTGAAGTTC AATTGGTACGTGGACGGCGTGGAAG TGCACAACGCCAAGACCAAGCCCAG AGAGGAACAGTACAACAGCACCTAC CGGGTGGTGTCCGTGCTGACCGTGC TGCACCAGGACTGGCTGAACGGCAA AGAGTACAAGTGCAAGGTGTCCAAC AAGGCCCTGCCTGCCCCTATCGAGA AAACCATCAGCAAGGCCAAGGGCCA GCCCCGCGAACCTCAGGTGTACACA CTGCCTCCCTGCCGGGAAGAGATGA CCAAGAACCAGGTGTCCCTGTGGTG CCTGGTCAAGGGCTTCTACCCCTCC GATATCGCCGTGGAATGGGAGAGCA ACGGCCAGCCCGAGAACAACTACAA GACCACCCCTCCCGTGCTGGACAGC GACGGCAGCTTCTTCCTGTACTCCA AACTGACCGTGGACAAGAGCCGGTG GCAGCAGGGCAATGTGTTCAGCTGT AGCGTGATGCACGAGGCCCTGCACA ACCACTACACCCAGAAGTCTCTGAG CCTGAGCCCCGGCAAGTAATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 126 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGCGAAGTGCAGCTGTTG CAGTCTGGCGGAGGATTGGTTCAGC CTGGCGGATCCCTGAGACTGTCTTG TGCCGCCTCTGGCTTCATGTTCAGC AGATACCCCATGCACTGGGTCCGAC AGGCCCCTGGAAAAGGACTGGAATG GGTCGGATCCATCTCCGGAAGTGGC GGCGCTACCCCTTACGCCGATTCTG TGAAGGGCAGATTCACCATCAGCCG GGACAACTCCAAGAACACCCTGTAC CTGCAGATGAACTCCCTGAGAGCCG AGGACACCGCCGTGTACTACTGCGC CAAGGACTTCTACCAGATCCTGACC GGCAACGCCTTCGACTATTGGGGCC AGGGCACAACCGTGACCGTGTCCTC TGCTTCTACCAAGGGACCCAGCGTG TTCCCTCTGGCTCCTTCCAGCAAGT CTACCTCTGGCGGAACAGCTGCTCT GGGCTGCCTGGTCAAGGACTACTTT CCTGAGCCTGTGACAGTGTCCTGGA ACTCTGGCGCTCTGACATCCGGCGT GCACACCTTTCCAGCTGTGCTGCAA

TCCAGCGGCCTGTACTCTCTGTCCT CCGTCGTGACAGTGCCTTCCAGCTC TCTGGGAACCCAGACCTACATCTGC AATGTGAACCACAAGCCTTCCAACA CCAAGGTGGACAAGAGAGTGGAACC CAAGTCCTGCGACAAGACCCACACC TGTCCTCCATGTCCTGCTCCAGAAC TGCTCGGCGGACCTTCCGTGTTCCT GTTTCCTCCAAAGCCTAAGGACACC CTGATGATCTCTCGGACCCCTGAAG TGACCTGCGTGGTGGTGGATGTGTC TCACGAGGATCCCGAAGTGAAGTTC AATTGGTACGTGGACGGCGTGGAAG TGCACAACGCCAAGACCAAGCCTAG AGAGGAACAGTACAACTCCACCTAC AGAGTGGTGTCCGTGCTGACCGTGC TGCACCAGGATTGGCTGAACGGCAA AGAGTACAAGTGCAAGGTGTCCAAC AAGGCCCTGCCTGCTCCTATCGAAA AGACCATCTCCAAGGCCAAGGGCCA GCCTCGGGAACCTCAAGTCTGTACC CTGCCTCCTAGCCGGGAAGAGATGA CCAAGAACCAGGTGTCCCTGTCCTG TGCCGTGAAGGGCTTCTACCCTTCC GATATCGCCGTGGAATGGGAGAGCA ATGGCCAGCCTGAGAACAACTACAA GACAACCCCTCCTGTGCTGGACTCC GACGGCTCATTCTTCCTGGTGTCCA AGCTGACAGTGGACAAGTCCAGATG GCAGCAGGGCAACGTGTTCTCCTGC TCCGTGATGCACGAGGCCCTGCACA ATCACTACACCCAGAAGTCCCTGTC TCTGAGCCCCGGCAAGTGATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 127 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACCGGCGACATCCAGATGACC CAGTCTCCATCCTCTCTGTCTGCCA GCCTGGGCGACAGAGTGACCATCAC CTGTAGAGCCTCTCAGGGCATCTCC TCCTACCTGGCCTGGTATCAGCAGA AGCCTGGCAAGGCTCCCAAGCTGCT GATCTACGCCAAGAGCACACTGCAG TCTGGCGTGCCCTCTAGATTCTCCG GCTCTGGCTCTGGCACCGACTTTAC CCTGACAATCTCCAGCCTGCAGCCT GAGGACTCCGCCACCTACTACTGTC AGCAGTACTGGACCTTTCCACTGAC CTTCGGCGGAGGCACCAAGGTGGAA ATCAAGAGAACCGTGGCCGCTCCTT CCGTGTTCATCTTCCCACCTTCCGA CGAGCAGCTGAAGTCCGGCACAGCT TCTGTCGTGTGCCTGCTGAACAACT TCTACCCTCGGGAAGCCAAAGTGCA GTGGAAGGTGGACAACGCTCTGCAG TCCGGCAACTCCCAAGAGTCTGTGA CCGAGCAGGACTCCAAGGACAGCAC CTACAGCCTGTCCTCCACACTGACC CTGTCCAAGGCCGACTACGAGAAGC ACAAGGTGTACGCCTGCGAAGTGAC CCATCAGGGCCTGTCTAGCCCTGTG ACCAAGTCTTTCAACCGGGGCGAGT GCTGATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 128 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGCGAAGTGCAGCTGTTG CAGTCTGGCGGAGGATTGGTTCAGC CTGGCGGATCCCTGAGACTGTCTTG TGCCGCCTCTGGCTTCATGTTCAGC AGATACCCCATGCACTGGGTCCGAC AGGCCCCTGGAAAAGGACTGGAATG GGTCGGATCCATCTCCGGAAGTGGC GGCGCTACCCCTTACGCCGATTCTG TGAAGGGCAGATTCACCATCAGCCG GGACAACTCCAAGAACACCCTGTAC CTGCAGATGAACTCCCTGAGAGCCG AGGACACCGCCGTGTACTACTGCGC CAAGGACTTCTACCAGATCCTGACC GGCAACGCCTTCGACTATTGGGGCC AGGGCACAACCGTGACCGTGTCCTC TGCTTCTACCAAGGGACCCAGCGTG TTCCCTCTGGCTCCTTCCAGCAAGT CTACCTCTGGCGGAACAGCTGCTCT GGGCTGCCTGGTCAAGGACTACTTT CCTGAGCCTGTGACAGTGTCCTGGA ACTCTGGCGCTCTGACATCCGGCGT GCACACCTTTCCAGCTGTGCTGCAA TCCAGCGGCCTGTACTCTCTGTCCT CCGTCGTGACAGTGCCTTCCAGCTC TCTGGGAACCCAGACCTACATCTGC AATGTGAACCACAAGCCTTCCAACA CCAAGGTGGACAAGAGAGTGGAACC CAAGTCCTGCGACAAGACCCACACC TGTCCTCCATGTCCTGCTCCAGAAC TGCTCGGCGGACCTTCCGTGTTCCT GTTTCCTCCAAAGCCTAAGGACACC CTGATGATCTCTCGGACCCCTGAAG TGACCTGCGTGGTGGTGGATGTGTC TCACGAGGATCCCGAAGTGAAGTTC AATTGGTACGTGGACGGCGTGGAAG TGCACAACGCCAAGACCAAGCCTAG AGAGGAACAGTACAACTCCACCTAC AGAGTGGTGTCCGTGCTGACCGTGC TGCACCAGGATTGGCTGAACGGCAA AGAGTACAAGTGCAAGGTGTCCAAC AAGGCCCTGCCTGCTCCTATCGAAA AGACCATCTCCAAGGCCAAGGGCCA GCCTCGGGAACCTCAAGTCTGTACC CTGCCTCCTAGCCGGGAAGAGATGA CCAAGAACCAGGTGTCCCTGTCCTG TGCCGTGAAGGGCTTCTACCCTTCC GATATCGCCGTGGAATGGGAGAGCA ATGGCCAGCCTGAGAACAACTACAA GACAACCCCTCCTGTGCTGGACTCC GACGGCTCATTCTTCCTGGTGTCCA AGCTGACAGTGGACAAGTCCAGATG GCAGCAGGGCAACGTGTTCTCCTGC TCCGTGATGCACGAGGCCCTGCACA ATCACTACACCCAGAAGTCCCTGTC TCTGAGCCCTGGCAAAGGCGGAGGC GGATCTGGTGGTGGCGGTTCTGGCG GCGGTGGATCTGCTCCTACATCCTC CAGCACCAAGAAAACCCAGCTGCAG TTGGAGCATCTGCTGCTGGACCTCC AGATGATCCTGAATGGCATCAACAA TTACAAGAACCCCAAGCTCACCCGG ATGCTGACCTTCAAGTTCTACATGC CCAAGAAGGCCACCGAGCTGAAACA TCTGCAGTGCCTGGAAGAGGAACTG AAGCCTCTGGAAGAAGTGCTGAATC TGGCCCAGTCCAAGAACTTCCACCT GAGGCCTCGGGACCTGATCTCCAAC ATCAACGTGATCGTGCTCGAGCTGA AGGGCTCCGAGACTACCTTCATGTG CGAGTACGCCGACGAGACAGCTACC ATCGTGGAATTTCTGAACCGGTGGA TCACCTTCTGCCAGTCCATCATCAG CACCCTGACCTGATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 129 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGCGAAGTGCAGCTGTTG CAGTCTGGCGGAGGATTGGTTCAGC CTGGCGGATCCCTGAGACTGTCTTG TGCCGCCTCTGGCTTCATGTTCAGC AGATACCCCATGCACTGGGTCCGAC AGGCCCCTGGAAAAGGACTGGAATG GGTCGGATCCATCTCCGGAAGTGGC GGCGCTACCCCTTACGCCGATTCTG TGAAGGGCAGATTCACCATCAGCCG GGACAACTCCAAGAACACCCTGTAC CTGCAGATGAACTCCCTGAGAGCCG AGGACACCGCCGTGTACTACTGCGC CAAGGACTTCTACCAGATCCTGACC GGCAACGCCTTCGACTATTGGGGCC AGGGCACAACCGTGACCGTGTCCTC TGCTTCTACCAAGGGACCCAGCGTG TTCCCTCTGGCTCCTTCCAGCAAGT CTACCTCTGGCGGAACAGCTGCTCT GGGCTGCCTGGTCAAGGACTACTTT CCTGAGCCTGTGACAGTGTCCTGGA ACTCTGGCGCTCTGACATCCGGCGT GCACACCTTTCCAGCTGTGCTGCAA TCCAGCGGCCTGTACTCTCTGTCCT CCGTCGTGACAGTGCCTTCCAGCTC TCTGGGAACCCAGACCTACATCTGC AATGTGAACCACAAGCCTTCCAACA CCAAGGTGGACAAGAGAGTGGAACC CAAGTCCTGCGACAAGACCCACACC TGTCCTCCATGTCCTGCTCCAGAAC TGCTCGGCGGACCTTCCGTGTTCCT GTTTCCTCCAAAGCCTAAGGACACC CTGATGATCTCTCGGACCCCTGAAG TGACCTGCGTGGTGGTGGATGTGTC TCACGAGGATCCCGAAGTGAAGTTC AATTGGTACGTGGACGGCGTGGAAG TGCACAACGCCAAGACCAAGCCTAG AGAGGAACAGTACAACTCCACCTAC AGAGTGGTGTCCGTGCTGACCGTGC TGCACCAGGATTGGCTGAACGGCAA AGAGTACAAGTGCAAGGTGTCCAAC AAGGCCCTGCCTGCTCCTATCGAAA AGACCATCTCCAAGGCCAAGGGCCA GCCTCGGGAACCTCAAGTCTGTACC CTGCCTCCTAGCCGGGAAGAGATGA CCAAGAACCAGGTGTCCCTGTCCTG TGCCGTGAAGGGCTTCTACCCTTCC GATATCGCCGTGGAATGGGAGAGCA ATGGCCAGCCTGAGAACAACTACAA GACAACCCCTCCTGTGCTGGACTCC GACGGCTCATTCTTCCTGGTGTCCA AGCTGACAGTGGACAAGTCCAGATG GCAGCAGGGCAACGTGTTCTCCTGC TCCGTGATGCACGAGGCCCTGCACA ATCACTACACCCAGAAGTCCCTGTC TCTGAGCCCTGGCAAAGGCGGAGGC GGATCTGGTGGTGGCGGTTCTGGCG GCGGTGGATCTGACTGTGATATCGA AGGCAAGGACGGCAAGCAGTACGAG TCCGTCCTGATGGTGTCCATCGACC AGCTGCTGGACAGCATGAAGGAAAT CGGCTCCAACTGCCTGAACAACGAG TTCAACTTCTTCAAGCGGCACATCT GCGACGCCAACAAAGAAGGCATGTT TCTGTTCCGGGCTGCCAGAAAGCTG CGGCAGTTCCTGAAGATGAACAGCA CCGGCGACTTCGACCTGCACCTGTT GAAAGTGTCTGAGGGCACCACCATC CTGCTGAACTGTACCGGCCAAGTGA AGGGAAGAAAGCCTGCCGCTCTGGG CGAAGCCCAGCCTACAAAGTCTCTG GAAGAGAACAAGTCCCTGAAAGAGC AGAAGAAGCTGAACGACCTCTGTTT CCTGAAGCGGCTGCTGCAAGAGATC AAGACCTGCTGGAACAAGATCCTGA TGGGCACCAAAGAGCACTGATAG SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 130 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGACAGGTGCAGCTGGTT CAGTCTGGCGGAGGATTGGTTCAGC CAGGCGGATCCCTGAGACTGTCTTG TGCCGCTTCTGGCTTCACCTTCGAC GACTACGCTATGCACTGGGTCCGAC AGGCCCCTGGCAAAGGATTGGAATG GGTGGCCGGCATCTCTTGGGACTCT GGCTCTACCGGCTACGCCGACTCTG TGAAGGGCAGATTCACCATCTCTCG GGACAACGCCAAGAACTCCCTGTAC CTGCAGATGAACAGCCTGAGAGCCG AGGACACCGCTCTGTACTACTGCGC TAGAGATCTGGGCGCCTACCAGTGG GTGGAAGGCTTTGATTATTGGGGCC AGGGCACCCTGGTCACCGTGTCTAG TGCTTCTACTGGTGGTGGCGGATCT GGCGGCGGAGGAAGCGGAGGCGGAG GTAGTGGTGGCGGTGGATCTTCTTA CGAGCTGACCCAGGATCCAGCCGTG TCTGTTGCTCTGGGCCAGACAGTGC GGATTACCTGCCAGGGCGACTCCCT GAGATCCTACTACGCCTCCTGGTAT CAGCAGAAGCCAGGCCAGGCTCCTG TGCTGGTCATCTACGGCAAGAACAA CCGGCCTAGCGGCATCCCTGACAGA TTCTCCGGCTCTACCTCCGGCAACT CTGCCAGCCTGACAATTACTGGCGC CCAGGCTGAGGACGAGGCCGACTAC TACTGCAACTCCAGAGACAGCCCTG GCAATCAGTGGGTTTTCGGCGGAGG CACCAAAGTGACAGTTCTTGGTGGC

GGAGGTGGAAGTGGCGGAGGCGGTT CTGATAAGACCCACACCTGTCCACC TTGTCCTGCTCCAGAACTGCTCGGC GGACCTTCCGTGTTCCTGTTTCCTC CAAAGCCTAAGGACACCCTGATGAT CTCTCGGACCCCTGAAGTGACCTGC GTGGTGGTGGATGTGTCTCACGAGG ATCCCGAAGTGAAGTTCAATTGGTA CGTGGACGGCGTGGAAGTGCACAAT GCCAAGACCAAGCCTAGAGAGGAAC AGTACAACTCCACCTATAGAGTGGT GTCCGTGCTGACCGTGCTGCACCAG GATTGGCTGAACGGCAAAGAGTACA AGTGCAAGGTGTCCAACAAGGCCCT GCCTGCTCCTATCGAAAAGACCATC TCCAAGGCCAAGGGCCAGCCTAGGG AACCCCAGGTTTACACCCTGCCTCC ATGCCGGGAAGAGATGACCAAGAAC CAGGTGTCCCTGTGGTGCCTGGTCA AGGGCTTCTACCCTTCCGATATCGC CGTGGAATGGGAGAGCAATGGCCAG CCAGAGAACAACTACAAGACCACAC CTCCAGTGCTGGACTCCGACGGCTC ATTCTTCCTGTACTCCAAGCTGACA GTGGACAAGTCCAGATGGCAGCAGG GCAACGTGTTCTCCTGCTCCGTGAT GCACGAGGCCCTGCACAATCACTAC ACCCAGAAGTCCCTGTCTCTGAGCC CCGGCAAGTGATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 131 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGACAGGTGCAGCTGGTT CAGTCTGGCGGAGGATTGGTTCAGC CAGGCGGATCCCTGAGACTGTCTTG TGCCGCTTCTGGCTTCACCTTCGAC GACTACGCTATGCACTGGGTCCGAC AGGCCCCTGGCAAAGGATTGGAATG GGTGGCCGGCATCTCTTGGGACTCT GGCTCTACCGGCTACGCCGACTCTG TGAAGGGCAGATTCACCATCTCTCG GGACAACGCCAAGAACTCCCTGTAC CTGCAGATGAACAGCCTGAGAGCCG AGGACACCGCTCTGTACTACTGCGC TAGAGATCTGGGCGCCTACCAGTGG GTGGAAGGCTTTGATTATTGGGGCC AGGGCACCCTGGTCACCGTGTCTAG TGCTTCTACTGGTGGTGGCGGATCT GGCGGCGGAGGAAGCGGAGGCGGAG GTAGTGGTGGCGGTGGATCTTCTTA CGAGCTGACCCAGGATCCAGCCGTG TCTGTTGCTCTGGGCCAGACAGTGC GGATTACCTGCCAGGGCGACTCCCT GAGATCCTACTACGCCTCCTGGTAT CAGCAGAAGCCAGGCCAGGCTCCTG TGCTGGTCATCTACGGCAAGAACAA CCGGCCTAGCGGCATCCCTGACAGA TTCTCCGGCTCTACCTCCGGCAACT CTGCCAGCCTGACAATTACTGGCGC CCAGGCTGAGGACGAGGCCGACTAC TACTGCAACTCCAGAGACAGCCCTG GCAATCAGTGGGTTTTCGGCGGAGG CACCAAAGTGACAGTTCTTGGTGGC GGAGGTGGAAGTGGCGGAGGCGGTT CTGATAAGACCCACACCTGTCCACC TTGTCCTGCTCCAGAACTGCTCGGC GGACCTTCCGTGTTCCTGTTTCCTC CAAAGCCTAAGGACACCCTGATGAT CTCTCGGACCCCTGAAGTGACCTGC GTGGTGGTGGATGTGTCTCACGAGG ATCCCGAAGTGAAGTTCAATTGGTA CGTGGACGGCGTGGAAGTGCACAAT GCCAAGACCAAGCCTAGAGAGGAAC AGTACAACTCCACCTATAGAGTGGT GTCCGTGCTGACCGTGCTGCACCAG GATTGGCTGAACGGCAAAGAGTACA AGTGCAAGGTGTCCAACAAGGCCCT GCCTGCTCCTATCGAAAAGACCATC TCCAAGGCCAAGGGCCAGCCTAGGG AACCCCAGGTTTACACCCTGCCTCC ATGCCGGGAAGAGATGACCAAGAAC CAGGTGTCCCTGTGGTGCCTGGTCA AGGGCTTCTACCCTTCCGATATCGC CGTGGAATGGGAGAGCAATGGCCAG CCAGAGAACAACTACAAGACCACAC CTCCAGTGCTGGACTCCGACGGCTC ATTCTTCCTGTACTCCAAGCTGACA GTGGACAAGTCCAGATGGCAGCAGG GCAACGTGTTCTCCTGCTCCGTGAT GCACGAGGCCCTGCACAATCACTAC ACCCAGAAGTCCCTGTCTCTGTCTC CCGGAAAAGGCGGTGGTGGATCAGG TGGCGGAGGCTCAGGCGGAGGCGGA TCTCAAGTTCAGTTGCAGCAGAGCG GACCCGAGCTGGTCAAACCTGGCGC TTCCGTGAAGATGTCCTGCAAGGCC TCCGGCTACACCTTCACCGATTACG TGATCAACTGGGGCAAGCAGCGCTC TGGCCAAGGCCTGGAATGGATCGGC GAGATCTATCCTGGCTCCGGCACCA ACTACTACAACGAGAAGTTCAAGGC TAAGGCTACCCTGACCGCCGACAAG TCCTCCAATATCGCCTACATGCAGC TGTCTAGCCTGACCTCCGAGGACTC TGCCGTGTACTTCTGCGCCAGAAGA GGCAGATACGGCCTGTACGCCATGG ACTACTGGGGACAGGGAACCTCCGT GACAGTTAGTAGCGGTGGCGGCGGT AGCGGCGGTGGTGGTTCTGGCGGTG GTGGTAGTGGCGGCGGAGGATCTGA TATCCAGATGACCCAGACCACCAGC AGCCTGTCTGCTTCCCTGGGCGATA GAGTGACCATCTCTTGCAGAGCCAG CCAGGACATCAGCAACTACCTGAAC TGGTATCAACAAAAACCCGACGGCA CCGTGAAGCTGCTGATCTACTACAC CTCTCGGCTGCACTCTGGCGTGCCC TCTAGATTTTCTGGCAGCGGCTCTG GAACCGACTACTCCCTGACCATCAA CAACCTGGAACAAGAGGATATCGCT ACCTACTTCTGCCAGCAAGGCAACA CCCGGCCTTGGACATTTGGAGGCGG CACCAAGCTGGAAATCAAGTGATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 132 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGACAGGTGCAGCTGGTT CAGTCTGGCGGAGGATTGGTTCAGC CAGGCGGATCCCTGAGACTGTCTTG TGCCGCTTCTGGCTTCACCTTCGAC GACTACGCTATGCACTGGGTCCGAC AGGCCCCTGGCAAAGGATTGGAATG GGTGGCCGGCATCTCTTGGGACTCT GGCTCTACCGGCTACGCCGACTCTG TGAAGGGCAGATTCACCATCTCTCG GGACAACGCCAAGAACTCCCTGTAC CTGCAGATGAACAGCCTGAGAGCCG AGGACACCGCTCTGTACTACTGCGC TAGAGATCTGGGCGCCTACCAGTGG GTGGAAGGCTTTGATTATTGGGGCC AGGGCACCCTGGTCACCGTGTCTAG TGCTTCTACTGGTGGTGGCGGATCT GGCGGCGGAGGAAGCGGAGGCGGAG GTAGTGGTGGCGGTGGATCTTCTTA CGAGCTGACCCAGGATCCAGCCGTG TCTGTTGCTCTGGGCCAGACAGTGC GGATTACCTGCCAGGGCGACTCCCT GAGATCCTACTACGCCTCCTGGTAT CAGCAGAAGCCAGGCCAGGCTCCTG TGCTGGTCATCTACGGCAAGAACAA CCGGCCTAGCGGCATCCCTGACAGA TTCTCCGGCTCTACCTCCGGCAACT CTGCCAGCCTGACAATTACTGGCGC CCAGGCTGAGGACGAGGCCGACTAC TACTGCAACTCCAGAGACAGCCCTG GCAATCAGTGGGTTTTCGGCGGAGG CACCAAAGTGACAGTTCTTGGTGGC GGAGGTGGAAGTGGCGGAGGCGGTT CTGATAAGACCCACACCTGTCCACC TTGTCCTGCTCCAGAACTGCTCGGC GGACCTTCCGTGTTCCTGTTTCCTC CAAAGCCTAAGGACACCCTGATGAT CTCTCGGACCCCTGAAGTGACCTGC GTGGTGGTGGATGTGTCTCACGAGG ATCCCGAAGTGAAGTTCAATTGGTA CGTGGACGGCGTGGAAGTGCACAAT GCCAAGACCAAGCCTAGAGAGGAAC AGTACAACTCCACCTATAGAGTGGT GTCCGTGCTGACCGTGCTGCACCAG GATTGGCTGAACGGCAAAGAGTACA AGTGCAAGGTGTCCAACAAGGCCCT GCCTGCTCCTATCGAAAAGACCATC TCCAAGGCCAAGGGCCAGCCTAGGG AACCCCAGGTTTACACCCTGCCTCC ATGCCGGGAAGAGATGACCAAGAAC CAGGTGTCCCTGTGGTGCCTGGTCA AGGGCTTCTACCCTTCCGATATCGC CGTGGAATGGGAGAGCAATGGCCAG CCAGAGAACAACTACAAGACCACAC CTCCAGTGCTGGACTCCGACGGCTC ATTCTTCCTGTACTCCAAGCTGACA GTGGACAAGTCCAGATGGCAGCAGG GCAACGTGTTCTCCTGCTCCGTGAT GCACGAGGCCCTGCACAATCACTAC ACCCAGAAGTCCCTGTCTCTGTCTC CCGGAAAAGGCGGTGGTGGATCAGG TGGCGGAGGCTCAGGCGGAGGCGGA TCTCAAGTTCAGTTGGTTCAAAGCG GTGGCGGCGTGGTGCAGCCTGGAAG ATCTCTCAGACTGTCCTGCAAGGCC TCCGGCTACACCTTCACCAGATACA CCATGCATTGGGTTCGACAAGCACC AGGCAAGGGCCTCGAGTGGATCGGC TACATCAACCCTTCCAGAGGCTACA CCAACTACAACCAGAAAGTGAAGGA CCGGTTCACCATCAGCAGAGACAAC AGCAAGAATACCGCCTTTCTGCAGA TGGACTCCCTGCGGCCTGAAGATAC CGGCGTGTACTTTTGCGCCCGGTAC TACGACGACCACTACTCCCTGGATT ACTGGGGACAGGGAACACCCGTGAC AGTGTCTAGCGGTGGCGGTGGTTCA GGCGGCGGTGGTAGTGGCGGCGGAG GTAGCGGCGGTGGCGGATCTGATAT TCAGATGACCCAGTCTCCTTCCAGC CTGTCCGCTTCTGTGGGCGACAGAG TGACTATTACCTGCTCCGCCTCTTC CTCCGTGTCCTACATGAACTGGTAT CAACAAACACCCGGCAAGGCCCCTA AGAGATGGATCTACGACACCAGCAA GCTGGCCTCTGGCGTGCCCTCTAGA TTTTCTGGCTCTGGCTCCGGCACCG ACTATACCTTTACAATCTCCAGCCT GCAGCCTGAGGATATCGCCACCTAC TACTGTCAGCAGTGGTCTAGCAACC CCTTCACCTTTGGACAGGGCACCAA GCTGCAGATCACCTGATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 133 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGACAGGTCCAGCTGCAA GAGTCTGGCCCTGGACTGGTCAAGC CCTCTCAGACCCTGTCTCTGACCTG TACCGTGTCCGGCGGCTCCATCAAC AACAACAATTACTACTGGACCTGGA TCCGGCAGCACCCTGGCAAAGGACT GGAATGGATCGGCTACATCTACTAC TCCGGCTCCACCTTCTACAACCCCA GCCTGAAGTCCAGAGTGACCATCTC CGTGGACACCAGCAAGACCCAGTTC TCCCTGAAGCTGTCCTCTGTGACCG CCGCTGATACCGCCGTGTACTACTG CGCCAGAGAAGATACCATGACCGGC CTGGATGTGTGGGGCCAGGGAACAA CAGTGACCGTGTCCTCCGCTTCCAC CAAGGGACCTTCCGTGTTTCCTCTG GCTCCCTCCAGCAAGTCTACCTCTG GTGGAACAGCTGCCCTGGGCTGCCT GGTCAAGGATTACTTTCCTGAGCCT GTGACAGTGTCCTGGAACTCTGGCG CTCTGACATCCGGCGTGCACACCTT TCCAGCTGTGCTGCAATCCTCCGGC CTGTACTCTCTGTCCTCCGTCGTGA CCGTGCCTTCTAGCTCTCTGGGCAC CCAGACCTACATCTGCAATGTGAAC CACAAGCCTTCCAACACCAAGGTGG ACAAGAGAGTGGAACCCAAGTCCTG CGACAAGACCCACACCTGTCCTCCA TGTCCTGCTCCAGAACTGCTCGGCG GACCCTCTGTGTTCCTGTTTCCACC TAAGCCTAAGGACACCCTGATGATC

TCTCGGACCCCTGAAGTGACCTGCG TGGTGGTGGATGTGTCTCACGAGGA TCCCGAAGTGAAGTTCAATTGGTAC GTGGACGGCGTGGAAGTGCACAACG CCAAGACCAAGCCTAGAGAGGAACA GTACAACTCCACCTACAGAGTGGTG TCCGTGCTGACCGTGCTGCACCAGG ATTGGCTGAACGGCAAAGAGTACAA GTGCAAGGTGTCCAACAAGGCCCTG CCTGCTCCTATCGAAAAGACCATCA GCAAGGCCAAGGGCCAGCCTAGGGA ACCCCAGGTTTACACCCTGCCTCCA TGCCGGGAAGAGATGACCAAGAACC AGGTGTCCCTGTGGTGCCTCGTGAA GGGCTTCTACCCTTCCGATATCGCC GTGGAATGGGAGAGCAATGGCCAGC CTGAGAACAACTACAAGACAACCCC TCCTGTGCTGGACTCCGACGGCTCA TTCTTCCTGTACTCCAAGCTGACAG TGGACAAGTCCAGATGGCAGCAGGG CAACGTGTTCTCCTGCTCCGTGATG CACGAGGCCCTGCACAATCACTACA CCCAGAAGAGTCTGTCTCTGTCTCC CGGCAAAGGCGGCGGAGGATCTGGC GGAGGCGGTAGCGGTGGTGGCGGAT CTCAGGTTCAGTTGCAGCAGTCCGG ACCTGAGCTGGTTAAGCCTGGCGCC TCCGTGAAGATGTCCTGCAAGGCTT CTGGCTACACCTTCACCGACTACGT GATCAACTGGGGCAAGCAGAGATCT GGCCAGGGACTCGAGTGGATCGGAG AGATCTATCCTGGCTCCGGCACCAA CTACTACAATGAGAAGTTCAAGGCT AAGGCTACCCTGACCGCCGACAAGT CCTCCAATATCGCCTACATGCAGCT GTCCAGCCTGACCTCTGAGGACTCC GCTGTGTACTTCTGTGCTCGGAGAG GCAGATACGGCCTGTATGCCATGGA TTACTGGGGACAGGGCACCTCCGTG ACTGTCTCTAGCGGTGGCGGAGGTA GCGGAGGCGGTGGTTCAGGCGGAGG CGGCTCTGGTGGCGGTGGATCTGAT ATTCAGATGACCCAGACCACCTCCA GCCTGTCCGCTTCTCTGGGCGACAG AGTGACAATCAGCTGCAGAGCCAGC CAGGACATCAGCAACTACCTGAACT GGTATCAGCAGAAACCCGACGGCAC CGTGAAGCTGCTGATCTACTACACC TCTCGGCTGCACTCTGGCGTGCCCT CTAGATTTTCTGGCAGCGGAAGCGG CACCGATTACTCCCTGACAATCAAC AACCTCGAGCAAGAGGATATCGCTA CCTACTTCTGCCAGCAAGGCAACAC CCGGCCTTGGACATTTGGCGGCGGA ACAAAGCTGGAAATCAAGTGATGA SEQ ID ATGGAAACCGATACCCTGCTGCTGT NO: 121 GGGTGCTGCTCCTCTGGGTGCCAGG CTCTACCGGCCAGTCTGCTCTGACC CAGCCTGCCTCTGTGTCTGGCTCCC CTGGCCAGTCCATCACCATCAGCTG TACCGGCACCTCCTCCGACGTGGGC GGCTACAACTACGTGTCCTGGTATC AGCAGCATCCCGGCAAGGCCCCTAA GCTGATGATCTACGACGTGTCCAAC CGGCCCTCCGGCGTGTCCAATCGGT TCTCTGGCTCCAAGTCCGGCAACAC CGCCTCCCTGACAATCAGCGGACTG CAGGCCGAGGACGAGGCCGACTACT ACTGCTCCTCCTACACCTCCAGCTC TACCCGGGTGTTCGGCACCGGCACC AAAGTGACAGTGCTGGGCCAGCCCA AGGCCAACCCCACCGTGACCCTGTT CCCTCCATCCTCCGAGGAACTGCAG GCTAACAAGGCCACCCTCGTGTGCC TGATCTCCGACTTCTACCCTGGCGC CGTGACCGTGGCTTGGAAGGCTGAT GGCTCTCCTGTGAAGGCCGGCGTGG AAACCACCAAGCCCTCCAAGCAGTC CAACAACAAATACGCCGCCTCCAGC TACCTGTCCCTGACCCCTGAGCAGT GGAAGTCCCACCGGTCCTACAGCTG CCAGGTCACACATGAGGGCTCCACC GTGGAAAAGACCGTGGCCCCTACCG AGTGCTCCTAATGA SEQ ID ATGGAAACCGATACCCTGCTGCTGT NO: 122 GGGTGCTGCTCCTCTGGGTGCCAGG CTCTACAGGACAGGTCCAGCTGCAG GAATCTGGCCCTGGCCTGGTCAAGC CCTCCGAGACACTGTCTCTGACCTG CACCGTGTCCGGCGGCTCTGTGTCC TCCGGCTCCTACTACTGGTCCTGGA TCCGGCAGCCTCCAGGCAAGGGACT GGAATGGATCGGCTACATCTACTAC TCCGGCAGCACCAACTACAACCCCA GCCTGAAGTCCAGAGTGACCATCTC CGTGGACACCTCCAAGAACCAGTTC TCCCTGAAGCTGTCCTCCGTGACCG CCGCTGACACCGCCGTGTACTACTG TGCCAGAGAGGGCAAGAACGGCGCC TTCGATATCTGGGGCGAGGGGACCA TGGTGAGGGTGTGTAGCGCTTCCAC CAAGGGCCCCTCCGTGTTCCCTCTG GCCCCTTCCAGCAAGTCCACCTCTG GCGGAACCGCTGCTCTGGGCTGCCT CGTGAAGGACTACTTCCCCGAGCCT GTGACCGTGTCCTGGAACTCTGGCG CCCTGACATCCGGCGTGCACACCTT TCCAGCCGTGCTGCAGTCCAGCGGC CTGTACTCTCTGTCCAGCGTCGTGA CCGTGCCTTCCAGCTCTCTGGGCAC ACAGACCTACATCTGCAACGTGAAC CACAAGCCTTCCAACACCAAGGTGG ACAAGCGGGTGGAACCCAAGTCCTG CGACAAGACCCACACCTGTCCTCCC TGTCCTGCCCCTGAACTGCTGGGCG GACCCAGCGTGTTCCTGTTCCCTCC AAAGCCCAAGGACACCCTGATGATC TCCCGGACCCCTGAAGTGACCTGCG TGGTGGTGGACGTGTCCCACGAGGA TCCCGAAGTGAAGTTCAATTGGTAC GTGGACGGCGTGGAAGTGCACAACG CCAAGACCAAGCCTAGAGAGGAACA GTACAACTCCACCTACCGGGTGGTG TCCGTGCTGACAGTGCTGCACCAGG ACTGGCTGAACGGCAAAGAGTACAA GTGCAAGGTGTCCAACAAGGCCCTG CCAGCCCCTATCGAAAAGACCATCA GCAAGGCTAAGGGCCAGCCCCGCGA GCCCCAGGTTTACACACTGCCTCCC TGCCGGGAAGAGATGACCAAGAATC AGGTGTCCCTGTGGTGTCTGGTCAA GGGCTTCTACCCCTCCGATATCGCC GTGGAATGGGAGTCCAACGGCCAGC CCGAGAACAACTACAAGACCACCCC TCCCGTGCTGGACTCCGACGGCTCA TTCTTCCTGTACTCCAAGCTGACCG TGGACAAGTCCCGGTGGCAGCAGGG CAACGTGTTCTCCTGCTCTGTGATG CACGAGGCCCTGCACAACCACTACA CCCAGAAGTCCCTGTCCCTGAGCCC CGGCAAGTAATGA SEQ ID ATGGAAACCGATACCCTGCTGCTGT NO: 123 GGGTGCTGCTCCTCTGGGTGCCAGG CTCTACCGGCGACATCCAGATGACC CAGAGCCCTTCCAGCCTGTCCGCCT CTGTGGGCGACAGAGTGACCATCAC CTGTCGGGCCTCCCAGTCCATCTCC TCCTACCTGAACTGGTATCAGCAGA AGCCCGGCAAGGCCCCTAAGCTGCT GATCTACGCCGCCTCCAGTCTGCAG TCTGGCGTGCCATCTGGCTTCTCCG GCTCTGGCTCTGGCACCGACTTCAC CCTGACCATCTCCAGCCTGCAGCCC GAGGACTTCGCCACCTACTACTGCC AGCAGTCCTACTCCACCCCTCTGAC CTTCGGCGGAGGCACCAAGGTGGAA ATCAAGCGGACCGTGGCCGCTCCCT CCGTGTTCATCTTCCCACCTTCCGA CGAGCAGCTGAAGTCCGGCACCGCT TCTGTCGTGTGCCTGCTGAACAACT TCTACCCTCGGGAAGCCAAGGTGCA GTGGAAGGTGGACAATGCCCTGCAG TCCGGCAACTCCCAGGAATCCGTCA CCGAGCAGGACTCCAAGGACAGCAC CTACTCCCTGTCCTCTACCCTGACC CTGTCCAAGGCCGACTACGAGAAGC ACAAGGTGTACGCCTGCGAAGTGAC CCACCAGGGCCTGAGCAGCCCCGTG ACCAAGTCCTTCAACAGAGGCGAGT GCTAATGA SEQ ID ATGGAAACCGATACACTGCTGCTGT NO: 118 GGGTGCTGCTCCTCTGGGTGCCAGG CAGCACCGGCGATATCCAGATGACA CAGAGCCCTAGCAGCCTGAGCGCCA GCGTGGGCGATAGAGTGACCATCAC CTGTCGGGCCAGCCAGAGCATCAAC AACTACCTGAACTGGTATCAGCAGA AGCCCGGCAAGGCCCCTACCCTGCT GATCTATGCCGCTTCTAGCCTGCAG AGCGGCGTGCCCAGCAGATTTTCTG GCAGCAGATCCGGCACCGACTTCAC CCTGACAATCAGCAGCCTGCAGCCC GAGGACTTCGCCGCCTACTTCTGCC AGCAGACCTACAGCAATCCCACCTT CGGCCAGGGCACCAAGGTGGAAGTG AAGAGAACAGTGGCCGCTCCCAGCG TGTTCATCTTCCCACCCAGCGACGA GCAGCTGAAGTCTGGCACAGCCAGC GTCGTGTGCCTGCTGAACAACTTCT ACCCCAGAGAAGCCAAGGTGCAGTG GAAGGTGGACAACGCCCTGCAGTCC GGCAACAGCCAGGAAAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTA CAGCCTGTCCAGCACCCTGACCCTG AGCAAGGCCGACTACGAGAAGCACA AAGTGTACGCCTGCGAAGTGACCCA CCAGGGCCTGAGCAGCCCCGTGACC AAGAGCTTCAATAGAGGCGAGTGCT AATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 134 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACCGGACAGTCTGCTCTGACC CAGCCTGCTTCTGTGTCTGGCTCTC CCGGCCAGTCCATCACCATCTCTTG TACCGGCACCTCCTCTGACGTCGGC GGCTACAACTACGTGTCCTGGTATC AGCAGCATCCCGGCAAGGCCCCTAA GCTGATGATCTACGACGTGTCCAAC CGGCCTTCCGGCGTGTCCAATAGAT TCTCCGGCTCCAAGTCCGGCAACAC CGCTTCTCTGACAATCAGCGGACTG CAGGCCGAGGACGAGGCCGACTACT ACTGTTCCTCCTACACCTCCTCCAG CACCAGAGTGTTTGGCACCGGCACC AAAGTGACCGTGCTGGGACAGCCTA AGGCCAATCCTACCGTGACACTGTT CCCTCCATCCTCCGAGGAACTGCAG GCTAACAAGGCTACCCTCGTGTGCC TGATCTCCGACTTTTACCCTGGCGC TGTGACCGTGGCCTGGAAGGCTGAT GGATCTCCTGTGAAGGCTGGCGTGG AAACCACCAAGCCTTCCAAGCAGTC CAACAACAAATACGCCGCCTCCTCC TACCTGTCTCTGACCCCTGAACAGT GGAAGTCCCACCGGTCCTACAGCTG CCAAGTGACCCATGAGGGCTCCACC GTGGAAAAGACCGTGGCTCCTACTG AGTGTTCTGGCGGCGGAGGATCTGG CGGAGGTGGAAGCGGAGGCGGTGGA TCTGCTCCTACCTCCAGCTCCACCA AGAAAACCCAGCTGCAGTTGGAGCA TCTGCTGCTGGACCTGCAGATGATC CTGAACGGCATCAACAACTACAAGA ACCCCAAGCTGACCCGGATGCTGAC CGCCAAGTTTGCCATGCCTAAGAAG GCCACCGAGCTGAAACATCTGCAGT GCCTGGAAGAGGAACTGAAGCCCCT GGAAGAAGTGCTGAATCTGGCCCAG TCCAAGAACTTCCACCTGAGGCCTC GGGACCTGATCAGCAACATCAACGT GATCGTGCTCGAGCTGAAGGGCTCC GAGACAACCTTCATGTGCGAGTACG CCGACGAGACAGCTACCATCGTGGA ATTTCTGAACCGGTGGATCACCTTC TGCCAGAGCATCATCAGCACCCTGA CCTGATGA

SEQ ID ATGGAAACCGATACCCTGCTGCTGT NO: 135 GGGTGCTGCTCCTCTGGGTGCCAGG ATCTACAGGCGAGGTGCAGCTGCTG GAATCTGGCGGAGGACTGGTGCAGC CTGGCGGCTCTCTGAGACTGTCTTG TGCCGCCTCCGGCTTCACCTTCTCC AGCTATATCATGATGTGGGTCCGAC AGGCCCCTGGCAAGGGCCTGGAATG GGTGTCCTCTATCTACCCCTCCGGC GGCATCACCTTTTACGCCGACACCG TGAAGGGCCGGTTCACCATCTCCCG GGACAACTCCAAGAACACCCTGTAC CTGCAGATGAACTCCCTGCGGGCCG AGGACACCGCCGTGTACTACTGCGC TAGAATCAAGCTGGGCACCGTGACC ACCGTGGACTATTGGGGCCAGGGCA CCCTGGTCACCGTGTCCTCTGCTTC TACCAAGGGCCCCTCCGTGTTCCCT CTGGCCCCTTCCAGCAAGTCCACCT CTGGCGGAACCGCTGCTCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAG CCCGTGACCGTGTCTTGGAACTCTG GCGCCCTGACCAGCGGCGTGCACAC ATTTCCAGCCGTGCTGCAGTCCAGC GGCCTGTACTCTCTGTCCTCCGTCG TGACAGTGCCCTCCAGCTCTCTGGG CACACAGACCTACATCTGCAACGTG AACCACAAGCCCTCCAACACCAAGG TGGACAAGCGGGTGGAACCCAAGTC CTGCGACAAGACCCACACCTGTCCT CCCTGTCCTGCCCCTGAACTGCTGG GCGGACCCAGCGTGTTCCTGTTCCC TCCAAAGCCTAAGGACACCCTGATG ATCTCCCGGACCCCTGAAGTGACCT GCGTGGTGGTGGACGTGTCCCACGA GGATCCCGAAGTGAAGTTCAATTGG TACGTGGACGGCGTGGAAGTGCACA ACGCCAAGACCAAGCCTAGAGAGGA ACAGTACAACTCCACCTACCGGGTG GTGTCCGTGCTGACAGTGCTGCATC AGGACTGGCTGAACGGCAAAGAGTA CAAGTGCAAGGTGTCCAACAAGGCC CTGCCAGCCCCTATCGAAAAGACCA TCTCCAAGGCCAAGGGCCAGCCAAG AGAGCCTCAAGTCTGCACACTGCCT CCCAGCCGGGAAGAGATGACCAAGA ACCAGGTGTCCCTGAGCTGCGCTGT GAAGGGCTTCTACCCTTCCGATATC GCCGTGGAATGGGAGAGCAACGGCC AGCCCGAGAACAATTACAAGACCAC CCCTCCCGTGCTGGACTCCGACGGC TCATTCTTCCTGGTGTCCAAGCTGA CCGTGGACAAGTCCCGGTGGCAGCA GGGCAACGTGTTCTCCTGCTCTGTG ATGCACGAGGCCCTGCACAACCACT ACACCCAGAAGTCCCTGTCCCTGTC TCCCGGCAAGTAATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 137 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGACAGGTCCAGCTGCAA GAGTCTGGCCCTGGACTGGTCAAGC CTTCCGAGACACTGTCTCTGACCTG CACCGTGTCTGGCGGCTCTGTGTCC TCTGGCTCCTACTACTGGTCCTGGA TCAGACAGCCTCCTGGCAAAGGCCT GGAATGGATCGGCTACATCTACTAC TCCGGCTCCACCAACTACAACCCCA GCCTGAAGTCCAGAGTGACCATCTC CGTGGACACCTCCAAGAACCAGTTC TCCCTGAAGCTGTCCTCCGTGACCG CTGCTGATACCGCCGTGTACTACTG TGCCAGAGAGGGCAAGAACGGCGCC TTCGATATTTGGGGCCAGGGCACCA TGGTCACCGTGTCCAGTGCTTCTAC CAAGGGACCCAGCGTGTTCCCACTG GCTCCCAGCTCTAAGTCTACCTCTG GCGGAACAGCTGCCCTGGGCTGTCT GGTCAAGGATTACTTCCCTGAGCCT GTGACCGTGTCCTGGAATTCTGGCG CTCTGACATCCGGCGTGCACACCTT TCCAGCTGTGCTGCAATCCTCCGGC CTGTACTCTCTGTCCAGCGTCGTGA CCGTGCCTTCTAGCTCTCTGGGCAC CCAGACCTACATCTGCAATGTGAAC CACAAGCCTAGCAACACCAAGGTGG ACAAGAGAGTGGAACCCAAGTCCTG CGACAAGACCCACACCTGTCCTCCA TGTCCTGCTCCAGAACTGCTCGGCG GACCTTCCGTGTTCCTGTTTCCTCC AAAGCCTAAGGACACCCTGATGATC TCTCGGACCCCTGAAGTGACCTGCG TGGTGGTGGATGTGTCTCACGAGGA TCCCGAAGTGAAGTTCAATTGGTAC GTGGACGGCGTGGAAGTGCACAACG CCAAGACCAAGCCTAGAGAGGAACA GTACAACTCCACCTACAGAGTGGTG TCCGTGCTGACCGTGCTGCACCAGG ATTGGCTGAACGGCAAAGAGTACAA GTGCAAGGTGTCCAACAAGGCCCTG CCTGCTCCTATCGAAAAGACCATCA GCAAGGCCAAGGGCCAGCCTAGGGA ACCCCAGGTTTACACCCTGCCTCCA TGCCGGGAAGAGATGACCAAGAATC AGGTGTCCCTGTGGTGCCTCGTGAA GGGCTTCTACCCTTCCGATATCGCC GTGGAATGGGAGAGCAATGGCCAGC CTGAGAACAACTACAAGACAACCCC TCCTGTGCTGGACTCCGACGGCTCA TTCTTCCTGTACTCCAAGCTGACAG TGGACAAGTCCAGATGGCAGCAGGG CAACGTGTTCTCCTGCTCCGTGATG CACGAGGCCCTGCACAATCACTACA CCCAGAAGTCCCTGTCTCTGTCCCC TGGAAAAGGCGGCGGAGGATCTGGC GGAGGTGGAAGCGGAGGCGGTGGAT CTGAAGTGCAGCTCCAAGAATCTGG ACCCGGGCTCGTGAAGCCCAGCCAG TCTCTGAGTCTGACCTGTACAGTGA CCGGCTACTCCATCACCTCCGACTA CGCTTGGAACTGGATCCGGCAGTTC CCCGGCAACAAGTTGGAGTGGATGG GCTATATCACCTACAGCGGCAGCAC CTCTTACAACCCTTCTCTGGAATCC CGGATCAGCATCACCCGGGACACCT CTACCAATCAGTTCTTTCTGCAGCT GAACAGCGTGACCACCGAGGACACC GCCACCTACTATTGTGCTAGAGGCG GCTACTACGGCTCCTCCTGGGGAGT GTTTGCTTACTGGGGACAGGGAACC CTCGTGACTGTTTCTGCTGGTGGCG GAGGAAGCGGCGGAGGCGGCTCTGG TGGTGGTGGTTCTGGTGGCGGCGGA TCTGACATCCAGATGACCCAGTCTC CAGCCAGCCTGTCTGCTTCTGTGGG CGAGACAGTGACCATTACCTGCCGG GTGTCCGAGAACATCTACTCCTACC TGGCCTGGTATCAACAGAAACAGGG CAAGTCCCCTCAGCTGCTGGTGTAC AATGCTAAGACCCTGGCTGAGGGCG TGCCCTCTAGATTTTCTGGCTCTGG CAGCGGCACCCAGTTTAGCCTGAAG ATCAACTCCCTGCAGCCTGAGGACT TCGGCAGCTACTACTGCCAGCACCA CTATGGCACCCCTTGGACATTTGGC GGAGGCACCAAGCTGGAAATCAAGT GATGA SEQ ID ATGGAAACCGACACACTGCTGCTGT NO: 138 GGGTGCTGCTCTTGTGGGTGCCAGG ATCTACAGGACAGGTCCAGCTGCAA GAGTCTGGCCCTGGACTGGTCAAGC CTTCCGAGACACTGTCTCTGACCTG CACCGTGTCTGGCGGCTCTGTGTCC TCTGGCTCCTACTACTGGTCCTGGA TCAGACAGCCTCCTGGCAAAGGCCT GGAATGGATCGGCTACATCTACTAC TCCGGCTCCACCAACTACAACCCCA GCCTGAAGTCCAGAGTGACCATCTC CGTGGACACCTCCAAGAACCAGTTC TCCCTGAAGCTGTCCTCCGTGACCG CTGCTGATACCGCCGTGTACTACTG TGCCAGAGAGGGCAAGAACGGCGCC TTCGATATTTGGGGCCAGGGCACCA TGGTCACCGTGTCCAGTGCTTCTAC CAAGGGACCCAGCGTGTTCCCACTG GCTCCCAGCTCTAAGTCTACCTCTG GCGGAACAGCTGCCCTGGGCTGTCT GGTCAAGGATTACTTCCCTGAGCCT GTGACCGTGTCCTGGAATTCTGGCG CTCTGACATCCGGCGTGCACACCTT TCCAGCTGTGCTGCAATCCTCCGGC CTGTACTCTCTGTCCAGCGTCGTGA CCGTGCCTTCTAGCTCTCTGGGCAC CCAGACCTACATCTGCAATGTGAAC CACAAGCCTAGCAACACCAAGGTGG ACAAGAGAGTGGAACCCAAGTCCTG CGACAAGACCCACACCTGTCCTCCA TGTCCTGCTCCAGAACTGCTCGGCG GACCTTCCGTGTTCCTGTTTCCTCC AAAGCCTAAGGACACCCTGATGATC TCTCGGACCCCTGAAGTGACCTGCG TGGTGGTGGATGTGTCTCACGAGGA TCCCGAAGTGAAGTTCAATTGGTAC GTGGACGGCGTGGAAGTGCACAACG CCAAGACCAAGCCTAGAGAGGAACA GTACAACTCCACCTACAGAGTGGTG TCCGTGCTGACCGTGCTGCACCAGG ATTGGCTGAACGGCAAAGAGTACAA GTGCAAGGTGTCCAACAAGGCCCTG CCTGCTCCTATCGAAAAGACCATCA GCAAGGCCAAGGGCCAGCCTAGGGA ACCCCAGGTTTACACCCTGCCTCCA TGCCGGGAAGAGATGACCAAGAATC AGGTGTCCCTGTGGTGCCTCGTGAA GGGCTTCTACCCTTCCGATATCGCC GTGGAATGGGAGAGCAATGGCCAGC CTGAGAACAACTACAAGACAACCCC TCCTGTGCTGGACTCCGACGGCTCA TTCTTCCTGTACTCCAAGCTGACAG TGGACAAGTCCAGATGGCAGCAGGG CAACGTGTTCTCCTGCTCCGTGATG CACGAGGCCCTGCACAATCACTACA CCCAGAAGTCCCTGTCTCTGTCCCC TGGAAAAGGCGGCGGAGGATCTGGC GGAGGTGGAAGCGGAGGCGGTGGAT CTCAGGTTCAGTTGCAGCAGTCTGC CGTGGAACTGGCTAGACCTGGCGCT TCCGTGAAGATGTCCTGCAAGGCCT CCGGCTACACCTTCACCAGCTTCAC CATGCACTGGGTCAAGCAGAGGCCT GGACAAGGCTTGGAGTGGATTGGAT ATATCAACCCTAGCTCTGGCTACAC CGAGTACAACCAGAAGTTCAAGGAC AAGACCACTCTGACCGCCGACAAGT CCTCCAGCACCGCTTACATGCAGCT CGACTCCCTGACCTCTGACGACTCT GCTGTGTACTATTGCGTGCGGGGCT CCTCCAGAGGCTTCGATTATTGGGG ACAAGGCACACTCGTGACAGTGTCA GCTGGTGGTGGCGGTAGTGGCGGTG GCGGTTCAGGTGGCGGAGGAAGCGG CGGAGGCGGATCTGATATCCAGATG ATCCAGTCTCCTGCCAGCCTGTCCG TGTCTGTGGGAGAGACTGTGACCAT CACCTGTCGGGCCTCCGAGAACATC TACTCCAACCTGGCCTGGTTCCAGC AGAAGCAGGGAAAGTCTCCTCAGCT GCTGGTGTACGCCGCCACCAATTTG GCTGATGGCGTGCCCTCTCGGTTCT CCGGATCTGGATCTGGCACACAGTA TTCCCTGAAGATCAACTCCCTGCAG TCCGAGGACTTCGGCATCTACTATT GCCAGCACTTCTGGGGCACCCCTAG AACCTTTGGCGGCGGAACAAAGCTG GAAATCAAGTGATGA

TABLE-US-00007 TABLE 4 Nucleic acid sequences of antigens. Sequence ID Description Nucleic Acid Sequence SEQ ID hIL2R.alpha. ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGT NO: 139 GCCAGGATCTACAGGCGAGCTGTGCGACGATGACCCTCCTGAGA TCCCTCACGCCACCTTCAAGGCCATGGCTTACAAAGAGGGCACC ATGCTGAACTGCGAGTGCAAGCGGGGCTTCAGACGGATCAAGTC CGGCAGCCTGTACATGCTGTGCACCGGCAACTCCTCTCACTCCT CCTGGGACAACCAGTGCCAGTGCACCTCCTCTGCCACCAGAAAC ACCACCAAGCAAGTGACCCCTCAGCCTGAGGAACAGAAAGAGCG CAAGACCACCGAGATGCAGAGCCCCATGCAGCCTGTGGATCAGG CTTCTCTGCCTGGCCACTGTAGAGAGCCTCCACCTTGGGAGAAT GAGGCCACCGAGCGGATCTACCACTTTGTCGTGGGCCAGATGGT GTACTACCAGTGCGTGCAGGGATACAGAGCCCTGCATAGAGGCC CTGCTGAGTCCGTGTGCAAGATGACCCATGGCAAGACCAGATGG ACCCAGCCTCAGCTGATCTGTACAGGCGGAGGCGGAGGATCTGG TGGTGGTGGATCTGGCCTGAACGACATCTTCGAGGCCCAGAAAA TCGAGTGGCACGAAGGCGGTGGCGGCTCCCACCATCATCATCAC CACCATCACTGATGA SEQ ID hMesothelin ATGGAAACCGACACCCTGCTGCTGTGGGTGCTGCTGCTCTGGGT NO: 140 CCCAGGCTCCACCGGCGGACTGAACGACATCTTCGAGGCCCAGA AAATCGAGTGGCACGAGGGCGGAGGCGGCTCCGAGCCTAGAACC GACACCGACACCTGTCCCAACCCCCCCGACCCCTGCCCTACCTG TCCTACCCCTGATCTGCTGGGCGGACCCTCCGTGTTCATCTTCC CACCCAAGCCTAAGGACGTGCTGATGATCTCCCTGACCCCCAAG ATCACCTGTGTGGTGGTGGACGTGTCCGAAGAGGAACCCGACGT GCAGTTCAATTGGTACGTGAACAACGTGGAAGATAAGACCGCCC AGACCGAGACACGGCAGCGGCAGTACAACTCCACCTACCGGGTG GTGTCCGTGCTGCCCATCAAGCACCAGGACTGGATGTCCGGCAA GGTGTTCAAGTGCAAAGTGAACAACAACGCCCTGCCCAGCCCCA TCGAAAAGACCATCTCCAAGCCTCGGGGCCAAGTCCGAGTGCCC CAGATCTACACCTTCCCACCCCCTATCGAGCAGACCGTGAAGAA AGACGTGTCCGTGACCTGCCTCGTGACCGGATTCCTGCCACAAG ACATCCACGTGGAATGGGAGTCCAACGGCCAGCCCCAGCCCGAG CAGAACTACAAGAACACCCAGCCCGTGCTGGACTCCGACGGCTC CTACTTCCTGTACTCCAAGCTGAACGTGCCCAAGTCCAGATGGG ACCAGGGCGACTCCTTCACCTGTTCCGTGATCCACGAGGCCCTG CACAACCACCACATGACCAAGACCATCAGCCGGTCCCTGGGCAA TGGCGGCGGAGGCTCCGAGGTGGAAAAGACCGCCTGCCCCTCCG GCAAGAAGGCCAGAGAGATCGACGAGTCCCTGATCTTCTACAAG AAGTGGGAGCTGGAAGCCTGCGTGGACGCCGCCCTGCTGGCCAC CCAGATGGACAGAGTGAACGCCATCCCCTTCACCTACGAGCAGC TGGATGTGCTGAAGCACAAGCTGGACGAGCTGTACCCCCAGGGC TACCCCGAGAGCGTGATCCAGCACCTGGGCTACCTGTTTCTGAA GATGTCCCCCGAGGACATCCGGAAGTGGAACGTGACCTCCCTGG AAACCCTGAAGGCCCTGCTGGAAGTGAACAAGGGCCACGAGATG AGCCCCCAGGCCCCCAGACGACCTCTGCCTCAGGTGGCAACCCT GATCGATAGATTCGTGAAGGGCAGAGGCCAGCTGGACAAGGACA CCCTGGACACACTGACCGCCTTCTACCCCGGCTACCTGTGCTCC CTGTCCCCTGAGGAACTGTCCTCCGTGCCCCCCTCCTCTATCTG GGCCGTGCGGCCTCAGGATCTGGACACCTGTGACCCTCGGCAGC TGGATGTCCTGTATCCCAAGGCCCGGCTGGCCTTCCAGAACATG AACGGCTCCGAGTACTTCGTGAAGATCCAGTCCTTCCTGGGCGG AGCCCCCACCGAGGACCTGAAGGCTCTGTCCCAGCAGAACGTGT CCATGGACCTGGCCACCTTCATGAAGCTGCGGACCGACGCCGTG CTGCCTCTGACCGTGGCTGAGGTGCAGAAGCTGCTGGGCCCCCA CGTGGAAGGCCTGAAGGCCGAGGAACGGCACAGACCCGTGCGGG ACTGGATCCTGCGGCAGAGACAGGACGACCTGGATACCCTGGGC CTGGGCCTGCAGTAATGA SEQ ID hPD1L1 ATGAGAATCTTCGCCGTGTTCATCTTCATGACCTACTGGCATCT NO: 141 GCTGAACGCCTTCACCGTGACCGTGCCCAAGGACCTGTACGTGG TGGAATACGGCTCCAACATGACCATCGAGTGCAAGTTCCCCGTG GAAAAGCAGCTGGACCTGGCCGCCCTGATCGTGTACTGGGAGAT GGAAGATAAGAACATCATCCAGTTCGTGCACGGGGAAGAGGACC TGAAGGTGCAGCACTCCTCCTACCGGCAGAGAGCCAGACTGCTG AAGGACCAGCTGTCCCTGGGCAATGCCGCCCTGCAGATCACCGA CGTGAAGCTGCAGGATGCCGGCGTGTACCGGTGCATGATCTCTT ACGGCGGAGCCGACTACAAGCGGATCACCGTGAAAGTGAACGCC CCCTACAACAAGATCAACCAGCGGATCCTGGTGGTGGACCCCGT GACCTCTGAGCACGAGCTGACCTGTCAGGCCGAGGGCTACCCTA AGGCCGAAGTGATCTGGACCTCCTCCGACCACCAGGTGCTGTCC GGCAAGACCACCACCACAAACTCCAAGCGGGAAGAGAAGCTGTT CAACGTGACCTCCACCCTGCGGATCAACACAACCACCAACGAGA TCTTCTACTGTACCTTCCGGCGGCTGGACCCCGAGGAAAATCAC ACCGCTGAGCTCGTGATCCCCGAGCTGCCTCTGGCCCACCCTCC TAATGAGAGAACAGGCGGCGGAGGCTCCGGCCTGAACGACATCT TTGAGGCCCAGAAAATCGAGTGGCACGAGGGCGGAGGCGGCTCC CACCATCATCACCACCACCATCACTGATGA SEQ ID hNKp30 ATGGCTTGGATGCTGCTGCTGATCCTGATCATGGTGCACCCCGG NO: 142 CTCTTGCGCCCTGTGGGTGTCCCAGCCTCCTGAGATCAGAACCC TGGAAGGCTCCTCCGCCTTCCTGCCCTGCTCCTTCAATGCCTCT CAGGGCAGACTGGCCATCGGCTCCGTGACCTGGTTCAGGGATGA GGTGGTGCCCGGCAAAGAAGTGCGGAACGGCACACCTGAGTTCA GAGGCAGACTCGCCCCTCTGGCCTCCTCTAGATTCCTGCACGAT CACCAGGCCGAGCTGCACATCAGAGATGTGCGGGGCCACGACGC CTCCATCTACGTGTGCAGAGTGGAAGTGCTGGGCCTGGGCGTGG GCACCGGCAATGGAACACGGCTGGTGGTGGAAAAAGAGGGCGGA GGCGGATCTGGCGGCGGAGGCTCTGATAAGACCCACACCTGTCC TCCCTGTCCTGCCCCTGAACTGCTGGGCGGACCTTCCGTGTTCC TGTTCCCTCCAAAGCCCAAGGACACCCTGATGATCTCCCGGACC CCTGAAGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGATCC CGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACA ACGCCAAGACCAAGCCCAGAGAGGAACAGTACAACTCCACCTAC CGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAA CGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCAG CCCCAATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGC GAGCCTCAGGTGTACACACTGCCTCCCAGCCGGGAAGAGATGAC CAAGAACCAGGTGTCCCTGACCTGTCTGGTCAAGGGCTTCTACC CCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCTCCCGTGCTGGACTCCGACGGCTC ATTCTTCCTGTACTCCAAGCTGACCGTGGACAAGTCCCGGTGGC AGCAGGGCAACGTGTTCTCCTGCTCTGTGATGCACGAGGCCCTG CACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCTGGCAA AGGTGGTGGTGGTAGCGGTGGCGGAGGCAGCGGCCTGAACGATA TCTTCGAGGCCCAGAAAATCGAGTGGCACGAGTAATGA SEQ ID hNKp46 ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGT NO: 143 GCCAGGATCTACCGGCCAGCAGCAGACACTGCCCAAGCCTTTTA TCTGGGCCGAGCCTCACTTCATGGTGCCCAAAGAAAAGCAAGTG ACCATCTGCTGCCAGGGCAACTACGGCGCTGTGGAATACCAGCT GCACTTCGAGGGCTCCCTGTTCGCCGTGGATAGACCTAAGCCTC CTGAGCGGATCAACAAAGTGAAGTTCTACATCCCCGACATGAAC TCCCGGATGGCTGGCCAGTACTCCTGCATCTATAGAGTGGGCGA GCTTTGGAGCGAGCCCTCCAATCTGCTGGATCTGGTGGTCACCG AGATGTACGACACCCCTACACTGAGCGTGCACCCCGGACCTGAA GTGATCTCTGGCGAGAAAGTGACCTTCTACTGCAGACTGGATAC CGCCACCTCCATGTTTCTGCTGCTCAAAGAGGGCAGATCCTCTC ACGTGCAGCGCGGCTATGGAAAGGTGCAGGCTGAGTTTCCTCTG GGCCCTGTGACCACCGCTCACAGAGGCACCTACAGATGCTTCGG CTCCTACAACAACCACGCCTGGTCTTTCCCATCCGAGCCTGTGA AGCTGCTGGTCACCGGCGACATCGAGAACACATCTCTGGCCCCT GAGGACCCCACCTTTCCTGATACCTGGGGCACCTATCTGCTGAC CACCGAGACAGGCCTGCAGAAAGATCACGCCCTGTGGGATCACA CCGCTCAGAATGGTGGCGGAGGATCTGGCGGAGGCGGATCTGAA CCTAGAACCGACACCGACACCTGTCCTAATCCTCCAGATCCTTG TCCTACCTGTCCAACACCTGACCTGCTCGGCGGACCTTCCGTGT TCATCTTCCCACCTAAGCCAAAGGACGTGCTGATGATCTCTCTG ACCCCTAAGATCACCTGTGTGGTGGTGGACGTGTCCGAAGAGGA ACCCGACGTGCAGTTCAATTGGTACGTGAACAACGTCGAGGACA AGACAGCCCAGACCGAGACACGGCAGCGGCAGTACAACTCTACC TACAGAGTGGTGTCCGTGCTGCCCATCAAGCACCAGGATTGGAT GTCCGGCAAGGTGTTCAAGTGCAAAGTGAACAACAACGCCCTGC CTTCTCCAATCGAAAAGACCATCTCCAAGCCTCGGGGCCAAGTG CGAGTGCCCCAGATCTATACCTTTCCACCTCCTATCGAGCAGAC CGTGAAGAAAGATGTGTCCGTGACCTGCCTCGTGACCGGCTTCC TGCCTCAAGACATCCATGTGGAATGGGAGTCCAACGGCCAGCCT CAGCCTGAGCAGAACTACAAGAACACCCAGCCTGTGCTGGACTC CGACGGCAGCTACTTCCTGTACTCCAAGCTGAACGTGCCCAAGT CCAGATGGGACCAGGGCGACTCCTTCACCTGTTCCGTGATCCAC GAGGCCCTGCACAACCACCACATGACCAAGACCATCAGCAGATC CCTCGGCAATGGCGGTGGTGGTTCTGGCGGCGGAGGTTCCGGAC TGAACGATATCTTCGAGGCCCAGAAAATCGAGTGGCACGAGTGA TGA SEQ ID BirA ATGGAAACTGACACCCTCCTCCTTTGGGTGCTGCTGCTTTGGGT NO: 144 GCCTGGATCGACCGGGATGAAGGACAATACCGTGCCTCTGAAGC TCATTGCCCTGCTGGCCAACGGAGAATTCCATTCCGGCGAACAG CTGGGGGAGACTCTCGGGATGTCCCGGGCCGCCATCAACAAGCA CATCCAGACTTTGCGCGACTGGGGAGTCGACGTGTTCACGGTGC CGGGGAAGGGCTACTCGCTCCCGGAACCGATCCAGCTGCTGAAC GCCAAGCAGATTCTGGGACAGCTGGATGGCGGAAGCGTGGCAGT GCTGCCCGTGATCGACTCAACCAACCAGTATCTGCTGGATAGAA TCGGTGAACTGAAATCCGGCGACGCTTGCATTGCCGAGTACCAA CAGGCCGGAAGGGGACGGCGCGGCAGGAAGTGGTTCTCTCCATT CGGCGCGAACCTCTACCTGAGCATGTTCTGGAGATTGGAGCAGG GTCCCGCCGCGGCCATCGGCCTCTCCCTGGTCATCGGCATTGTG ATGGCTGAAGTGCTGAGGAAGTTGGGTGCCGACAAGGTCCGCGT GAAGTGGCCGAACGACCTGTACCTCCAAGACCGGAAATTGGCGG GGATTCTCGTCGAGCTTACCGGAAAGACTGGCGATGCCGCACAA ATTGTGATCGGGGCGGGAATCAACATGGCGATGCGACGGGTGGA AGAGAGCGTCGTGAACCAGGGATGGATCACCCTGCAAGAGGCCG GAATCAACCTGGATCGCAACACCCTGGCTGCCATGCTCATTCGC GAACTGAGAGCCGCACTGGAGCTGTTTGAGCAGGAGGGTCTGGC CCCCTACCTGTCACGCTGGGAAAAGCTTGATAACTTCATCAATC GGCCTGTGAAGCTGATCATCGGAGACAAGGAGATTTTCGGCATC TCGAGAGGCATCGACAAACAAGGAGCCCTCCTGCTGGAACAGGA CGGAATCATTAAGCCCTGGATGGGTGGAGAGATCTCCCTGCGGT CCGCCGAAAAGTCCGGGAAGGATGAACTC

TABLE-US-00008 TABLE 5 Amino Acid sequences. Sequence ID Description Amino Acid Sequence SEQ ID .alpha.Mesothelin QVQLQESGPGLVKPSQTLSLTCTVSGGSINNNNYYWTWIRQHPGKG NO: 145 Ab237 LEWIGYIYYSGSTFYNPSLKSRVTISVDTSKTQFSLKLSSVTAADT VH AVYYCAREDTMTGLDVWGQGTTVTVSS SEQ ID .alpha.Mesothelin DIQMTQSPSSLSASVGDRVTITCRASQSINNYLNWYQQKPGKAPTL NO: 146 Ab237 LIYAASSLQSGVPSRFSGSRSGTDFTLTISSLQPEDFAAYFCQQTY VL SNPTFGQGTKVEVK SEQ ID hIL2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYM NO: 20 PKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVI VLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT SEQ ID: 2x4GS GGGGSGGGGS 43 linker SEQ ID: Human DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 83 CH2, CH3 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD knob WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEM TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID: Human DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 82 CH2, CH3 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD hole WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEM TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID: CH1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 14 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKRVEPKSC SEQ ID: CL (kappa) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA 11 LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID: CL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADG 147 (lambda) SPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS SEQ ID: .alpha.PD1L1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLE 148 Avelumab WVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTA VH VYYCARIKLGTVTTVDYWGQGTLVTVSS SEQ ID: .alpha.PD1L1 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAP 149 Avelumab KLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSS VL YTSSSTRVFGTGTKVTVL SEQ ID: 3x4GS GGCGGCGGAGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCT 96 linker SEQ ID: .alpha.NKp46 QVQLQQSGPELVKPGASVKMSCKASGYTFTDYVINWGKQRSGQGLE 150 VH WIGEIYPGSGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTSEDSA VYFCARRGRYGLYAMDYWGQGTSVTVSS SEQ ID: .alpha.NKp46 DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKL 151 VL LIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGN TRPWTFGGGTKLEIK SEQ ID: 4x4GS GGGGSGGGGSGGGGSGGGGS 152 linker SEQ ID: .alpha.Mesothelin QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKG 153 M912 LEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADT VH AVYYCAREGKNGAFDIWGQGTMVTVSS SEQ ID: .alpha.Mesothelin RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA 154 M912 VL LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID: 1x4GS GGGGS 42 .alpha.NKp30 BioLegend Catalog #325207 scFv SEQ ID hIL7 DCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHI NO: 156 CDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNC TGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEI KTCWNKILMGTKEH SEQ ID .alpha.IGF1R, EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLE NO: 157 Istiratumab WVGSISGSGGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA heavy VYYCAKDFYQILTGNAFDYWGQGTTVTVSS SEQ ID .alpha.IGF1R, DIQMTQSPSSLSASLGDRVTITCRASQGISSYLAWYQQKPGKAPKL NO: 158 Istiratumab LIYAKSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDSATYYCQQYW light TFPLTFGGGTKVEIK SEQ ID .alpha.HER3 QVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLE NO: 159 Istiratumab WVAGISWDSGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA heavy LYYCARDLGAYQWVEGFDYWGQGTLVTVSS SEQ ID .alpha.HER3 SYELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLV NO: 160 Istiratumab IYGKNNRPSGIPDRFSGSTSGNSASLTITGAQAEDEADYYCNSRDS light PGNQWVFGGGTKVTVLG SEQ ID .alpha.CD3 QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLE NO: 161 Teplizumab WIGYINPSRGYTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTG heavy VYFCARYYDDHYSLDYWGQGTPVTVSS SEQ ID .alpha.CD3 DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRW NO: 162 Teplizumab IYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSS light NPFTFGQGTKLQIT SEQ ID hIL2F42A APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFAM NO: 163 Y45A PKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVI VLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT SEQ ID .alpha.NKp462 QLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEW NO: 164 heavy MGYITYSGSTSYNPSLESRISITRDTSTNQFFLQLNSVTTEDTATY YCARGGYYGSSWGVFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGG GS SEQ ID .alpha.NKp462 DIQMTQSPASLSASVGETVTITCRVSENIYSYLAWYQQKQGKSPQL NO: 165 light LVYNAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHY GTPWTFGGGTKLEIK SEQ ID .alpha.NKp46 QVQLQQSAVELARPGASVKMSCKASGYTFTSFTMHWVKQRPGQGLE NO: 166 heavy 4 WIGYINPSSGYTEYNQKFKDKTTLTADKSSSTAYMQLDSLTSDDSA VYYCVRGSSRGFDYWGQGTLVTVSA SEQ ID .alpha.NKp46 DIQMIQSPASLSVSVGETVTITCRASENIYSNLAWFQQKQGKSPQL NO: 167 light 4 LVYAATNLADGVPSRFSGSGSGTQYSLKINSLQSEDFGIYYCQHFW GTPRTFGGGTKLEIK

TABLE-US-00009 TABLE 6 Amino Acid sequences for full heavy and light chains. Construct SEQ ID NO: N-term Linker Variable Constant Fc Linker C-term SEQ ID SEQ ID SEQ ID SEQ ID NO: 168 NO: 145 NO: 14 NO: 83 SEQ ID SEQ ID SEQ ID NO: 169 NO: 146 NO: 11 SEQ ID SEQ ID SEQ ID SEQ ID NO: 170 NO: 20 NO: 43 NO: 82 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 120 NO: 148 NO: 14 NO: 82 NO: 96 NO: 20 SEQ ID SEQ ID SEQ ID NO: 171 NO: 149 NO: 147 SEQ ID SEQ ID SEQ ID SEQ ID NO: 172 NO: 153 NO: 14 NO: 83 SEQ ID SEQ ID SEQ ID NO: 173 NO: 154 NO: 11 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 174 NO: 145 NO: 14 NO: 83 NO: 96 NO: 155 SEQ ID SEQ ID NO: 82 NO: 82 SEQ ID SEQ ID NO: 176 NO: 83 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 177 NO: 148 NO: 14 NO: 82 NO: 96 NO: 20 SEQ ID SEQ ID SEQ ID NO: 178 NO: 42 NO: 42 SEQ ID SEQ ID SEQ ID NO: 179 NO: 43 NO: 43 SEQ ID SEQ ID SEQ ID NO: 180 NO: 43 NO: 43 SEQ ID SEQ ID SEQ ID NO: 181 NO: 42 NO: 42 SEQ ID SEQ ID SEQ ID SEQ ID NO: 182 NO: NO: 43 NO: 42 SEQ ID SEQ ID SEQ ID SEQ ID NO: 183 NO: 157 NO: 14 NO: 82 SEQ ID SEQ ID SEQ ID NO: 184 NO: 158 NO: 11 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 185 NO: 157 NO: 14 NO: 82 NO: 96 NO: 20 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 186 NO: 157 NO: 14 NO: 82 NO: 96 NO: 156 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 187 NO: 159 NO: 152 NO: 160 NO: 43 NO: 83 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 188 NO: 159 NO: 152 NO: 160 NO: 43 NO: 83 NO: 96 NO: 150, 152, 151 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 189 NO: 159 NO: 152 NO: 160 NO: 43 NO: 83 NO: 96 NO: 161, 152, 162 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 190 NO: 145 NO: 14 NO: 83 NO: 96 NO: 150, 152, 151 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 191 NO: 149 NO: 147 NO: 96 NO: 163 SEQ ID SEQ ID SEQ ID SEQ ID NO: 192 NO: 148 NO: 14 NO: 82 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 193 NO: 153 NO: 11 NO: 83 NO: 96 NO: 150, 152, 151 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 194 NO: 153 NO: 11 NO: 83 NO: 96 NO: 164, 152, 165 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 195 NO: 153 NO: 11 NO: 83 NO: 96 NO: 166, 152, 167

TABLE-US-00010 TABLE 7 Amino acid sequences of the chains used to construct multispecific molecules. Sequence ID Amino Acid Sequence SEQ ID QVQLQESGPGLVKPSQTLSLTCTVSGGSINNNNYYWTWIRQHPGKGLEWIGYIY NO: 168 YSGSTFYNPSLKSRVTISVDTSKTQFSLKLSSVTAADTAVYYCAREDTMTGLDV WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQSINNYLNWYQQKPGKAPTLLIYAASSL NO: 169 QSGVPSRFSGSRSGTDFTLTISSLQPEDFAAYFCQQTYSNPTFGQGTKVEVKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELK NO: 170 HLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYA DETATIVEFLNRWITFCQSIISTLTGGGGSGGGGSDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID QVQLQESGPGLVKPSQTLSLTCTVSGGSINNNNYYWTWIRQHPGKGLEWIGYIY NO: 174 YSGSTFYNPSLKSRVTISVDTSKTQFSLKLSSVTAADTAVYYCAREDTMTGLDV (+protein WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS sequence GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR of VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH BioLegend EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK Catalog VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD #325207) IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGS SEQ ID GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVE NO: 197 TTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS NO: 176 GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVD knob YWGQGTLVTVSS SEQ ID EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS NO: 177 GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDL QMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSII STLT SEQ ID EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLEWVGSISGS NO: 183 GGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFYQILTGNA FDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK SEQ ID DIQMTQSPSSLSASLGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAKSTL NO: 184 QSGVPSRFSGSGSGTDFTLTISSLQPEDSATYYCQQYWTFPLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLEWVGSISGS NO: 185 GGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFYQILTGNA FDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLL DLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQS ITSTLT SEQ ID EVQLLQSGGGLVQPGGSLRLSCAASGFMFSRYPMHWVRQAPGKGLEWVGSISGS NO: 186 GGATPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDFYQILTGNA FDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSDCDIEGKDGKQYESVLMVS IDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTG DFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLND LCFLKRLLQEIKTCWNKILMGTKEH SEQ ID QVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVAGISWD NO: 187 SGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARDLGAYQWVEG FDYWGQGTLVTVSSASTGGGGSGGGGSGGGGSGGGGSSYELTQDPAVSVALGQT VRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSTSGNSAS LTITGAQAEDEADYYCNSRDSPGNQWVFGGGTKVTVLGGGGGSGGGGSDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK SEQ ID QVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVAGISWD NO: 188 SGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARDLGAYQWVEG FDYWGQGTLVTVSSASTGGGGSGGGGSGGGGSGGGGSSYELTQDPAVSVALGQT VRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSTSGNSAS LTITGAQAEDEADYYCNSRDSPGNQWVFGGGTKVTVLGGGGGSGGGGSDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKGGGGSGGGGSGGGGSQVQLQQSGPELVKPGASVKMSCKASGYTFTDYVI NWGKQRSGQGLEWIGETYPGSGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTS EDSAVYFCARRGRYGLYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSDI QMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHS GVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFGGGTKLEIK SEQ ID QVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVAGISWD NO: 189 SGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCARDLGAYQWVEG FDYWGQGTLVTVSSASTGGGGSGGGGSGGGGSGGGGSSYELTQDPAVSVALGQT VRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSTSGNSAS LTITGAQAEDEADYYCNSRDSPGNQWVFGGGTKVTVLGGGGGSGGGGSDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKGGGGSGGGGSGGGGSQVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTM HWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRFTISRDNSKNTAFLQMDSLRP EDTGVYFCARYYDDHYSLDYWGQGTPVTVSSGGGGSGGGGSGGGGSGGGGSDIQ MTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGV PSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQIT SEQ ID QVQLQESGPGLVKPSQTLSLTCTVSGGSINNNNYYWTWIRQHPGKGLEWIGYIY NO: 190 YSGSTFYNPSLKSRVTISVDTSKTQFSLKLSSVTAADTAVYYCAREDTMTGLDV WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSQVQLQQSGPELVKPGASVKMSC KASGYTFTDYVINWGKQRSGQGLEWIGEWPGSGTNYYNEKFKAKATLTADKSSN IAYMQLSSLTSEDSAVYFCARRGRYGLYAMDYWGQGTSVTVSSGGGGSGGGGSG GGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVK LLIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFG GGTKLEIK SEQ ID QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIY NO: 193 YSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGKNGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSQVQLQQSGPELVKPGASVKMSC KASGYTFTDYVINWGKQRSGQGLEWIGEWPGSGTNYYNEKFKAKATLTADKSSN IAYMQLSSLTSEDSAVYFCARRGRYGLYAMDYWGQGTSVTVSSGGGGSGGGGSG GGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVK LLIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFG GGTKLEIK SEQ ID DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSL NO: 173 QSGVPSGFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS NO: 171 NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVT VLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAG VETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIY NO: 172 YSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGKNGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK SEQ ID QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVS NO: 191 NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVT VLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAG VETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS GGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRM LTAKFAMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIV LELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT SEQ ID EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPS NO: 192 GGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK SEQ ID QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIY NO: 194 YSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGKNGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSEVQLQESGPGLVKPSQSLSLTC TVTGYSITSDYAWNWIRQFPGNKLEWMGYITYSGSTSYNPSLESRISITRDTST NQFFLQLNSVTTEDTATYYCARGGYYGSSWGVFAYWGQGTLVTVSAGGGGSGGG GSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRVSENIYSYLAWYQQKQGK SPQLLVYNAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPW TFGGGTKLEIK SEQ ID QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIY NO: 195 YSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGKNGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSQVQLQQSAVELARPGASVKMSC KASGYTFTSFTMHWVKQRPGQGLEWIGYINPSSGYTEYNQKFKDKTTLTADKSS STAYMQLDSLTSDDSAVYYCVRGSSRGFDYWGQGTLVTVSAGGGGSGGGGSGGG GSGGGGSDIQMIQSPASLSVSVGETVTITCRASENIYSNLAWFQQKQGKSPQLL VYAATNLADGVPSRFSGSGSGTQYSLKINSLQSEDFGIYYCQHFWGTPRTFGGG TKLEIK

TABLE-US-00011 TABLE 8 Amino Acid sequences of antigens. Sequence ID Description Amino Acid Sequence SEQ ID NO: hMeso 1-7 GLNDIFEAQKIEWHEGGGGSEPRTDTDTCPNPPDPCPTCPTPDLL 181 GGPSVFIFPPKPKDVLMISLTPKITCVVVDVSEEEPDVQFNWYVN NVEDKTAQTETRQRQYNSTYRVVSVLPIKHQDWMSGKVFKCKVNN NALPSPIEKTISKPRGQVRVPQIYTFPPPIEQTVKKDVSVTCLVT GFLPQDIHVEWESNGQPQPEQNYKNTQPVLDSDGSYFLYSKLNVP KSRWDQGDSFTCSVIHEALHNHHMTKTISRSLGNGGGGSEVEKTA CPSGKKAREIDESLIFYKKWELEACVDAALLATQMDRVNAIPFTY EQLDVLKHKLDELYPQGYPESVIQHLGYLFLKMSPEDIRKWNVTS LETLKALLEVNKGHEMSPQAPRRPLPQVATLIDRFVKGRGQLDKD TLDTLTAFYPGYLCSLSPEELSSVPPSSIWAVRPQDLDTCDPRQL DVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALSQQNVSM DLATFMKLRTDAVLPLTVAEVQKLLGPHVEGLKAEERHRPVRDWI LRQRQDDLDTLGLGLQ SEQ ID NO: hPD1L1 FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKN 178 IIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQD AGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHEL TCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLR INTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTGGGG SGLNDIFEAQKIEWHEGGGGSHHHHHHHH SEQ ID NO: hIL2Ra ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYML 182 CTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQS PMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGY RALHRGPAESVCKMTHGKTRWTQPQLICTGGGGGSGGGGSGLNDI FEAQKIEWHEGGGGSHHHHHHHH SEQ ID NO: hNKp30 LWVSQPPEIRTLEGSSAFLPCSFNASQGRLAIGSVTWFRDEVVPG 180 KEVRNGTPEFRGRLAPLASSRFLHDHQAELHIRDVRGHDASIYVC RVEVLGLGVGTGNGTRLVVEKEGGGGSGGGGSDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSG LNDIFEAQKIEWHE SEQ ID NO: hNKp46 TEMYDTPTLSVHPGPEVISGEKVTFYCRLDTATSMFLLLKEGRSS 179 HVQRGYGKVQAEFPLGPVTTAHRGTYRCFGSYNNHAWSFPSEPVK LLVTGDIENTSLAPEDPTFPDTWGTYLLTTETGLQKDHALWDHTA QNGGGGSGGGGSEPRTDTDTCPNPPDPCPTCPTPDLLGGPSVFIF PPKPKDVLMISLTPKITCVVVDVSEEEPDVQFNWYVNNVEDKTAQ TETRQRQYNSTYRVVSVLPIKHQDWMSGKVFKCKVNNNALPSPIE KTISKPRGQVRVPQIYTFPPPIEQTVKKDVSVTCLVTGFLPQDIH VEWESNGQPQPEQNYKNTQPVLDSDGSYFLYSKLNVPKSRWDQGD SFTCSVIHEALHNHHMTKTISRSLGNGGGGSGGGGSGLNDIFEAQ KIEWHE

TABLE-US-00012 TABLE 9 Sequences used to generate multispecific molecules. Multispecific Molecule Heavy Chain 1 Light Chain 1 Heavy Chain 2 Light Chain 2 1 SEQ ID NO: 168 SEQ ID NO: 169 SEQ ID NO: 170 2 SEQ ID NO: 174 SEQ ID NO: 169 SEQ ID NO: 170 3 SEQ ID NO: 174 SEQ ID NO: 169 SEQ ID NO: 197 4 SEQ ID NO: 176 SEQ ID NO: 170 5 SEQ ID NO: 172 SEQ ID NO: 173 SEQ ID NO: 192 SEQ ID NO: 171 6 SEQ ID NO: 172 SEQ ID NO: 173 SEQ ID NO: 177 SEQ ID NO: 171 7 SEQ ID NO: 193 SEQ ID NO: 173 SEQ ID NO: 192 SEQ ID NO: 171 8 SEQ ID NO: 193 SEQ ID NO: 173 SEQ ID NO: 177 SEQ ID NO: 171 9 SEQ ID NO: 194 SEQ ID NO: 173 SEQ ID NO: 192 SEQ ID NO: 171 10 SEQ ID NO: 194 SEQ ID NO: 173 SEQ ID NO: 177 SEQ ID NO: 171 11 SEQ ID NO: 195 SEQ ID NO: 173 SEQ ID NO: 192 SEQ ID NO: 171 12 SEQ ID NO: 195 SEQ ID NO: 173 SEQ ID NO: 177 SEQ ID NO: 171 13 SEQ ID NO: 187 SEQ ID NO: 185 SEQ ID NO: 184 14 SEQ ID NO: 188 SEQ ID NO: 183 SEQ ID NO: 184 15 SEQ ID NO: 189 SEQ ID NO: 183 SEQ ID NO: 184 16 SEQ ID NO: 188 SEQ ID NO: 185 SEQ ID NO: 184 17 SEQ ID NO: 189 SEQ ID NO: 185 SEQ ID NO: 184 18 SEQ ID NO: 187 SEQ ID NO: 183 SEQ ID NO: 184 19 SEQ ID NO: 187 SEQ ID NO: 186 SEQ ID NO: 184 20 SEQ ID NO: 189 SEQ ID NO: 186 SEQ ID NO: 184 21 SEQ ID NO: 190 SEQ ID NO: 169 SEQ ID NO: 186 SEQ ID NO: 184 22 SEQ ID NO: 190 SEQ ID NO: 169 SEQ ID NO: 192 SEQ ID NO: 191 23 SEQ ID NO: 168 SEQ ID NO: 169 SEQ ID NO: 192 SEQ ID NO: 171

TABLE-US-00013 TABLE 10 Nucleic acid sequences. Sequence ID Description Nucleic Acid Sequence SEQ ID NO: 2x4GS linker GGCGGCGGAGGATCTGGCGGAGGCGGCAGC 88 SEQ ID NO: Human CH2, GATAAGACCCACACCTGTCCTCCATGTCCTGCCCCTGAGCT 89 CH3 knob GCTGGGCGGACCTAGCGTGTTCCTGTTCCCTCCAAAGCCCA AGGACACCCTGATGATCAGCCGGACCCCTGAAGTGACCTGC GTGGTGGTGGATGTGTCCCACGAGGATCCCGAAGTGAAGTT CAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGA CCAAGCCCAGAGAGGAACAGTACAACAGCACCTACCGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGG CAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTG CCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCC CGCGAACCTCAGGTGTACACACTGCCTCCCTGCCGGGAAGA GATGACCAAGAACCAGGTGTCCCTGTGGTGCCTGGTCAAGG GCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAAC GGCCAGCCCGAGAACAACTACAAGACCACCCCTCCCGTGCT GGACAGCGACGGCAGCTTCTTCCTGTACTCCAAACTGACCG TGGACAAGAGCCGGTGGCAGCAGGGCAATGTGTTCAGCTGT AGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAA GTCTCTGAGCCTGAGCCCCGGCAAGTAATGA SEQ ID NO: Human CH2, GATAAGACCCACACCTGTCCTCCATGTCCTGCCCCTGAGCT 90 CH3 hole GCTGGGCGGACCTAGCGTGTTCCTGTTCCCTCCAAAGCCCA AGGACACCCTGATGATCAGCCGGACCCCTGAAGTGACCTGC GTGGTGGTGGATGTGTCCCACGAGGATCCCGAAGTGAAGTT CAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGA CCAAGCCCAGAGAGGAACAGTACAACAGCACCTACCGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGG CAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTG CCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCT AGAGAGCCTCAGGTCTGCACCCTGCCTCCCAGCCGGGAAGA GATGACCAAGAACCAGGTGTCCCTGTCCTGCGCCGTGAAGG GCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGAGCAAC GGCCAGCCCGAGAACAACTACAAGACCACCCCTCCCGTGCT GGACAGCGACGGCAGCTTCTTCCTGGTGTCCAAACTGACCG TGGACAAGAGCCGGTGGCAGCAGGGCAATGTGTTCAGCTGT AGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAA GTCTCTGAGCCTGAGCCCCGGCAAGTAATGA SEQ ID NO: CH1 GCCAGCACCAAGGGCCCTAGCGTGTTCCCTCTGGCCCCTAG 91 CTCTAAGAGCACATCTGGCGGAACAGCCGCCCTGGGCTGCC TGGTCAAGGATTACTTTCCTGAGCCCGTGACCGTGTCCTGG AACTCTGGTGCTCTGACCAGCGGCGTGCACACCTTTCCAGC TGTGCTGCAGAGCAGCGGCCTGTACAGCCTGTCTAGCGTGG TCACAGTGCCTAGCAGCAGCCTGGGCACACAGACCTACATC TGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAA GCGGGTGGAACCCAAGAGCTGC SEQ ID NO: CL (kappa) AGAACAGTGGCCGCTCCCAGCGTGTTCATCTTCCCACCCAG 92 CGACGAGCAGCTGAAGTCTGGCACAGCCAGCGTCGTGTGCC TGCTGAACAACTTCTACCCCAGAGAAGCCAAGGTGCAGTGG AAGGTGGACAACGCCCTGCAGTCCGGCAACAGCCAGGAAAG CGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGT CCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCAC AAAGTGTACGCCTGCGAAGTGACCCACCAGGGCCTGAGCAG CCCCGTGACCAAGAGCTTCAATAGAGGCGAGTGCTAATGA SEQ ID NO: CL (lambda) GGCCAGCCCAAGGCCAACCCCACCGTGACCCTGTTCCCTCC 93 ATCCTCCGAGGAACTGCAGGCTAACAAGGCCACCCTCGTGT GCCTGATCTCCGACTTCTACCCTGGCGCCGTGACCGTGGCT TGGAAGGCTGATGGCTCTCCTGTGAAGGCCGGCGTGGAAAC CACCAAGCCCTCCAAGCAGTCCAACAACAAATACGCCGCCT CCAGCTACCTGTCCCTGACCCCTGAGCAGTGGAAGTCCCAC CGGTCCTACAGCTGCCAGGTCACACATGAGGGCTCCACCGT GGAAAAGACCGTGGCCCCTACCGAGTGCTCCTAATGA SEQ ID NO: .alpha.PD1L1 GAGGTGCAGCTGCTGGAATCTGGCGGAGGACTGGTGCAGCC 94 Avelumab TGGCGGCTCTCTGAGACTGTCTTGTGCCGCCTCCGGCTTCA VH CCTTCTCCAGCTATATCATGATGTGGGTCCGACAGGCCCCT GGCAAGGGCCTGGAATGGGTGTCCTCTATCTACCCCTCCGG CGGCATCACCTTTTACGCCGACACCGTGAAGGGCCGGTTCA CCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAG ATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTG CGCTAGAATCAAGCTGGGCACCGTGACCACCGTGGACTATT GGGGCCAGGGCACCCTGGTCACCGTGTCCTCT SEQ ID NO: .alpha.PD1L1 CAGTCTGCTCTGACCCAGCCTGCCTCTGTGTCTGGCTCCCC 95 Avelumab TGGCCAGTCCATCACCATCAGCTGTACCGGCACCTCCTCCG VL ACGTGGGCGGCTACAACTACGTGTCCTGGTATCAGCAGCAT CCCGGCAAGGCCCCTAAGCTGATGATCTACGACGTGTCCAA CCGGCCCTCCGGCGTGTCCAATCGGTTCTCTGGCTCCAAGT CCGGCAACACCGCCTCCCTGACAATCAGCGGACTGCAGGCC GAGGACGAGGCCGACTACTACTGCTCCTCCTACACCTCCAG CTCTACCCGGGTGTTCGGCACCGGCACCAAAGTGACAGTGC TG SEQ ID NO: 3x4GS linker GGCGGCGGAGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGG 96 ATCT SEQ ID NO: .alpha.NKp46 VH CAGGTTCAGTTGCAGCAGTCCGGACCTGAGCTGGTTAAGCC 97 TGGCGCTTCCGTGAAGATGTCCTGCAAGGCTTCCGGCTACA CCTTCACCGACTACGTGATCAACTGGGGCAAGCAGAGATCT GGCCAGGGACTCGAGTGGATCGGCGAGATCTATCCTGGCTC CGGCACCAATTACTACAACGAGAAGTTCAAGGCTAAGGCTA CCCTGACCGCCGACAAGTCCTCCAATATCGCCTACATGCAG CTGTCCAGCCTGACCTCTGAGGACTCCGCTGTGTACTTCTG CGCTCGGAGAGGCAGATACGGCCTGTATGCCATGGATTACT GGGGACAGGGAACCAGTGTGACAGTGTCAAGT SEQ ID NO: .alpha.NKp46 VL GATATTCAGATGACCCAGACCACCTCCAGCCTGTCCGCTTC 98 TCTGGGCGACAGAGTGACAATCAGCTGCAGAGCCAGCCAGG ACATCAGCAACTACCTGAACTGGTATCAACAGAAACCCGAC GGCACCGTGAAGCTGCTGATCTACTACACCTCTCGGCTGCA CTCTGGCGTGCCCTCTAGATTTTCTGGCAGCGGAAGCGGCA CCGACTATTCCCTGACCATCAACAACCTGGAACAAGAGGAT ATCGCTACCTACTTCTGCCAGCAAGGCAACACCCGGCCTTG GACATTTGGCGGCGGAACAAAGCTGGAAATCAAGTGATGA SEQ ID NO: 4x4GS GGTGGCGGAGGAAGCGGCGGAGGCGGCTCTGGTGGTGGTGG 99 linker TTCTGGTGGCGGTGGCTCC SEQ ID NO: 1x4GS GGCGGCGGAGGCTCC 102 SEQ ID NO: MMP2 TACAACTTCTTCCCACGGAAACCCAAGTGGGACAAGAACCA 198 GATCACCTACCGGATCATCGGCTACACCCCTGACCTGGATC CTGAGACAGTGGACGATGCCTTCGCCAGAGCCTTCCAAGTT TGGAGCGACGTGACCCCTCTGCGGTTCTCCAGAATCCATGA TGGCGAGGCCGACATCATGATCAACTTCGGCAGATGGGAGC ACGGCGACGGCTACCCTTTTGATGGCAAGGATGGCCTGCTG GCCCACGCTTTTGCCCCTGGAACAGGTGTTGGCGGCGACTC TCACTTCGACGACGATGAGTTGTGGACCCTCGGCGAAGGAC AGGTCGTCAGAGTGAAGTACGGCAACGCCGATGGCGAGTAC TGCAAGTTCCCCTTCCTGTTCAACGGCAAAGAGTACAACTC CTGCACCGACACCGGCAGATCTGACGGCTTCCTGTGGTGCT CCACCACCTACAACTTTGAGAAGGACGGCAAATACGGCTTC TGCCCTCACGAGGCCCTGTTTACCATGGGCGGAAATGCTGA GGGCCAGCCATGCAAGTTTCCATTCCGGTTCCAAGGGACCT CCTACGACAGCTGTACCACCGAGGGAAGAACCGATGGCTAT CGTTGGTGCGGCACCACAGAGGACTACGACAGAGACAAGAA GTATGGCTTCTGTCCCGAGACAGCCATGTCTACCGTCGGCG GCAATTCTGAAGGCGCCCCTTGTGTGTTCCCTTTCACCTTC CTGGGCAACAAATACGAGTCCTGCACCTCCGCTGGCCGCTC TGATGGAAAAATGTGGTGCGCTACCACCGCCAACTACGACG ACGACAGAAAGTGGGGCTTTTGTCCTGACCAGGGCTACTCC CTGTTTCTGGTGGCCGCTCACGAGTTTGGCCATGCTATGGG CCTCGAGCACTCTCAAGATCCCGGTGCACTGATGGCCCCTA TCTACACCTACACCAAGAACTTCCGGCTGTCCCAGGACGAC ATCAAGGGCATCCAAGAGCTGTACGGCGCCTCTCCTGATAT CGATCTCGGCACCGGACCTACTCCTACACTGGGACCTGTGA CACCCGAGATCTGCAAGCAGGACATCGTGTTCGACGGAATC GCCCAGATCCGGGGCGAGATCTTCTTTTTTAAGGACCGGTT CATCTGGCGGACAGTGACCCCTAGAGACAAGCCTATGGGAC CTCTGCTGGTGGCTACCTTCTGGCCTGAGCTGCCTGAGAAG ATCGACGCCGTGTACGAGGCCCCTCAAGAGGAAAAGGCCGT CTTTTTCGCCGGCAACGAGTACTGGATCTACTCCGCTTCTA CCCTGGAACGGGGCTACCCCAAGCCTCTGACATCTCTGGGA CTGCCTCCAGACGTGCAGAGAGTGGACGCCGCCTTCAACTG GTCCAAGAACAAGAAAACCTACATCTTCGCCGGGGACAAGT TCTGGCGGTACAACGAAGTGAAGAAAAAGATGGACCCTGGC TTCCCCAAGCTGATCGCCGATGCCTGGAACGCTATCCCCGA TAACCTGGACGCTGTGGTGGATCTCCAAGGCGGCGGACACT CCTACTTTTTCAAGGGCGCCTACTACCTGAAGCTGGAAAAC CAGAGCCTGAAGTCCGTGAAGTTCGGCTCCATCAAGTCCGA CTGGCTCGGATGT SEQ ID NO: HYAL1 TTCAGAGGCCCTCTGCTGCCCAACAGACCCTTCACCACCGT 199 GTGGAACGCCAACACCCAGTGGTGCCTGGAAAGACACGGCG TGGACGTGGACGTGTCCGTGTTCGATGTGGTGGCCAACCCC GGCCAGACCTTCAGGGGCCCTGACATGACCATCTTCTACTC CAGCCAGCTGGGCACCTACCCCTACTACACCCCTACAGGCG AGCCTGTGTTTGGCGGCCTGCCTCAGAACGCCTCTCTGATC GCTCACCTGGCCCGGACCTTCCAGGACATCCTGGCTGCTAT CCCTGCCCCCGACTTTTCTGGCCTGGCCGTGATCGATTGGG AGGCCTGGCGACCTAGATGGGCCTTCAACTGGGACACCAAG GACATCTACCGGCAGCGGTCCAGAGCCCTGGTGCAGGCTCA GCATCCTGATTGGCCTGCCCCTCAGGTGGAAGCCGTGGCCC AGGATCAGTTTCAGGGCGCTGCCAGAGCTTGGATGGCTGGC ACACTGCAGCTGGGAAGGGCCCTGAGGCCTAGAGGACTGTG GGGCTTCTACGGCTTCCCCGACTGCTACAACTACGACTTCC TGTCCCCCAACTACACCGGCCAGTGCCCCTCTGGAATCCGG GCCCAGAATGATCAGCTGGGCTGGCTGTGGGGCCAGTCTAG AGCCCTGTACCCCTCCATCTACATGCCCGCCGTGCTGGAAG GCACCGGCAAGTCCCAGATGTACGTGCAGCACAGAGTGGCC GAGGCCTTCAGGGTGGCAGTGGCTGCTGGCGATCCTAACCT GCCCGTGCTGCCCTACGTGCAGATCTTCTACGATACCACCA ACCACTTTCTGCCCCTGGACGAGCTGGAACACTCCCTGGGA GAGTCTGCTGCTCAGGGTGCTGCAGGCGTGGTGCTGTGGGT GTCCTGGGAGAACACCCGGACCAAAGAGTCCTGCCAGGCCA TCAAAGAGTACATGGACACCACCCTGGGCCCCTTCATCCTG AACGTGACCTCTGGCGCCCTGCTGTGTAGCCAGGCTCTGTG TTCTGGCCACGGCAGATGCGTGCGGAGAACCTCTCACCCTA AGGCTCTGCTGCTGCTGAACCCCGCCTCCTTCAGCATCCAG CTGACACCTGGCGGCGGACCCCTGTCTCTGAGAGGTGCTCT GTCCCTGGAAGATCAGGCCCAGATGGCCGTGGAATTCAAGT GCCGGTGCTACCCTGGCTGGCAGGCCCCTTGGTGCGAGCGG AAATCTATGTGG SEQ ID NO: .alpha.FAP Heavy CAGGTGCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACC 200 TGGCGCCTCTGTGAAGGTGTCCTGCAAGACCTCTCGGTACA CCTTTACCGAGTACACCATCCACTGGGTCCGACAGGCTCCA GGCCAGAGACTGGAATGGATCGGCGGCATCAACCCCAACAA CGGCATCCCCAACTACAACCAGAAATTCAAGGGCCGCGTGA CCATCACCGTGGACACCTCTGCTTCTACCGCCTACATGGAA CTGTCCAGCCTGAGATCTGAGGACACCGCCGTGTACTACTG CGCCAGAAGAAGAATCGCCTACGGCTACGATGAGGGCCACG CCATGGATTATTGGGGCCAGGGAACACTGGTCACCGTGTCC TCT SEQ ID NO: .alpha.FAP light GACATCGTGATGACCCAGTCTCCAGACTCTCTGGCCGTGTC 201 TCTGGGCGAGAGAGCCACCATCAACTGCAAGTCCTCTCAGT CCCTGCTGTACTCCCGGAACCAGAAGAACTACCTGGCCTGG TATCAGCAGAAGCCCGGCCAGCCTCCTAAGCTGCTGATCTT CTGGGCCTCCACCAGAGAATCTGGCGTGCCCGATAGATTCT CCGGCTCTGGCTTTGGCACCGACTTTACCCTGACCATCAGC TCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGCCAGCA GTACTTCAGCTACCCTCTGACCTTTGGCCAGGGCACCAAGG TGGAAATCAAG SEQ ID NO: hIL2F42A GCTCCTACCTCCTCCAGCACCAAGAAAACCCAGCTGCAGTT 111 Y45A GGAGCATCTGCTGCTGGACCTCCAGATGATCCTGAATGGCA TCAACAATTACAAGAACCCCAAGCTCACCCGGATGCTGACC GCCAAGTTTGCCATGCCTAAGAAGGCCACCGAGCTGAAACA TCTGCAGTGCCTGGAAGAGGAACTGAAGCCCCTGGAAGAAG TGCTGAATCTGGCCCAGTCCAAGAACTTCCACCTGAGGCCT CGGGACCTGATCTCCAACATCAACGTGATCGTGCTCGAGCT GAAGGGCTCCGAGACAACCTTCATGTGCGAGTACGCCGACG AGACAGCTACCATCGTGGAATTTCTGAACCGGTGGATCACC TTCTGTCAGTCCATCATCAGCACCCTGACC

TABLE-US-00014 TABLE 11 Sequences used to construct ORFs. Construct SEQ ID NO N-term Linker Variable Constant Fc Linker C-term SEQ ID SEQ ID SEQ ID SEQ ID NO: 202 NO: 200 NO: 91 NO: 89 SEQ ID SEQ ID SEQ ID NO: 203 NO: 201 NO: 92 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 204 NO: 200 NO: 91 NO: 90 NO: 96 NO: 198 SEQ ID SEQ ID SEQ ID SEQ ID NO: 205 NO: 198 NO: 96 NO: 90 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 206 NO: 200 NO: 91 NO: 89 NO: 96 NO: 111 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 207 NO: 200 NO: 91 NO: 90 NO: 96 NO: 199 SEQ ID SEQ ID SEQ ID SEQ ID NO: 208 NO: 94 NO: 91 NO: 89 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 209 NO: 94 NO: 91 NO: 89 NO: 96 NO: 111 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 210 NO: 97 NO: 91 NO: 90 NO: 96 NO: 199 SEQ ID SEQ ID SEQ ID NO: 211 NO: 98 NO: 92 SEQ ID SEQ ID SEQ ID NO: 121 NO: 95 NO: 93 SEQ ID SEQ ID SEQ ID SEQ ID NO: 212 NO: 199 NO: 16 NO: 90

TABLE-US-00015 TABLE 12 Nucleic acid sequences for ORFs. Sequence ID Nucleic Acid Sequence SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 202 TCTACAGGACAGGTGCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACC TGGCGCCTCTGTGAAGGTGTCCTGCAAGACCTCTCGGTACACCTTTACCGA GTACACCATCCACTGGGTCCGACAGGCTCCAGGCCAGAGACTGGAATGGA TCGGCGGCATCAACCCCAACAACGGCATCCCCAACTACAACCAGAAATTC AAGGGCCGCGTGACCATCACCGTGGACACCTCTGCTTCTACCGCCTACATG GAACTGTCCAGCCTGAGATCTGAGGACACCGCCGTGTACTACTGCGCCAGA AGAAGAATCGCCTACGGCTACGATGAGGGCCACGCCATGGATTATTGGGG CCAGGGAACACTGGTCACCGTGTCCTCTGCCTCTACAAAGGGCCCCTCTGT GTTCCCTCTGGCTCCTTCCAGCAAGTCTACCTCTGGCGGAACAGCTGCTCTG GGCTGCCTGGTCAAGGACTACTTTCCTGAGCCTGTGACCGTGTCTTGGAAC TCTGGCGCTCTGACATCCGGCGTGCACACCTTTCCAGCTGTGCTGCAATCTT CCGGCCTGTACTCCCTGTCCTCCGTCGTGACAGTGCCTTCTAGCTCTCTGGG CACCCAGACCTACATCTGCAATGTGAACCACAAGCCTTCCAACACCAAGGT GGACAAGAGAGTGGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCAC CATGTCCTGCTCCAGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCC AAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGT GGTGGTGGATGTGTCTCACGAGGACCCAGAAGTGAAGTTCAATTGGTACGT GGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAG TACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT TGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCC TGCTCCTATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGGGAAC CCCAGGTTTACACCCTGCCTCCATGCCGGGAAGAGATGACCAAGAACCAG GTGTCCCTGTGGTGCCTCGTGAAGGGCTTCTACCCTTCCGATATCGCCGTGG AATGGGAGAGCAATGGCCAGCCAGAGAACAACTACAAGACAACCCCTCCT GTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGAC AAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAG GCCCTGCACAATCACTACACACAGAAGTCCCTGTCTCTGTCCCCTGGCAAG TGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 203 TCTACCGGCGACATCGTGATGACCCAGTCTCCAGACTCTCTGGCCGTGTCT CTGGGCGAGAGAGCCACCATCAACTGCAAGTCCTCTCAGTCCCTGCTGTAC TCCCGGAACCAGAAGAACTACCTGGCCTGGTATCAGCAGAAGCCCGGCCA GCCTCCTAAGCTGCTGATCTTCTGGGCCTCCACCAGAGAATCTGGCGTGCC CGATAGATTCTCCGGCTCTGGCTTTGGCACCGACTTTACCCTGACCATCAG CTCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGCCAGCAGTACTTCAG CTACCCTCTGACCTTTGGCCAGGGCACCAAGGTGGAAATCAAGCGGACAG TGGCCGCTCCTTCCGTGTTCATCTTCCCACCTTCCGACGAGCAGCTGAAGTC TGGCACAGCCTCTGTCGTGTGCCTGCTGAACAACTTCTACCCTCGGGAAGC CAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGTCCGGCAACTCCCAAG AGTCTGTGACCGAGCAGGACTCCAAGGACAGCACCTACAGCCTGTCCTCCA CACTGACCCTGTCCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGC GAAGTGACCCATCAGGGCCTGTCTAGCCCTGTGACCAAGTCTTTCAACCGG GGCGAGTGCTGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 204 TCTACAGGACAGGTGCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACC TGGCGCCTCTGTGAAGGTGTCCTGCAAGACCTCTCGGTACACCTTTACCGA GTACACCATCCACTGGGTCCGACAGGCTCCAGGCCAGAGACTGGAATGGA TCGGCGGCATCAACCCCAACAACGGCATCCCCAACTACAACCAGAAATTC AAGGGCCGCGTGACCATCACCGTGGACACCTCTGCTTCTACCGCCTACATG GAACTGTCCAGCCTGAGATCTGAGGACACCGCCGTGTACTACTGCGCCAGA AGAAGAATCGCCTACGGCTACGATGAGGGCCACGCCATGGATTATTGGGG CCAGGGAACACTGGTCACCGTGTCCTCTGCCTCTACAAAGGGCCCCTCTGT GTTCCCTCTGGCTCCTTCCAGCAAGTCTACCTCTGGCGGAACAGCTGCTCTG GGCTGCCTGGTCAAGGACTACTTTCCTGAGCCTGTGACCGTGTCTTGGAAC TCTGGCGCTCTGACATCCGGCGTGCACACCTTTCCAGCTGTGCTGCAATCTT CCGGCCTGTACTCCCTGTCCTCCGTCGTGACAGTGCCTTCTAGCTCTCTGGG CACCCAGACCTACATCTGCAATGTGAACCACAAGCCTTCCAACACCAAGGT GGACAAGAGAGTGGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCAC CATGTCCTGCTCCAGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCC AAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGT GGTGGTGGATGTGTCTCACGAGGACCCAGAAGTGAAGTTCAATTGGTACGT GGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAG TACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT TGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCC TGCTCCTATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTCGGGAAC CTCAAGTCTGTACCCTGCCTCCTAGCCGGGAAGAGATGACCAAGAACCAG GTGTCCCTGAGCTGCGCCGTGAAGGGCTTCTACCCTTCTGATATCGCCGTG GAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACAACCCCTCC TGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGTCCAAGCTGACAGTGGA CAAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGA GGCCCTGCACAATCACTACACACAGAAGTCCCTGTCTCTGTCCCCTGGCAA AGGTGGCGGAGGATCTGGCGGAGGTGGAAGCGGCGGAGGCGGCTCTTACA ACTTCTTCCCACGGAAACCCAAGTGGGATAAGAACCAGATCACCTACCGG ATCATCGGCTACACCCCTGACCTGGATCCTGAGACTGTGGACGATGCCTTC GCCAGGGCCTTCCAAGTTTGGAGCGACGTGACCCCTCTGCGGTTCTCCAGA ATCCATGATGGCGAGGCCGACATCATGATCAACTTCGGCAGATGGGAGCA CGGCGACGGCTACCCTTTTGATGGCAAGGATGGCCTGCTGGCCCACGCTTT TGCCCCTGGAACAGGTGTTGGCGGCGACTCTCACTTCGACGACGATGAGTT GTGGACCCTCGGCGAAGGACAGGTCGTCAGAGTGAAGTACGGCAACGCCG ATGGCGAGTACTGCAAGTTCCCCTTCCTGTTCAATGGGAAAGAGTATAACT CCTGCACCGACACCGGCAGATCTGACGGCTTCCTGTGGTGCTCCACCACCT ACAACTTCGAGAAGGACGGCAAATACGGCTTCTGCCCTCACGAGGCTCTGT TCACCATGGGCGGAAATGCTGAGGGACAGCCCTGCAAGTTTCCATTCAGAT TCCAAGGGACCTCCTACGACTCTTGCACCACCGAGGGAAGAACCGATGGC TATCGTTGGTGCGGCACCACAGAGGACTACGACCGGGACAAGAAGTATGG CTTCTGTCCCGAGACAGCCATGTCTACCGTCGGCGGCAATTCTGAGGGTGC CCCTTGCGTGTTCCCTTTCACCTTCCTGGGCAACAAATACGAGTCCTGCACC TCCGCTGGCAGATCCGATGGAAAGATGTGGTGCGCTACCACCGCCAACTAC GACGACGACAGAAAGTGGGGCTTTTGTCCTGACCAGGGCTACAGCCTGTTT CTGGTGGCCGCTCACGAGTTCGGCCATGCTATGGGACTCGAGCACTCTCAA GATCCCGGCGCACTGATGGCCCCTATCTACACCTACACCAAGAACTTCCGG CTGTCCCAGGACGACATCAAGGGCATCCAAGAGCTGTACGGCGCCTCTCCT GATATCGATCTCGGCACCGGACCTACTCCTACACTGGGACCTGTGACACCC GAGATCTGCAAGCAGGATATCGTGTTCGACGGAATCGCCCAGATCCGGGG CGAGATCTTCTTTTTTAAGGACCGCTTCATTTGGCGGACCGTGACTCCTCGG GACAAGCCTATGGGACCTCTGCTGGTGGCTACCTTCTGGCCTGAACTGCCC GAGAAGATCGATGCCGTGTACGAGGCCCCTCAAGAGGAAAAGGCCGTCTT TTTCGCCGGCAACGAGTACTGGATCTACTCCGCTAGCACCCTGGAACGGGG CTACCCTAAGCCTCTGACTTCTCTGGGACTGCCACCTGACGTGCAGCGAGT GGATGCCGCCTTCAACTGGTCCAAGAACAAGAAAACCTATATCTTCGCCGG GGACAAGTTCTGGCGGTACAACGAAGTCAAGAAAAAGATGGACCCTGGCT TCCCCAAGCTGATCGCCGATGCCTGGAACGCTATCCCCGATAACCTGGACG CTGTGGTGGACTTGCAAGGCGGCGGACACTCCTACTTTTTCAAGGGCGCCT ACTACCTGAAGCTGGAAAACCAGAGCCTGAAGTCCGTGAAGTTCGGCTCC ATCAAGTCCGACTGGCTGGGCTGCTGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGC 205 TCTACCGGCTACAACTTCTTCCCACGGAAACCCAAGTGGGACAAGAACCA GATCACCTACCGGATCATCGGCTACACCCCTGACCTGGATCCTGAGACAGT GGACGATGCCTTCGCCAGAGCCTTCCAAGTTTGGAGCGACGTGACCCCTCT GCGGTTCTCCAGAATCCATGATGGCGAGGCCGACATCATGATCAACTTCGG CAGATGGGAGCACGGCGACGGCTACCCTTTTGATGGCAAGGATGGCCTGCT GGCCCACGCTTTTGCCCCTGGAACAGGTGTTGGCGGCGACTCTCACTTCGA CGACGATGAGTTGTGGACCCTCGGCGAAGGACAGGTCGTCAGAGTGAAGT ACGGCAACGCCGATGGCGAGTACTGCAAGTTCCCCTTCCTGTTCAACGGCA AAGAGTACAACTCCTGCACCGACACCGGCAGATCTGACGGCTTCCTGTGGT GCTCCACCACCTACAACTTTGAGAAGGACGGCAAATACGGCTTCTGCCCTC ACGAGGCCCTGTTTACCATGGGCGGAAATGCTGAGGGCCAGCCATGCAAG TTTCCATTCCGGTTCCAAGGGACCTCCTACGACAGCTGTACCACCGAGGGA AGAACCGATGGCTATCGTTGGTGCGGCACCACAGAGGACTACGACAGAGA CAAGAAGTATGGCTTCTGTCCCGAGACAGCCATGTCTACCGTCGGCGGCAA TTCTGAAGGCGCCCCTTGTGTGTTCCCTTTCACCTTCCTGGGCAACAAATAC GAGTCCTGCACCTCCGCTGGCCGCTCTGATGGAAAAATGTGGTGCGCTACC ACCGCCAACTACGACGACGACAGAAAGTGGGGCTTTTGTCCTGACCAGGG CTACTCCCTGTTTCTGGTGGCCGCTCACGAGTTTGGCCATGCTATGGGCCTC GAGCACTCTCAAGATCCCGGTGCACTGATGGCCCCTATCTACACCTACACC AAGAACTTCCGGCTGTCCCAGGACGACATCAAGGGCATCCAAGAGCTGTA CGGCGCCTCTCCTGATATCGATCTCGGCACCGGACCTACTCCTACACTGGG ACCTGTGACACCCGAGATCTGCAAGCAGGACATCGTGTTCGACGGAATCG CCCAGATCCGGGGCGAGATCTTCTTTTTTAAGGACCGGTTCATCTGGCGGA CAGTGACCCCTAGAGACAAGCCTATGGGACCTCTGCTGGTGGCTACCTTCT GGCCTGAGCTGCCTGAGAAGATCGACGCCGTGTACGAGGCCCCTCAAGAG GAAAAGGCCGTCTTTTTCGCCGGCAACGAGTACTGGATCTACTCCGCTTCT ACCCTGGAACGGGGCTACCCCAAGCCTCTGACATCTCTGGGACTGCCTCCA GACGTGCAGAGAGTGGACGCCGCCTTCAACTGGTCCAAGAACAAGAAAAC CTACATCTTCGCCGGGGACAAGTTCTGGCGGTACAACGAAGTGAAGAAAA AGATGGACCCTGGCTTCCCCAAGCTGATCGCCGATGCCTGGAACGCTATCC CCGATAACCTGGACGCTGTGGTGGATCTCCAAGGCGGCGGACACTCCTACT TTTTCAAGGGCGCCTACTACCTGAAGCTGGAAAACCAGAGCCTGAAGTCCG TGAAGTTCGGCTCCATCAAGTCCGACTGGCTCGGATGTGGTGGCGGAGGAA GCGGAGGCGGAGGATCTGGCGGTGGCGGATCTGATAAGACCCACACCTGT CCACCTTGTCCTGCTCCAGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTC CTCCAAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCT GCGTGGTGGTGGATGTGTCCCACGAGGACCCAGAAGTGAAGTTCAATTGGT ACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGA ACAGTACAACAGCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCA GGATTGGCTGAATGGGAAAGAGTATAAGTGCAAGGTGTCCAACAAGGCCC TGCCTGCTCCTATCGAAAAGACCATCAGCAAGGCCAAGGGACAGCCCCGG GAACCTCAAGTCTGTACCCTGCCTCCTAGCCGGGAAGAGATGACCAAGAA TCAGGTGTCCCTGTCTTGCGCCGTGAAGGGCTTTTACCCCTCCGATATCGCC GTGGAATGGGAGTCTAATGGCCAGCCTGAGAACAACTACAAGACCACACC TCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGTCCAAGCTGACTGTG GACAAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCAC GAGGCTCTGCACAACCACTACACACAGAAGTCTCTGAGCCTGTCTCCTGGC AAGTGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 206 TCTACAGGACAGGTGCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACC TGGCGCCTCTGTGAAGGTGTCCTGCAAGACCTCTCGGTACACCTTTACCGA GTACACCATCCACTGGGTCCGACAGGCTCCAGGCCAGAGACTGGAATGGA TCGGCGGCATCAACCCCAACAACGGCATCCCCAACTACAACCAGAAATTC AAGGGCCGCGTGACCATCACCGTGGACACCTCTGCTTCTACCGCCTACATG GAACTGTCCAGCCTGAGATCTGAGGACACCGCCGTGTACTACTGCGCCAGA AGAAGAATCGCCTACGGCTACGATGAGGGCCACGCCATGGATTATTGGGG CCAGGGAACACTGGTCACCGTGTCCTCTGCCTCTACAAAGGGCCCCTCTGT GTTCCCTCTGGCTCCTTCCAGCAAGTCTACCTCTGGCGGAACAGCTGCTCTG GGCTGCCTGGTCAAGGACTACTTTCCTGAGCCTGTGACCGTGTCTTGGAAC TCTGGCGCTCTGACATCCGGCGTGCACACCTTTCCAGCTGTGCTGCAATCTT CCGGCCTGTACTCCCTGTCCTCCGTCGTGACAGTGCCTTCTAGCTCTCTGGG CACCCAGACCTACATCTGCAATGTGAACCACAAGCCTTCCAACACCAAGGT GGACAAGAGAGTGGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCAC CATGTCCTGCTCCAGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCC AAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGT GGTGGTGGATGTGTCTCACGAGGACCCAGAAGTGAAGTTCAATTGGTACGT GGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAG TACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT TGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCC TGCTCCTATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGGGAAC CCCAGGTTTACACCCTGCCTCCATGCCGGGAAGAGATGACCAAGAACCAG GTGTCCCTGTGGTGCCTCGTGAAGGGCTTCTACCCTTCCGATATCGCCGTGG AATGGGAGAGCAATGGCCAGCCAGAGAACAACTACAAGACAACCCCTCCT GTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGAC AAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAG GCCCTGCACAATCACTACACACAGAAGTCCCTGTCTCTGTCCCCTGGCAAA GGTGGCGGAGGATCTGGCGGAGGTGGAAGCGGCGGAGGCGGATCTGCTCC TACATCCTCCAGCACCAAGAAAACCCAGCTGCAGTTGGAGCATCTGCTGCT GGACCTGCAGATGATCCTGAATGGCATCAACAATTACAAGAACCCCAAGC TGACCCGGATGCTGACCGCCAAGTTTGCCATGCCTAAGAAGGCCACCGAG CTGAAACATCTGCAGTGCCTGGAAGAGGAACTGAAGCCCCTGGAAGAAGT GCTGAATCTGGCCCAGTCCAAGAACTTCCACCTGAGGCCTCGGGACCTGAT CTCCAACATCAACGTGATCGTGCTCGAGCTGAAGGGCTCCGAGACAACCTT CATGTGCGAGTACGCCGACGAGACAGCTACCATCGTGGAATTTCTGAACCG GTGGATCACCTTCTGCCAGTCCATCATCAGCACCCTGACCTGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 207 TCTACAGGACAGGTGCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACC TGGCGCCTCTGTGAAGGTGTCCTGCAAGACCTCTCGGTACACCTTTACCGA GTACACCATCCACTGGGTCCGACAGGCTCCAGGCCAGAGACTGGAATGGA TCGGCGGCATCAACCCCAACAACGGCATCCCCAACTACAACCAGAAATTC AAGGGCCGCGTGACCATCACCGTGGACACCTCTGCTTCTACCGCCTACATG GAACTGTCCAGCCTGAGATCTGAGGACACCGCCGTGTACTACTGCGCCAGA AGAAGAATCGCCTACGGCTACGATGAGGGCCACGCCATGGATTATTGGGG CCAGGGAACACTGGTCACCGTGTCCTCTGCCTCTACAAAGGGCCCCTCTGT GTTCCCTCTGGCTCCTTCCAGCAAGTCTACCTCTGGCGGAACAGCTGCTCTG GGCTGCCTGGTCAAGGACTACTTTCCTGAGCCTGTGACCGTGTCTTGGAAC TCTGGCGCTCTGACATCCGGCGTGCACACCTTTCCAGCTGTGCTGCAATCTT CCGGCCTGTACTCCCTGTCCTCCGTCGTGACAGTGCCTTCTAGCTCTCTGGG CACCCAGACCTACATCTGCAATGTGAACCACAAGCCTTCCAACACCAAGGT GGACAAGAGAGTGGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCAC CATGTCCTGCTCCAGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCC AAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGT GGTGGTGGATGTGTCTCACGAGGACCCAGAAGTGAAGTTCAATTGGTACGT GGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAG TACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGAT TGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCC TGCTCCTATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTCGGGAAC CTCAAGTCTGTACCCTGCCTCCTAGCCGGGAAGAGATGACCAAGAACCAG GTGTCCCTGAGCTGCGCCGTGAAGGGCTTCTACCCTTCTGATATCGCCGTG GAATGGGAGAGCAACGGCCAGCCAGAGAACAACTACAAGACAACCCCTCC TGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGTCCAAGCTGACAGTGGA CAAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGA GGCCCTGCACAATCACTACACACAGAAGTCCCTGTCTCTGTCCCCTGGCAA AGGTGGCGGAGGATCTGGCGGAGGTGGAAGCGGCGGAGGCGGATCTTTTA GAGGACCTCTGCTGCCCAACCGGCCTTTCACCACAGTGTGGAACGCTAACA CCCAGTGGTGCCTGGAAAGACACGGCGTTGACGTGGACGTGTCCGTGTTCG ATGTGGTGGCTAATCCCGGCCAGACCTTCAGAGGCCCTGACATGACCATCT TCTACTCCAGCCAGCTGGGCACCTATCCTTACTACACCCCTACAGGCGAGC CCGTGTTTGGAGGCTTGCCTCAGAATGCCAGCCTGATCGCTCACCTGGCCA GAACCTTTCAGGACATCCTGGCTGCTATCCCCGCTCCTGACTTTTCCGGACT GGCCGTGATCGATTGGGAAGCCTGGCGACCTAGATGGGCCTTCAACTGGG ACACCAAGGACATCTACCGGCAGCGGTCTAGAGCACTGGTGCAGGCTCAA CATCCTGACTGGCCTGCTCCACAGGTTGAGGCTGTTGCCCAGGATCAGTTT CAGGGCGCTGCCAGAGCTTGGATGGCTGGAACATTGCAGCTGGGGAGAGC CCTGAGGCCTAGAGGACTGTGGGGCTTTTACGGCTTCCCCGACTGCTACAA CTACGACTTCCTGTCTCCTAACTACACCGGCCAGTGTCCTTCCGGCATCAG AGCCCAGAATGATCAGCTCGGATGGCTCTGGGGACAGTCCAGGGCTCTGTA CCCCTCCATCTACATGCCTGCTGTCCTGGAAGGCACCGGCAAGTCCCAGAT GTACGTGCAGCATAGAGTGGCCGAGGCCTTCAGAGTGGCTGTTGCTGCTGG CGATCCTAACCTGCCTGTGCTGCCTTACGTGCAGATCTTCTACGATACCACC AACCACTTTCTGCCCCTGGACGAGCTGGAACACTCCCTGGGAGAATCTGCT GCTCAAGGTGCTGCAGGCGTGGTGTTGTGGGTGTCCTGGGAAAACACCCGG ACCAAAGAGTCCTGCCAGGCCATCAAAGAGTATATGGACACCACACTGGG

CCCCTTCATCCTGAACGTGACATCTGGCGCACTGCTGTGCAGCCAGGCACT GTGTTCTGGACACGGAAGATGCGTGCGGAGAACCTCTCATCCCAAGGCTCT GCTGCTGCTGAACCCTGCCAGCTTCTCCATCCAGTTGACACCAGGCGGAGG CCCTCTGTCTTTGAGAGGTGCACTGTCCCTGGAAGATCAGGCCCAGATGGC TGTGGAATTCAAGTGCAGATGCTACCCCGGCTGGCAAGCTCCTTGGTGCGA GAGAAAGTCCATGTGGTAGTGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 208 TCTACAGGCGAGGTGCAGCTGTTGGAATCTGGCGGAGGATTGGTTCAGCCT GGCGGCTCTCTGAGACTGTCTTGTGCCGCTTCCGGCTTCACCTTCTCCAGCT ATATCATGATGTGGGTCCGACAGGCCCCTGGCAAAGGACTGGAATGGGTG TCCTCTATCTACCCCTCTGGCGGCATCACCTTTTACGCCGACACCGTGAAG GGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAG ATGAACTCCCTGAGAGCCGAGGACACCGCCGTGTACTACTGCGCCAGAAT CAAGCTGGGCACCGTGACCACCGTGGATTATTGGGGACAGGGCACCCTGG TCACCGTGTCCTCTGCTTCTACCAAGGGACCCAGCGTGTTCCCTCTGGCTCC TTCCAGCAAGTCTACCTCCGGTGGAACAGCTGCTCTGGGCTGCCTGGTCAA GGACTACTTTCCTGAGCCTGTGACCGTGTCTTGGAACTCCGGCGCTCTGAC ATCTGGCGTGCACACATTTCCAGCCGTGCTGCAGTCCTCCGGCCTGTACTCT CTCAGCTCTGTCGTGACCGTGCCTTCCAGCTCTCTGGGAACCCAGACCTAC ATCTGCAATGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGAGAGT GGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCTCCATGTCCTGCTCC AGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGA CACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGTGGTGGTGGATGT GTCTCACGAGGATCCCGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGG AAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACAACTCCACC TACAGAGTGGTGTCCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGC AAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCTCCTATCGA AAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGGGAACCCCAGGTTTACA CCCTGCCTCCATGCCGGGAAGAGATGACCAAGAACCAGGTGTCCCTGTGGT GCCTGGTTAAGGGCTTCTACCCTTCCGATATCGCCGTGGAATGGGAGAGCA ATGGCCAGCCTGAGAACAACTACAAGACAACCCCTCCTGTGCTGGACTCCG ACGGCTCATTCTTCCTGTACTCCAAGCTGACCGTGGACAAGTCCAGATGGC AGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAATC ACTACACCCAGAAGTCCCTGTCTCTGAGCCCCGGCAAGTGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 209 TCTACAGGCGAGGTGCAGCTGTTGGAATCTGGCGGAGGATTGGTTCAGCCT GGCGGCTCTCTGAGACTGTCTTGTGCCGCTTCCGGCTTCACCTTCTCCAGCT ATATCATGATGTGGGTCCGACAGGCCCCTGGCAAAGGACTGGAATGGGTG TCCTCTATCTACCCCTCTGGCGGCATCACCTTTTACGCCGACACCGTGAAG GGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAG ATGAACTCCCTGAGAGCCGAGGACACCGCCGTGTACTACTGCGCCAGAAT CAAGCTGGGCACCGTGACCACCGTGGATTATTGGGGACAGGGCACCCTGG TCACCGTGTCCTCTGCTTCTACCAAGGGACCCAGCGTGTTCCCTCTGGCTCC TTCCAGCAAGTCTACCTCCGGTGGAACAGCTGCTCTGGGCTGCCTGGTCAA GGACTACTTTCCTGAGCCTGTGACCGTGTCTTGGAACTCCGGCGCTCTGAC ATCTGGCGTGCACACATTTCCAGCCGTGCTGCAGTCCTCCGGCCTGTACTCT CTCAGCTCTGTCGTGACCGTGCCTTCCAGCTCTCTGGGAACCCAGACCTAC ATCTGCAATGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGAGAGT GGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCTCCATGTCCTGCTCC AGAACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGA CACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGTGGTGGTGGATGT GTCTCACGAGGATCCCGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGG AAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACAACTCCACC TACAGAGTGGTGTCCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGC AAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCTCCTATCGA AAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGGGAACCCCAGGTTTACA CCCTGCCTCCATGCCGGGAAGAGATGACCAAGAACCAGGTGTCCCTGTGGT GCCTGGTTAAGGGCTTCTACCCTTCCGATATCGCCGTGGAATGGGAGAGCA ATGGCCAGCCTGAGAACAACTACAAGACAACCCCTCCTGTGCTGGACTCCG ACGGCTCATTCTTCCTGTACTCCAAGCTGACCGTGGACAAGTCCAGATGGC AGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAATC ACTACACCCAGAAGTCCCTGTCTCTGTCTCCCGGAAAAGGCGGAGGTGGA AGCGGCGGAGGCGGATCTGGTGGCGGTGGATCTGCTCCTACCTCCTCCAGC ACCAAGAAAACCCAGCTGCAGTTGGAGCATCTGCTGCTGGACCTCCAGAT GATCCTGAATGGCATCAACAATTACAAGAACCCCAAGCTCACCCGGATGCT GACCGCCAAGTTTGCCATGCCTAAGAAGGCCACCGAGCTGAAACATCTGC AGTGCCTGGAAGAGGAACTGAAGCCCCTGGAAGAAGTGCTGAATCTGGCC CAGTCCAAGAACTTCCACCTGAGGCCTCGGGACCTGATCTCCAACATCAAC GTGATCGTGCTCGAGCTGAAGGGCTCCGAGACAACCTTCATGTGCGAGTAC GCCGACGAGACAGCTACCATCGTGGAATTTCTGAACCGGTGGATCACCTTC TGTCAGTCCATCATCAGCACCCTGACCTGATGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 210 TCTACAGGACAGGTCCAGCTGCAGCAGTCTGGCCCTGAACTTGTGAAGCCT GGCGCCTCCGTGAAGATGTCCTGCAAGGCTTCTGGCTACACCTTCACCGAC TACGTGATCAACTGGGGCAAGCAGAGATCTGGCCAGGGCCTCGAGTGGAT CGGCGAGATCTATCCTGGCTCCGGCACCAACTACTACAACGAGAAGTTCAA GGCCAAGGCTACCCTGACCGCCGACAAGTCCTCCAATATCGCCTACATGCA GCTGTCCAGCCTGACCTCTGAGGACTCCGCCGTGTACTTCTGCGCCAGAAG AGGCAGATACGGCCTGTACGCCATGGACTATTGGGGCCAGGGCACCTCTGT GACCGTGTCCTCTGCTTCTACCAAGGGACCCAGCGTGTTCCCTCTGGCTCCT TCCAGCAAGTCTACCTCTGGCGGAACAGCTGCTCTGGGCTGCCTGGTCAAG GACTACTTTCCTGAGCCTGTGACAGTGTCTTGGAACTCTGGCGCCCTGACA TCCGGCGTGCACACATTTCCAGCTGTGCTGCAGTCCTCTGGCCTGTACTCTC TGTCCTCCGTCGTGACCGTGCCTTCTAGCTCTCTGGGCACCCAGACCTACAT CTGCAATGTGAACCACAAGCCTTCCAACACCAAGGTGGACAAGAGAGTGG AACCCAAGTCCTGCGACAAGACCCACACCTGTCCTCCATGTCCTGCTCCAG AACTGCTCGGCGGACCTTCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGACA CCCTGATGATCTCTCGGACCCCTGAAGTGACCTGCGTGGTGGTGGATGTGT CTCACGAGGATCCCGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAA GTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACAACTCCACCTA CAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAA AGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCTCCTATCGAAA AGACCATCTCCAAGGCTAAGGGCCAGCCTCGCGAACCCCAAGTCTGTACA CTGCCTCCTAGCCGGGAAGAGATGACCAAGAACCAGGTGTCCCTGTCCTGC GCCGTGAAGGGCTTCTACCCTTCTGATATCGCCGTGGAATGGGAGTCCAAC GGCCAGCCTGAGAACAACTACAAGACAACCCCTCCTGTGCTGGACTCCGA CGGCTCATTCTTCCTGGTGTCCAAGCTGACAGTGGACAAGTCCCGATGGCA GCAGGGCAACGTGTTCTCCTGCTCTGTGATGCACGAGGCTCTGCACAACCA CTACACCCAGAAGTCCCTGTCTCTGTCCCCTGGAAAAGGCGGCGGAGGATC TGGCGGAGGTGGAAGCGGAGGCGGTGGATCTTTTAGAGGACCTCTGCTGC CCAACCGGCCTTTCACCACAGTGTGGAACGCTAACACCCAGTGGTGCCTGG AAAGACATGGCGTCGACGTGGACGTGTCCGTGTTCGATGTGGTGGCTAATC CCGGCCAGACCTTCAGAGGCCCCGACATGACCATCTTCTACTCCAGCCAGC TGGGCACCTATCCTTACTACACCCCTACAGGCGAGCCCGTGTTTGGTGGCT TGCCTCAGAATGCCTCTCTGATCGCCCACCTGGCTAGAACCTTCCAGGATA TTCTGGCTGCTATCCCCGCTCCTGACTTTTCTGGCCTGGCCGTGATCGATTG GGAAGCTTGGAGGCCTAGATGGGCCTTCAACTGGGACACCAAGGACATCT ACCGGCAGCGGTCTAGAGCACTGGTGCAGGCTCAACATCCTGACTGGCCTG CTCCACAGGTTGAGGCTGTTGCCCAGGATCAGTTTCAGGGCGCTGCCAGAG CTTGGATGGCTGGAACATTGCAGCTGGGGAGAGCCCTGAGGCCAAGAGGA TTGTGGGGCTTTTACGGCTTCCCCGACTGCTACAACTACGACTTCCTGTCTC CTAACTACACCGGCCAGTGTCCTTCCGGCATCAGAGCCCAGAATGATCAGC TCGGATGGCTCTGGGGACAGTCCAGGGCTCTGTACCCCTCCATCTACATGC CTGCTGTGCTCGAAGGCACCGGCAAGTCCCAGATGTACGTGCAGCATAGA GTGGCCGAGGCCTTCAGAGTGGCTGTTGCTGCTGGCGATCCTAACCTGCCT GTGCTGCCTTACGTGCAGATCTTCTACGATACCACCAACCACTTTCTGCCCC TGGACGAGCTGGAACACTCCCTGGGAGAATCTGCTGCTCAAGGTGCTGCAG GCGTGGTGTTGTGGGTGTCCTGGGAAAACACCCGGACCAAAGAGTCCTGCC AGGCCATCAAAGAGTATATGGACACCACACTGGGCCCCTTCATCCTGAACG TGACATCTGGCGCTCTGCTGTGCAGCCAGGCTCTGTGTTCTGGCCATGGTA GATGCGTGCGGAGAACCTCTCATCCCAAGGCTCTGCTGCTGCTGAACCCTG CCAGCTTCTCCATCCAGTTGACACCAGGCGGAGGCCCTCTGTCTTTGAGAG GTGCACTGTCCCTGGAAGATCAGGCCCAGATGGCTGTGGAATTCAAGTGCA GATGCTACCCCGGCTGGCAAGCTCCTTGGTGCGAGAGAAAGTCCATGTGGT AGTGA SEQ ID NO: ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGA 211 TCTACCGGCGACATCCAGATGACCCAGACCACCTCTAGCCTGTCTGCCTCT CTGGGCGACAGAGTGACCATCTCCTGTAGAGCCAGCCAGGACATCTCCAA CTACCTGAACTGGTATCAGCAGAAACCCGACGGCACCGTGAAGCTGCTGA TCTACTACACCTCTCGGCTGCACTCTGGCGTGCCCTCTAGATTTTCTGGCTC CGGCTCTGGCACCGACTACTCCCTGACCATCAACAACCTGGAACAAGAGG ATATCGCTACCTACTTCTGCCAGCAAGGCAACACCCGGCCTTGGACATTTG GCGGCGGAACAAAGCTGGAAATCAAGCGGACAGTGGCCGCTCCTTCCGTG TTCATCTTCCCACCTTCCGACGAGCAGCTGAAGTCCGGCACAGCTTCTGTC GTGTGCCTGCTGAACAACTTCTACCCTCGGGAAGCCAAGGTGCAGTGGAAG GTGGACAATGCCCTGCAGTCCGGCAACTCCCAAGAGTCTGTGACCGAGCA GGACTCCAAGGACAGCACCTACAGCCTGTCCTCCACACTGACCCTGAGCAA GGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAAGTGACCCATCAGG GCCTGTCTAGCCCTGTGACCAAGTCTTTCAACCGGGGCGAGTGCTGATGA SEQ ID NO: ATGGAAACCGATACCCTGCTGCTGTGGGTGCTGCTCCTCTGGGTGCCAGGC 121 TCTACCGGCCAGTCTGCTCTGACCCAGCCTGCCTCTGTGTCTGGCTCCCCTG GCCAGTCCATCACCATCAGCTGTACCGGCACCTCCTCCGACGTGGGCGGCT ACAACTACGTGTCCTGGTATCAGCAGCATCCCGGCAAGGCCCCTAAGCTGA TGATCTACGACGTGTCCAACCGGCCCTCCGGCGTGTCCAATCGGTTCTCTG GCTCCAAGTCCGGCAACACCGCCTCCCTGACAATCAGCGGACTGCAGGCC GAGGACGAGGCCGACTACTACTGCTCCTCCTACACCTCCAGCTCTACCCGG GTGTTCGGCACCGGCACCAAAGTGACAGTGCTGGGCCAGCCCAAGGCCAA CCCCACCGTGACCCTGTTCCCTCCATCCTCCGAGGAACTGCAGGCTAACAA GGCCACCCTCGTGTGCCTGATCTCCGACTTCTACCCTGGCGCCGTGACCGT GGCTTGGAAGGCTGATGGCTCTCCTGTGAAGGCCGGCGTGGAAACCACCA AGCCCTCCAAGCAGTCCAACAACAAATACGCCGCCTCCAGCTACCTGTCCC TGACCCCTGAGCAGTGGAAGTCCCACCGGTCCTACAGCTGCCAGGTCACAC ATGAGGGCTCCACCGTGGAAAAGACCGTGGCCCCTACCGAGTGCTCCTAAT GA SEQ ID NO: ATGGCTGCTCATCTGCTGCCTATCTGCGCCCTGTTCCTGACCCTGCTGGATA 212 TGGCCCAGGGCTTCAGAGGCCCTCTGCTGCCCAACAGACCCTTCACCACCG TGTGGAACGCCAACACCCAGTGGTGCCTGGAAAGACACGGCGTGGACGTG GACGTGTCCGTGTTCGATGTGGTGGCCAACCCCGGCCAGACCTTCAGGGGC CCTGACATGACCATCTTCTACTCCAGCCAGCTGGGCACCTACCCCTACTAC ACCCCTACAGGCGAGCCTGTGTTTGGCGGCCTGCCTCAGAACGCCTCTCTG ATCGCTCACCTGGCCCGGACCTTCCAGGACATCCTGGCTGCTATCCCTGCC CCCGACTTTTCTGGCCTGGCCGTGATCGATTGGGAGGCCTGGCGACCTAGA TGGGCCTTCAACTGGGACACCAAGGACATCTACCGGCAGCGGTCCAGAGC CCTGGTGCAGGCTCAGCATCCTGATTGGCCTGCCCCTCAGGTGGAAGCCGT GGCCCAGGATCAGTTTCAGGGCGCTGCCAGAGCTTGGATGGCTGGCACACT GCAGCTGGGAAGGGCCCTGAGGCCTAGAGGACTGTGGGGCTTCTACGGCT TCCCCGACTGCTACAACTACGACTTCCTGTCCCCCAACTACACCGGCCAGT GCCCCTCTGGAATCCGGGCCCAGAATGATCAGCTGGGCTGGCTGTGGGGCC AGTCTAGAGCCCTGTACCCCTCCATCTACATGCCCGCCGTGCTGGAAGGCA CCGGCAAGTCCCAGATGTACGTGCAGCACAGAGTGGCCGAGGCCTTCAGG GTGGCAGTGGCTGCTGGCGATCCTAACCTGCCCGTGCTGCCCTACGTGCAG ATCTTCTACGATACCACCAACCACTTTCTGCCCCTGGACGAGCTGGAACAC TCCCTGGGAGAGTCTGCTGCTCAGGGTGCTGCAGGCGTGGTGCTGTGGGTG TCCTGGGAGAACACCCGGACCAAAGAGTCCTGCCAGGCCATCAAAGAGTA CATGGACACCACCCTGGGCCCCTTCATCCTGAACGTGACCTCTGGCGCCCT GCTGTGTAGCCAGGCTCTGTGTTCTGGCCACGGCAGATGCGTGCGGAGAAC CTCTCACCCTAAGGCTCTGCTGCTGCTGAACCCCGCCTCCTTCAGCATCCAG CTGACACCTGGCGGCGGACCCCTGTCTCTGAGAGGTGCTCTGTCCCTGGAA GATCAGGCCCAGATGGCCGTGGAATTCAAGTGCCGGTGCTACCCTGGCTGG CAGGCCCCTTGGTGCGAGCGGAAATCTATGTGGGGCGGAGGCGGATCAGG CGGCGGAGGATCTGGGGGTGGTGGCTCTGATAAGACCCACACCTGTCCTCC CTGCCCTGCCCCTGAACTGCTGGGAGGCCCTTCCGTGTTCCTGTTCCCCCCA AAGCCCAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGT GGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGT GGACGGGGTGGAAGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAG TACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCATCAGGAC TGGCTGAACGGCAAAGAGTATAAGTGCAAGGTGTCCAACAAGGCCCTGCC CGCTCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAAC CTCAAGTGTGCACCCTGCCTCCATCCCGGGAAGAGATGACCAAGAACCAG GTGTCCCTGTCCTGCGCCGTGAAGGGCTTTTACCCCTCCGATATCGCTGTGG AATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCCCCT GTGCTGGACTCCGACGGCTCATTCTTCCTGGTGTCCAAGCTGACAGTGGAC AAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAG GCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGTCCCCTGGCAAG TGATGA

TABLE-US-00016 TABLE 13 DNA sequences for antigens used. Sequence ID Description Nucleic Acid Sequence SEQ ID Human ATGAGAATCTTCGCCGTGTTCATCTTCATGACCTACTGGCATCTGC NO: 141 PD1L1 TGAACGCCTTCACCGTGACCGTGCCCAAGGACCTGTACGTGGTGG AATACGGCTCCAACATGACCATCGAGTGCAAGTTCCCCGTGGAAA AGCAGCTGGACCTGGCCGCCCTGATCGTGTACTGGGAGATGGAA GATAAGAACATCATCCAGTTCGTGCACGGGGAAGAGGACCTGAA GGTGCAGCACTCCTCCTACCGGCAGAGAGCCAGACTGCTGAAGG ACCAGCTGTCCCTGGGCAATGCCGCCCTGCAGATCACCGACGTGA AGCTGCAGGATGCCGGCGTGTACCGGTGCATGATCTCTTACGGCG GAGCCGACTACAAGCGGATCACCGTGAAAGTGAACGCCCCCTAC AACAAGATCAACCAGCGGATCCTGGTGGTGGACCCCGTGACCTCT GAGCACGAGCTGACCTGTCAGGCCGAGGGCTACCCTAAGGCCGA AGTGATCTGGACCTCCTCCGACCACCAGGTGCTGTCCGGCAAGAC CACCACCACAAACTCCAAGCGGGAAGAGAAGCTGTTCAACGTGA CCTCCACCCTGCGGATCAACACAACCACCAACGAGATCTTCTACT GTACCTTCCGGCGGCTGGACCCCGAGGAAAATCACACCGCTGAG CTCGTGATCCCCGAGCTGCCTCTGGCCCACCCTCCTAATGAGAGA ACAGGCGGCGGAGGCTCCGGCCTGAACGACATCTTTGAGGCCCA GAAAATCGAGTGGCACGAGGGCGGAGGCGGCTCCCACCATCATC ACCACCACCATCACTGATGA SEQ ID hFAP ATGAAGACCTGGGTCAAGATCGTGTTTGGCGTGGCCACCTCTGCT NO: 213 GTGCTGGCTCTGCTGGTCATGTGCATCGTGCTGCGGCCTTCCAGA GTGCACAACTCCGAAGAGAACACCATGCGGGCTCTGACCCTGAA GGACATCCTGAACGGCACCTTCAGCTACAAGACCTTCTTTCCCAA CTGGATCTCCGGCCAAGAGTACCTGCACCAGTCCGCCGACAACAA TATCGTGCTGTACAACATCGAGACAGGCCAGTCCTACACCATCCT GTCCAACCGGACCATGAAGTCCGTGAACGCCTCCAACTACGGACT GTCTCCTGACCGGCAGTTCGTGTACCTGGAATCCGACTACTCCAA GCTGTGGCGGTACTCCTACACCGCCACCTACTACATCTACGACCT GAGCAACGGCGAGTTCGTGCGGGGAAATGAGCTGCCCAGACCTA TCCAGTACCTGTGCTGGTCCCCTGTGGGCTCTAAGCTGGCTTACGT GTACCAGAACAACATCTACCTGAAGCAGCGGCCTGGCGACCCTCC ATTCCAGATCACCTTCAACGGCAGAGAGAACAAGATCTTTAACGG CATCCCCGACTGGGTGTACGAGGAAGAGATGCTGCCCACTAAGT ACGCCCTCTGGTGGTCCCCTAACGGCAAGTTTCTGGCCTACGCCG AGTTCAACGACAAGGATATCCCCGTGATCGCCTACTCCTACTACG GCGACGAGCAGTACCCTCGGACCATCAACATCCCTTATCCTAAGG CTGGCGCCAAGAATCCCGTCGTGCGGATCTTCATCATCGACACCA CCTATCCTGCCTACGTGGGCCCTCAAGAGGTGCCAGTGCCTGCTA TGATCGCCTCCAGCGACTACTACTTCTCCTGGCTGACATGGGTCA CCGACGAGCGAGTTTGTCTGCAGTGGCTGAAGCGGGTGCAGAAC GTGTCCGTGCTGTCCATCTGCGACTTCAGAGAGGACTGGCAGACC TGGGACTGCCCCAAGACACAAGAGCACATCGAGGAATCTCGGAC CGGATGGGCTGGCGGCTTCTTCGTGTCTAGACCCGTGTTCTCCTAC GACGCCATCAGCTACTATAAGATCTTCTCCGACAAGGACGGCTAC AAGCACATCCACTACATCAAGGACACCGTCGAGAACGCCATCCA GATTACCTCCGGCAAGTGGGAAGCCATCAATATCTTCAGAGTGAC CCAGGACTCCCTGTTCTACTCCTCCAACGAGTTCGAGGAATACCC CGGCAGACGGAACATCTACAGAATCTCCATCGGCAGCTACCCTCC ATCCAAGAAATGCGTGACCTGCCACCTGAGAAAAGAGCGGTGCC AGTACTATACCGCCAGCTTCTCTGACTACGCCAAGTACTACGCCC TCGTGTGTTACGGCCCTGGCATCCCTATCTCTACCCTGCACGATGG CAGAACCGACCAAGAGATCAAGATCCTGGAAGAAAACAAAGAGC TGGAAAACGCCCTGAAGAACATTCAGCTGCCCAAAGAGGAAATC AAGAAGCTGGAAGTCGACGAGATCACCCTGTGGTACAAGATGAT CCTGCCTCCTCAGTTCGACCGGTCCAAGAAGTACCCTCTGCTGAT CCAGGTGTACGGCGGACCTTGCTCTCAGTCCGTCAGATCTGTGTT CGCCGTGAATTGGATCTCCTACCTGGCCTCCAAAGAAGGCATGGT TATCGCCCTGGTGGACGGCAGAGGCACAGCTTTTCAAGGCGACA AGCTGCTGTACGCCGTGTACAGAAAGCTGGGCGTGTACGAAGTG GAAGATCAGATCACCGCCGTGCGGAAGTTCATCGAGATGGGCTTC ATCGACGAGAAGCGGATCGCTATCTGGGGCTGGTCTTACGGCGGC TACGTTTCCTCTCTGGCCCTGGCTTCTGGCACCGGCCTGTTCAAGT GTGGAATCGCTGTTGCCCCTGTGTCCTCCTGGGAGTACTATGCCTC TGTGTACACCGAGCGGTTCATGGGCCTGCCTACCAAGGACGACAA CCTGGAACACTACAAGAACAGCACCGTGATGGCCAGAGCCGAGT ACTTCCGGAACGTGGACTACCTGCTGATTCACGGCACCGCCGACG ACAACGTGCACTTCCAAAACAGCGCCCAGATCGCCAAGGCTCTG GTCAATGCCCAGGTGGACTTTCAGGCCATGTGGTACTCCGACCAG AACCACGGCCTGTCTGGCCTGAGCACCAATCACCTGTACACCCAC ATGACCCACTTTCTGAAGCAGTGCTTCTCCCTGTCTGATGGCGGC GGAGGCTCTGGACTGAACGATATCTTCGAGGCCCAGAAAATCGA GTGGCACGAAGGCGGAGGCGGCTCCCACCATCATCATCACCACC ATCACTGATGA SEQ ID hNKp46 ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTG NO: 143 CCAGGATCTACCGGCCAGCAGCAGACACTGCCCAAGCCTTTTATC TGGGCCGAGCCTCACTTCATGGTGCCCAAAGAAAAGCAAGTGAC CATCTGCTGCCAGGGCAACTACGGCGCTGTGGAATACCAGCTGCA CTTCGAGGGCTCCCTGTTCGCCGTGGATAGACCTAAGCCTCCTGA GCGGATCAACAAAGTGAAGTTCTACATCCCCGACATGAACTCCCG GATGGCTGGCCAGTACTCCTGCATCTATAGAGTGGGCGAGCTTTG GAGCGAGCCCTCCAATCTGCTGGATCTGGTGGTCACCGAGATGTA CGACACCCCTACACTGAGCGTGCACCCCGGACCTGAAGTGATCTC TGGCGAGAAAGTGACCTTCTACTGCAGACTGGATACCGCCACCTC CATGTTTCTGCTGCTCAAAGAGGGCAGATCCTCTCACGTGCAGCG CGGCTATGGAAAGGTGCAGGCTGAGTTTCCTCTGGGCCCTGTGAC CACCGCTCACAGAGGCACCTACAGATGCTTCGGCTCCTACAACAA CCACGCCTGGTCTTTCCCATCCGAGCCTGTGAAGCTGCTGGTCAC CGGCGACATCGAGAACACATCTCTGGCCCCTGAGGACCCCACCTT TCCTGATACCTGGGGCACCTATCTGCTGACCACCGAGACAGGCCT GCAGAAAGATCACGCCCTGTGGGATCACACCGCTCAGAATGGTG GCGGAGGATCTGGCGGAGGCGGATCTGAACCTAGAACCGACACC GACACCTGTCCTAATCCTCCAGATCCTTGTCCTACCTGTCCAACAC CTGACCTGCTCGGCGGACCTTCCGTGTTCATCTTCCCACCTAAGCC AAAGGACGTGCTGATGATCTCTCTGACCCCTAAGATCACCTGTGT GGTGGTGGACGTGTCCGAAGAGGAACCCGACGTGCAGTTCAATT GGTACGTGAACAACGTCGAGGACAAGACAGCCCAGACCGAGACA CGGCAGCGGCAGTACAACTCTACCTACAGAGTGGTGTCCGTGCTG CCCATCAAGCACCAGGATTGGATGTCCGGCAAGGTGTTCAAGTGC AAAGTGAACAACAACGCCCTGCCTTCTCCAATCGAAAAGACCATC TCCAAGCCTCGGGGCCAAGTGCGAGTGCCCCAGATCTATACCTTT CCACCTCCTATCGAGCAGACCGTGAAGAAAGATGTGTCCGTGACC TGCCTCGTGACCGGCTTCCTGCCTCAAGACATCCATGTGGAATGG GAGTCCAACGGCCAGCCTCAGCCTGAGCAGAACTACAAGAACAC CCAGCCTGTGCTGGACTCCGACGGCAGCTACTTCCTGTACTCCAA GCTGAACGTGCCCAAGTCCAGATGGGACCAGGGCGACTCCTTCAC CTGTTCCGTGATCCACGAGGCCCTGCACAACCACCACATGACCAA GACCATCAGCAGATCCCTCGGCAATGGCGGTGGTGGTTCTGGCGG CGGAGGTTCCGGACTGAACGATATCTTCGAGGCCCAGAAAATCG AGTGGCACGAGTGATGA SEQ ID hIL2R.alpha. ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTG NO: 139 CCAGGATCTACAGGCGAGCTGTGCGACGATGACCCTCCTGAGATC CCTCACGCCACCTTCAAGGCCATGGCTTACAAAGAGGGCACCATG CTGAACTGCGAGTGCAAGCGGGGCTTCAGACGGATCAAGTCCGG CAGCCTGTACATGCTGTGCACCGGCAACTCCTCTCACTCCTCCTG GGACAACCAGTGCCAGTGCACCTCCTCTGCCACCAGAAACACCAC CAAGCAAGTGACCCCTCAGCCTGAGGAACAGAAAGAGCGCAAGA CCACCGAGATGCAGAGCCCCATGCAGCCTGTGGATCAGGCTTCTC TGCCTGGCCACTGTAGAGAGCCTCCACCTTGGGAGAATGAGGCCA CCGAGCGGATCTACCACTTTGTCGTGGGCCAGATGGTGTACTACC AGTGCGTGCAGGGATACAGAGCCCTGCATAGAGGCCCTGCTGAG TCCGTGTGCAAGATGACCCATGGCAAGACCAGATGGACCCAGCC TCAGCTGATCTGTACAGGCGGAGGCGGAGGATCTGGTGGTGGTG GATCTGGCCTGAACGACATCTTCGAGGCCCAGAAAATCGAGTGG CACGAAGGCGGTGGCGGCTCCCACCATCATCATCACCACCATCAC TGATGA SEQ ID BirA ATGGAAACTGACACCCTCCTCCTTTGGGTGCTGCTGCTTTGGGTG NO: 144 CCTGGATCGACCGGGATGAAGGACAATACCGTGCCTCTGAAGCTC ATTGCCCTGCTGGCCAACGGAGAATTCCATTCCGGCGAACAGCTG GGGGAGACTCTCGGGATGTCCCGGGCCGCCATCAACAAGCACAT CCAGACTTTGCGCGACTGGGGAGTCGACGTGTTCACGGTGCCGGG GAAGGGCTACTCGCTCCCGGAACCGATCCAGCTGCTGAACGCCA AGCAGATTCTGGGACAGCTGGATGGCGGAAGCGTGGCAGTGCTG CCCGTGATCGACTCAACCAACCAGTATCTGCTGGATAGAATCGGT GAACTGAAATCCGGCGACGCTTGCATTGCCGAGTACCAACAGGC CGGAAGGGGACGGCGCGGCAGGAAGTGGTTCTCTCCATTCGGCG CGAACCTCTACCTGAGCATGTTCTGGAGATTGGAGCAGGGTCCCG CCGCGGCCATCGGCCTCTCCCTGGTCATCGGCATTGTGATGGCTG AAGTGCTGAGGAAGTTGGGTGCCGACAAGGTCCGCGTGAAGTGG CCGAACGACCTGTACCTCCAAGACCGGAAATTGGCGGGGATTCTC GTCGAGCTTACCGGAAAGACTGGCGATGCCGCACAAATTGTGATC GGGGCGGGAATCAACATGGCGATGCGACGGGTGGAAGAGAGCGT CGTGAACCAGGGATGGATCACCCTGCAAGAGGCCGGAATCAACC TGGATCGCAACACCCTGGCTGCCATGCTCATTCGCGAACTGAGAG CCGCACTGGAGCTGTTTGAGCAGGAGGGTCTGGCCCCCTACCTGT CACGCTGGGAAAAGCTTGATAACTTCATCAATCGGCCTGTGAAGC TGATCATCGGAGACAAGGAGATTTTCGGCATCTCGAGAGGCATCG ACAAACAAGGAGCCCTCCTGCTGGAACAGGACGGAATCATTAAG CCCTGGATGGGTGGAGAGATCTCCCTGCGGTCCGCCGAAAAGTCC GGGAAGGATGAACTC

TABLE-US-00017 TABLE 14 Amino Acid sequences. Sequence ID Description Amino Acid Sequence SEQ ID 2x4GS GGGGSGGGGS NO: 43 linker SEQ ID Human DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS NO: 83 CH2, CH3 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ knob DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREE MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID Human DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS NO: 82 CH2, CH3 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ hole DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREE MTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID CH1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL NO: 14 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKRVEPKSC SEQ ID CL (kappa) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA NO: 11 LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID CL (lambda) GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADG NO: 147 SPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE GSTVEKTVAPTECS SEQ ID .alpha.PD1L1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLE NO: 148 Avelumab WVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTA VH VYYCARIKLGTVTTVDYWGQGTLVTVSS SEQ ID .alpha.PD1L1 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAP NO: 149 Avelumab KLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSY VL TSSSTRVFGTGTKVTVL SEQ ID 3x4GS GGGGSGGGGSGGGGS NO: 44 linker SEQ ID .alpha.NKp46 QVQLQQSGPELVKPGASVKMSCKASGYTFTDYVINWGKQRSGQGL NO: 150 VH EWIGEIYPGSGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTSEDSA VYFCARRGRYGLYAMDYWGQGTSVTVSS SEQ ID .alpha.NKp46 VL DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKL NO: 151 LIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTR PWTFGGGTKLEIK SEQ ID 4x 4GS GGGGSGGGGSGGGGSGGGGS NO: 152 linker SEQ ID 1x4GS GGGGS NO: 42 SEQ ID MMP2 YNFFPRKPKWDKNQITYRIIGYTPDLDPETVDDAFARAFQVWSDVT NO: 63 PLRFSRIHDGEADIMINFGRWEHGDGYPFDGKDGLLAHAFAPGTGV GGDSHFDDDELWTLGEGQVVRVKYGNADGEYCKFPFLFNGKEYN SCTDTGRSDGFLWCSTTYNFEKDGKYGFCPHEALFTMGGNAEGQP CKFPFRFQGTSYDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPET AMSTVGGNSEGAPCVFPFTFLGNKYESCTSAGRSDGKMWCATTAN YDDDRKWGFCPDQGYSLFLVAAHEFGHAMGLEHSQDPGALMAPI YTYTKNFRLSQDDIKGIQELYGASPDIDLGTGPTPTLGPVTPEICKQD IVFDGIAQIRGEIFFFKDRFIWRTVTPRDKPMGPLLVATFWPELPEKI DAVYEAPQEEKAVFFAGNEYWIYSASTLERGYPKPLTSLGLPPDVQ RVDAAFNWSKNKKTYIFAGDKFWRYNEVKKKMDPGFPKLIADAW NAIPDNLDAVVDLQGGGHSYFFKGAYYLKLENQSLKSVKFGSIKSD WLGC SEQ ID HYAL1 FRGPLLPNRPFTTVWNANTQWCLERHGVDVDVSVFDVVANPGQTF NO: 236 RGPDMTIFYSSQLGTYPYYTPTGEPVFGGLPQNASLIAHLARTFQDI LAAIPAPDFSGLAVIDWEAWRPRWAFNWDTKDIYRQRSRALVQAQ HPDWPAPQVEAVAQDQFQGAARAWMAGTLQLGRALRPRGLWGF YGFPDCYNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSRALYPSIY MPAVLEGTGKSQMYVQHRVAEAFRVAVAAGDPNLPVLPYVQIFY DTTNHFLPLDELEHSLGESAAQGAAGVVLWVSWENTRTKESCQAI KEYMDTTLGPFILNVTSGALLCSQALCSGHGRCVRRTSHPKALLLL NPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRCYPGWQAP WCERKSMW SEQ ID .alpha.FAP QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRL NO: 65 Heavy EWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTA VYYCARRRIAYGYDEGHAMDYWGQGTLVTVSS SEQ ID .alpha.FAP light DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKP NO: 69 GQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYY CQQYFSYPLTFGQGTKVEIK SEQ ID hIL2 F42A APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFAM NO: 163 Y45A PKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVL ELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT

TABLE-US-00018 TABLE 15 Amino Acid sequences for full heavy and light chains. Construct SEQ ID NO: N-term Linker Variable Constant Fc Linker C-term SEQ ID SEQ ID SEQ ID SEQ ID NO: 214 NO: 65 NO: 14 NO: 83 SEQ ID SEQ ID SEQ ID NO: 215 NO: 69 NO: 11 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 216 NO: 65 NO: 14 NO: 82 NO: 96 NO: 63 SEQ ID SEQ ID SEQ ID SEQ ID NO: 217 NO: 63 NO: 96 NO: 82 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 218 NO: 65 NO: 14 NO: 83 NO: 96 NO: 163 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 219 NO: 65 NO: 14 NO: 82 NO: 96 NO: 62 SEQ ID SEQ ID SEQ ID SEQ ID NO: 220 NO: 148 NO: 14 NO: 83 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 221 NO: 148 NO: 14 NO: 83 NO: 96 NO: 163 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: 222 NO: 150 NO: 14 NO: 82 NO: 96 NO: 62 SEQ ID SEQ ID SEQ ID NO: 223 NO: 151 NO: 11 SEQ ID SEQ ID SEQ ID NO: 171 NO: 149 NO: 147 SEQ ID SEQ ID SEQ ID SEQ ID NO: 224 NO: 62 NO: 96 NO: 82

TABLE-US-00019 TABLE 16 Amino acid sequences of the chains used to construct multispecific molecules. Sequence ID Amino Acid Sequence SEQ ID QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPN NO: 214 NGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGH AMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK SEQ ID DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIF NO: 215 WASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPN NO: 216 NGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGH AMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSYNFFPRKPKWDKNQITYRIIGYT PDLDPETVDDAFARAFQVWSDVTPLRFSRIHDGEADIMINFGRWEHGDGYPFDG KDGLLAHAFAPGTGVGGDSHFDDDELWTLGEGQVVRVKYGNADGEYCKFPFLF NGKEYNSCTDTGRSDGFLWCSTTYNFEKDGKYGFCPHEALFTMGGNAEGQPCK FPFRFQGTSYDSCTTEGRTDGYRWCGTTEDYDRDKKYGFCPETAMSTVGGNSEG APCVFPFTFLGNKYESCTSAGRSDGKMWCATTANYDDDRKWGFCPDQGYSLFL VAAHEFGHAMGLEHSQDPGALMAPIYTYTKNFRLSQDDIKGIQELYGASPDIDLG TGPTPTLGPVTPEICKQDIVFDGIAQIRGEIFFFKDRFIWRTVTPRDKPMGPLLVATF WPELPEKIDAVYEAPQEEKAVFFAGNEYWIYSASTLERGYPKPLTSLGLPPDVQR VDAAFNWSKNKKTYIFAGDKFWRYNEVKKKMDPGFPKLIADAWNAIPDNLDAV VDLQGGGHSYFFKGAYYLKLENQSLKSVKFGSIKSDWLGC SEQ ID YNFFPRKPKWDKNQITYRIIGYTPDLDPETVDDAFARAFQVWSDVTPLRFSRIHD NO: 217 GEADIMINFGRWEHGDGYPFDGKDGLLAHAFAPGTGVGGDSHFDDDELWTLGE GQVVRVKYGNADGEYCKFPFLFNGKEYNSCTDTGRSDGFLWCSTTYNFEKDGK YGFCPHEALFTMGGNAEGQPCKFPFRFQGTSYDSCTTEGRTDGYRWCGTTEDYD RDKKYGFCPETAMSTVGGNSEGAPCVFPFTFLGNKYESCTSAGRSDGKMWCATT ANYDDDRKWGFCPDQGYSLFLVAAHEFGHAMGLEHSQDPGALMAPIYTYTKNF RLSQDDIKGIQELYGASPDIDLGTGPTPTLGPVTPEICKQDIVFDGIAQIRGEIFFFK DRFIWRTVTPRDKPMGPLLVATFWPELPEKIDAVYEAPQEEKAVFFAGNEYWIYS ASTLERGYPKPLTSLGLPPDVQRVDAAFNWSKNKKTYIFAGDKFWRYNEVKKK MDPGFPKLIADAWNAIPDNLDAVVDLQGGGHSYFFKGAYYLKLENQSLKSVKFG SIKSDWLGCGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMT KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPN NO: 218 NGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGH AMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDL QMILNGINNYKNPKLTRMLTAKFAMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT SEQ ID QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPN NO: 219 NGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGH AMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSFRGPLLPNRPFTTVWNANTQW CLERHGVDVDVSVFDVVANPGQTFRGPDMTIFYSSQLGTYPYYTPTGEPVFGGLP QNASLIAHLARTFQDILAAIPAPDFSGLAVIDWEAWRPRWAFNWDTKDIYRQRSR ALVQAQHPDWPAPQVEAVAQDQFQGAARAWMAGTLQLGRALRPRGLWGFYGF PDCYNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSRALYPSIYMPAVLEGTGKS QMYVQHRVAEAFRVAVAAGDPNLPVLPYVQIFYDTTNHFLPLDELEHSLGESAA QGAAGVVLWVSWENTRTKESCQAIKEYMDTTLGPFILNVTSGALLCSQALCSGH GRCVRRTSHPKALLLLNPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRCY PGWQAPWCERKSMW SEQ ID EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSG NO: 220 GITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK SEQ ID EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSG NO: 221 GITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILN GINNYKNPKLTRMLTAKFAMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHL RPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT SEQ ID QVQLQQSGPELVKPGASVKMSCKASGYTFTDYVINWGKQRSGQGLEWIGEIYPG NO: 222 SGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTSEDSAVYFCARRGRYGLYAMD YWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSFRGPLLPNRPFTTVWNANTQWCLER HGVDVDVSVFDVVANPGQTFRGPDMTIFYSSQLGTYPYYTPTGEPVFGGLPQNA SLIAHLARTFQDILAAIPAPDFSGLAVIDWEAWRPRWAFNWDTKDIYRQRSRALV QAQHPDWPAPQVEAVAQDQFQGAARAWMAGTLQLGRALRPRGLWGFYGFPDC YNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSRALYPSIYMPAVLEGTGKSQM YVQHRVAEAFRVAVAAGDPNLPVLPYVQIFYDTTNHFLPLDELEHSLGESAAQG AAGVVLWVSWENTRTKESCQAIKEYMDTTLGPFILNVTSGALLCSQALCSGHGR CVRRTSHPKALLLLNPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRCYPG WQAPWCERKSMW SEQ ID DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHS NO: 223 GVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFGGGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN NO: 171 RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLG QPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETT KPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID FRGPLLPNRPFTTVWNANTQWCLERHGVDVDVSVFDVVANPGQTFRGPDMTIFY NO: 224 SSQLGTYPYYTPTGEPVFGGLPQNASLIAHLARTFQDILAAIPAPDFSGLAVIDWE AWRPRWAFNWDTKDIYRQRSRALVQAQHPDWPAPQVEAVAQDQFQGAARAW MAGTLQLGRALRPRGLWGFYGFPDCYNYDFLSPNYTGQCPSGIRAQNDQLGWL WGQSRALYPSIYMPAVLEGTGKSQMYVQHRVAEAFRVAVAAGDPNLPVLPYVQ IFYDTTNHFLPLDELEHSLGESAAQGAAGVVLWVSWENTRTKESCQAIKEYMDT TLGPFILNVTSGALLCSQALCSGHGRCVRRTSHPKALLLLNPASFSIQLTPGGGPLS LRGALSLEDQAQMAVEFKCRCYPGWQAPWCERKSMWGGGGSGGGGSGGGGS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK

TABLE-US-00020 TABLE 17 Sequences of antigens. Sequence ID Description Amino Acid Sequence SEQ ID NO: hPD1L1 FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMED 178 KNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVK LQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTS EHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNV TSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTG GGGSGLNDIFEAQKIEWHEGGGGSHHHHHHHH SEQ ID NO: hFAP LLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPNWIS 225 GQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSP DRQFVYLESDYSKLWRYSYTATYY1YDLSNGEFVRGNELPRPIQ YLCWSPVGSKLAYVYQNNIYLKQRPGDPPFQITFNGRENKIFNGI PDWVYEEEMLPTKYALWWSPNGKFLAYAEFNDKDIPVIAYSYY GDEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPA MIASSDYYFSWLTWVTDERVCLQWLKRVQNVSVLSICDFREDW QTWDCPKTQEHIEESRTGWAGGFFVSRPVFSYDAISYYKIFSDKD GYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEY PGRRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYA LVCYGPGIPISTLHDGRTDQEIKILEENKELENALKNIQLPKEEIKK LEVDEITLWYKMILPPQFDRSKKYPLLIQVYGGPCSQSVRSVFAV NWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVE DQITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKC GIAVAPVSSWEYYASVYTERFMGLPTKDDNLEHYKNSTVMARA EYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNAQVDFQAMW YSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSDGGGGSGLNDIFE AQKIEWHEGGGGSHHHHHHHH SEQ ID NO: hNKp46 QQQTLPKPFIWAEPHFMVPKEKQVTICCQGNYGAVEYQLHFEGS 237 LFAVDRPKPPERINKVKFYIPDMNSRMAGQYSCIYRVGELWSEPS NLLDLVVTEMYDTPTLSVHPGPEVISGEKVTFYCRLDTATSMFLL LKEGRSSHVQRGYGKVQAEFPLGPVTTAHRGTYRCFGSYNNHA WSFPSEPVKLLVTGDIENTSLAPEDPTFPDTWGTYLLTTETGLQK DHALWDHTAQNGGGGSGGGGSEPRTDTDTCPNPPDPCPTCPTPD LLGGPSVFIFPPKPKDVLMISLTPKITCVVVDVSEEEPDVQFNWY VNNVEDKTAQTETRQRQYNSTYRVVSVLPIKHQDWMSGKVFKC KVNNNALPSPIEKTISKPRGQVRVPQIYTFPPPIEQTVKKDVSVTC LVTGFLPQDIHVEWESNGQPQPEQNYKNTQPVLDSDGSYFLYSK LNVPKSRWDQGDSFTCSVIHEALHNHHMTKTISRSLGNGGGGSG GGGSGLNDIFEAQKIEWHE SEQ ID NO: hIL2R.alpha. ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYM 182 LCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEM QSPMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQC VQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGGGGGSGGG GSGLNDIFEAQKIEWHEGGGGSHHHHHHHH SEQ ID: 226 BirA MKDNTVPLKLIALLANGEFHSGEQLGETLGMSRAAINKHIQTLR DWGVDVFTVPGKGYSLPEPIQLLNAKQILGQLDGGSVAVLPVID STNQYLLDRIGELKSGDACIAEYQQAGRGRRGRKWFSPFGANLY LSMFWRLEQGPAAAIGLSLVIGIVMAEVLRKLGADKVRVKWPN DLYLQDRKLAGILVELTGKTGDAAQIVIGAGINMAMRRVEESVV NQGWITLQEAGINLDRNTLAAMLIRELRAALELFEQEGLAPYLSR WEKLDNFINRPVKLIIGDKEIFGISRGIDKQGALLLEQDGIIKPWM GGEISLRSAEKSGKDEL

TABLE-US-00021 TABLE 18 Sequences used to generate multispecific molecules. Multispecific Molecule Heavy Chain 1 Light Chain 1 Heavy Chain 2 Light Chain 2 24 SEQ ID NO: 214 SEQ ID NO: 215 SEQ ID NO: 219 SEQ ID NO: 215 25 SEQ ID NO: 218 SEQ ID NO: 215 SEQ ID NO: 219 SEQ ID NO: 215 26 SEQ ID NO: 214 SEQ ID NO: 215 SEQ ID NO: 224 27 SEQ ID NO: 220 SEQ ID NO: 171 SEQ ID NO: 219 SEQ ID NO: 215 28 SEQ ID NO: 221 SEQ ID NO: 171 SEQ ID NO: 219 SEQ ID NO: 215 29 SEQ ID NO: 221 SEQ ID NO: 171 SEQ ID NO: 222 SEQ ID NO: 223 30 SEQ ID NO: 214 SEQ ID NO: 215 SEQ ID NO: 216 SEQ ID NO: 215 31 SEQ ID NO: 214 SEQ ID NO: 215 SEQ ID NO: 217 32 SEQ ID NO: 221 SEQ ID NO: 171 SEQ ID NO: 216 SEQ ID NO: 215

Nucleic Acids

[1154] The invention also features nucleic acids comprising nucleotide sequences that encode heavy and light chain variable regions and CDRs or hypervariable loops of the antibody molecules, as described herein. For example, the invention features a first and second nucleic acid encoding heavy and light chain variable regions, respectively, of an antibody molecule chosen from one or more of the antibody molecules disclosed herein. The nucleic acid can comprise a nucleotide sequence as set forth in the tables herein, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in the tables herein.

[1155] In certain embodiments, the nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a heavy chain variable region having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one or more substitutions, e.g., conserved substitutions). In other embodiments, the nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a light chain variable region having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one or more substitutions, e.g., conserved substitutions). In yet another embodiment, the nucleic acid can comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops from heavy and light chain variable regions having an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one or more substitutions, e.g., conserved substitutions).

[1156] In certain embodiments, the nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a heavy chain variable region having the nucleotide sequence as set forth in the tables herein, a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or capable of hybridizing under the stringency conditions described herein). In another embodiment, the nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a light chain variable region having the nucleotide sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or capable of hybridizing under the stringency conditions described herein). In yet another embodiment, the nucleic acid can comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops from heavy and light chain variable regions having the nucleotide sequence as set forth in the tables herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or capable of hybridizing under the stringency conditions described herein).

[1157] In another aspect, the application features host cells and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or separate host cell, as described in more detail hereinbelow.

Vectors

[1158] Further provided herein are vectors comprising the nucleotide sequences encoding an antibody molecule described herein. In one embodiment, the vectors comprise nucleotides encoding an antibody molecule described herein. In one embodiment, the vectors comprise the nucleotide sequences described herein. The vectors include, but are not limited to, a virus, plasmid, cosmid, lambda phage or a yeast artificial chromosome (YAC).

[1159] Numerous vector systems can be employed. For example, one class of vectors utilizes DNA elements which are derived from animal viruses such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV or MOMLV) or SV40 virus. Another class of vectors utilizes RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern Equine Encephalitis virus and Flaviviruses.

[1160] Additionally, cells which have stably integrated the DNA into their chromosomes may be selected by introducing one or more markers which allow for the selection of transfected host cells. The marker may provide, for example, prototropy to an auxotrophic host, biocide resistance (e.g., antibiotics), or resistance to heavy metals such as copper, or the like. The selectable marker gene can be either directly linked to the DNA sequences to be expressed, or introduced into the same cell by cotransformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include splice signals, as well as transcriptional promoters, enhancers, and termination signals.

[1161] Once the expression vector or DNA sequence containing the constructs has been prepared for expression, the expression vectors may be transfected or introduced into an appropriate host cell. Various techniques may be employed to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid based transfection or other conventional techniques. In the case of protoplast fusion, the cells are grown in media and screened for the appropriate activity.

[1162] Methods and conditions for culturing the resulting transfected cells and for recovering the antibody molecule produced are known to those skilled in the art, and may be varied or optimized depending upon the specific expression vector and mammalian host cell employed, based upon the present description.

Cells

[1163] In another aspect, the application features host cells and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or separate host cell. The host cell can be a eukaryotic cell, e.g., a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, e.g., E. coli. For example, the mammalian cell can be a cultured cell or a cell line. Exemplary mammalian cells include lymphocytic cell lines (e.g., NSO), Chinese hamster ovary cells (CHO), COS cells, oocyte cells, and cells from a transgenic animal, e.g., mammary epithelial cell.

[1164] The invention also provides host cells comprising a nucleic acid encoding an antibody molecule as described herein.

[1165] In one embodiment, the host cells are genetically engineered to comprise nucleic acids encoding the antibody molecule.

[1166] In one embodiment, the host cells are genetically engineered by using an expression cassette. The phrase "expression cassette," refers to nucleotide sequences, which are capable of affecting expression of a gene in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or helpful in effecting expression may also be used, such as, for example, an inducible promoter.

[1167] The invention also provides host cells comprising the vectors described herein.

[1168] The cell can be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.

Uses and Combination Therapies

[1169] Methods described herein include treating a cancer in a subject by using a multispecific molecule described herein, e.g., using a pharmaceutical composition described herein. Also provided are methods for reducing or ameliorating a symptom of a cancer in a subject, as well as methods for inhibiting the growth of a cancer and/or killing one or more cancer cells. In embodiments, the methods described herein decrease the size of a tumor and/or decrease the number of cancer cells in a subject administered with a described herein or a pharmaceutical composition described herein.

[1170] In embodiments, the cancer is a hematological cancer. In embodiments, the hematological cancer is a leukemia or a lymphoma. As used herein, a "hematologic cancer" refers to a tumor of the hematopoietic or lymphoid tissues, e.g., a tumor that affects blood, bone marrow, or lymph nodes. Exemplary hematologic malignancies include, but are not limited to, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, acute monocytic leukemia (AMoL), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), or large granular lymphocytic leukemia), lymphoma (e.g., AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma (e.g., classical Hodgkin lymphoma or nodular lymphocyte-predominant Hodgkin lymphoma), mycosis fungoides, non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma (e.g., Burkitt lymphoma, small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma) or T-cell non-Hodgkin lymphoma (mycosis fungoides, anaplastic large cell lymphoma, or precursor T-lymphoblastic lymphoma)), primary central nervous system lymphoma, Sezary syndrome, Waldenstrom macroglobulinemia), chronic myeloproliferative neoplasm, Langerhans cell histiocytosis, multiple myeloma/plasma cell neoplasm, myelodysplastic syndrome, or myelodysplastic/myeloproliferative neoplasm.

[1171] In embodiments, the cancer is a solid cancer. Exemplary solid cancers include, but are not limited to, ovarian cancer, rectal cancer, stomach cancer, testicular cancer, cancer of the anal region, uterine cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, Kaposi's sarcoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, brain stem glioma, pituitary adenoma, epidermoid cancer, carcinoma of the cervix squamous cell cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the vagina, sarcoma of soft tissue, cancer of the urethra, carcinoma of the vulva, cancer of the penis, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, spinal axis tumor, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, metastatic lesions of said cancers, or combinations thereof.

[1172] In embodiments, the multispecific molecules (or pharmaceutical composition) are administered in a manner appropriate to the disease to be treated or prevented. The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient's disease. Appropriate dosages may be determined by clinical trials. For example, when "an effective amount" or "a therapeutic amount" is indicated, the precise amount of the pharmaceutical composition (or multispecific molecules) to be administered can be determined by a physician with consideration of individual differences in tumor size, extent of infection or metastasis, age, weight, and condition of the subject. In embodiments, the pharmaceutical composition described herein can be administered at a dosage of 10.sup.4 to 10.sup.9 cells/kg body weight, e.g., 10.sup.5 to 10.sup.6 cells/kg body weight, including all integer values within those ranges. In embodiments, the pharmaceutical composition described herein can be administered multiple times at these dosages. In embodiments, the pharmaceutical composition described herein can be administered using infusion techniques described in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med. 319:1676, 1988).

[1173] In embodiments, the multispecific molecules or pharmaceutical composition is administered to the subject parenterally. In embodiments, the cells are administered to the subject intravenously, subcutaneously, intratumorally, intranodally, intramuscularly, intradermally, or intraperitoneally. In embodiments, the cells are administered, e.g., injected, directly into a tumor or lymph node. In embodiments, the cells are administered as an infusion (e.g., as described in Rosenberg et al., New Eng. J. of Med. 319:1676, 1988) or an intravenous push. In embodiments, the cells are administered as an injectable depot formulation.

[1174] In embodiments, the subject is a mammal. In embodiments, the subject is a human, monkey, pig, dog, cat, cow, sheep, goat, rabbit, rat, or mouse. In embodiments, the subject is a human. In embodiments, the subject is a pediatric subject, e.g., less than 18 years of age, e.g., less than 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less years of age. In embodiments, the subject is an adult, e.g., at least 18 years of age, e.g., at least 19, 20, 21, 22, 23, 24, 25, 25-30, 30-35, 35-40, 40-50, 50-60, 60-70, 70-80, or 80-90 years of age.

Combination Therapies

[1175] The multispecific molecules disclosed herein can be used in combination with a second therapeutic agent or procedure.

[1176] In embodiments, the multispecific molecule and the second therapeutic agent or procedure are administered/performed after a subject has been diagnosed with a cancer, e.g., before the cancer has been eliminated from the subject. In embodiments, the multispecific molecule and the second therapeutic agent or procedure are administered/performed simultaneously or concurrently. For example, the delivery of one treatment is still occurring when the delivery of the second commences, e.g., there is an overlap in administration of the treatments. In other embodiments, the multispecific molecule and the second therapeutic agent or procedure are administered/performed sequentially. For example, the delivery of one treatment ceases before the delivery of the other treatment begins.

[1177] In embodiments, combination therapy can lead to more effective treatment than monotherapy with either agent alone. In embodiments, the combination of the first and second treatment is more effective (e.g., leads to a greater reduction in symptoms and/or cancer cells) than the first or second treatment alone. In embodiments, the combination therapy permits use of a lower dose of the first or the second treatment compared to the dose of the first or second treatment normally required to achieve similar effects when administered as a monotherapy. In embodiments, the combination therapy has a partially additive effect, wholly additive effect, or greater than additive effect.

[1178] In one embodiment, the multispecific molecule is administered in combination with a therapy, e.g., a cancer therapy (e.g., one or more of anti-cancer agents, immunotherapy, photodynamic therapy (PDT), surgery and/or radiation). The terms "chemotherapeutic," "chemotherapeutic agent," and "anti-cancer agent" are used interchangeably herein. The administration of the multispecific molecule and the therapy, e.g., the cancer therapy, can be sequential (with or without overlap) or simultaneous. Administration of the multispecific molecule can be continuous or intermittent during the course of therapy (e.g., cancer therapy). Certain therapies described herein can be used to treat cancers and non-cancerous diseases. For example, PDT efficacy can be enhanced in cancerous and non-cancerous conditions (e.g., tuberculosis) using the methods and compositions described herein (reviewed in, e.g., Agostinis, P. et al. (2011) CA Cancer J. Clin. 61:250-281).

[1179] Anti-Cancer Therapies

[1180] In other embodiments, the multispecific molecule is administered in combination with a low or small molecular weight chemotherapeutic agent. Exemplary low or small molecular weight chemotherapeutic agents include, but not limited to, 13-cis-retinoic acid (isotretinoin, ACCUTANE.RTM.), 2-CdA (2-chlorodeoxyadenosine, cladribine, LEUSTATIN.TM.), 5-azacitidine (azacitidine, VIDAZA.RTM.), 5-fluorouracil (5-FU, fluorouracil, ADRUCIL.RTM.), 6-mercaptopurine (6-MP, mercaptopurine, PURINETHOL.RTM.), 6-TG (6-thioguanine, thioguanine, THIOGUANINE TABLOID.RTM.), abraxane (paclitaxel protein-bound), actinomycin-D (dactinomycin, COSMEGEN.RTM.), alitretinoin (PANRETIN.RTM.), all-transretinoic acid (ATRA, tretinoin, VESANOID.RTM.), altretamine (hexamethylmelamine, HMM, HEXALEN.RTM.), amethopterin (methotrexate, methotrexate sodium, MTX, TREXALL.TM., RHEUMATREX.RTM.), amifostine (ETHYOL.RTM.), arabinosylcytosine (Ara-C, cytarabine, CYTOSAR-U.RTM.), arsenic trioxide (TRISENOX.RTM.), asparaginase (Erwinia L-asparaginase, L-asparaginase, ELSPAR.RTM., KIDROLASE.RTM.), BCNU (carmustine, BiCNU.RTM.), bendamustine (TREANDA.RTM.), bexarotene (TARGRETIN.RTM.), bleomycin (BLENOXANE.RTM.), busulfan (BUSULFEX.RTM., MYLERAN.RTM.), calcium leucovorin (Citrovorum Factor, folinic acid, leucovorin), camptothecin-11 (CPT-11, irinotecan, CAMPTOSAR.RTM.), capecitabine (XELODA.RTM.), carboplatin (PARAPLATIN.RTM.), carmustine wafer (prolifeprospan 20 with carmustine implant, GLIADEL.RTM. wafer), CCI-779 (temsirolimus, TORISEL.RTM.), CCNU (lomustine, CeeNU), CDDP (cisplatin, PLATINOL.RTM., PLATINOL-AQ.RTM.), chlorambucil (leukeran), cyclophosphamide (CYTOXAN.RTM., NEOSAR.RTM.), dacarbazine (DIC, DTIC, imidazole carboxamide, DTIC-DOME.RTM.), daunomycin (daunorubicin, daunorubicin hydrochloride, rubidomycin hydrochloride, CERUBIDINE.RTM.), decitabine (DACOGEN.RTM.), dexrazoxane (ZINECARD.RTM.), DHAD (mitoxantrone, NOVANTRONE.RTM.), docetaxel (TAXOTERE.RTM.), doxorubicin (ADRIAMYCIN.RTM., RUBEX.RTM.), epirubicin (ELLENCE.TM.), estramustine (EMCYT.RTM.), etoposide (VP-16, etoposide phosphate, TOPOSAR.RTM., VEPESID.RTM., ETOPOPHOS.RTM.), floxuridine (FUDR.RTM.), fludarabine (FLUDARA.RTM.), fluorouracil (cream) (CARAC.TM., EFUDEX.RTM., FLUOROPLEX.RTM.), gemcitabine (GEMZAR.RTM.), hydroxyurea (HYDREA.RTM., DROXIA.TM., MYLOCEL.TM.), idarubicin (IDAMYCIN.RTM.), ifosfamide (IFEX.RTM.), ixabepilone (IXEMPRA.TM.), LCR (leurocristine, vincristine, VCR, ONCOVIN.RTM., VINCASAR PFS.RTM.), L-PAM (L-sarcolysin, melphalan, phenylalanine mustard, ALKERAN.RTM.), mechlorethamine (mechlorethamine hydrochloride, mustine, nitrogen mustard, MUSTARGEN.RTM.), mesna (MESNEX.TM.), mitomycin (mitomycin-C, MTC, MUTAMYCIN.RTM.), nelarabine (ARRANON.RTM.), oxaliplatin (ELOXATIN.TM.), paclitaxel (TAXOL.RTM., ONXAL.TM.), pegaspargase (PEG-L-asparaginase, ONCOSPAR.RTM.), PEMETREXED (ALIMTA.RTM.), pentostatin (NIPENT.RTM.), procarbazine (MATULANE.RTM.), streptozocin (ZANOSAR.RTM.), temozolomide (TEMODAR.RTM.), teniposide (VM-26, VUMON.RTM.), TESPA (thiophosphoamide, thiotepa, TSPA, THIOPLEX.RTM.), topotecan (HYCAMTIN.RTM.), vinblastine (vinblastine sulfate, vincaleukoblastine, VLB, ALKABAN-AQ.RTM., VELBAN.RTM.), vinorelbine (vinorelbine tartrate, NAVELBINE.RTM.), and vorinostat (ZOLINZA.RTM.).

[1181] In another embodiment, the multispecific molecule is administered in conjunction with a biologic. Biologics useful in the treatment of cancers are known in the art and a binding molecule of the invention may be administered, for example, in conjunction with such known biologics. For example, the FDA has approved the following biologics for the treatment of breast cancer: HERCEPTIN.RTM. (trastuzumab, Genentech Inc., South San Francisco, Calif.; a humanized monoclonal antibody that has anti-tumor activity in HER2-positive breast cancer); FASLODEX.RTM. (fulvestrant, AstraZeneca Pharmaceuticals, LP, Wilmington, Del.; an estrogen-receptor antagonist used to treat breast cancer); ARIMIDEX.RTM. (anastrozole, AstraZeneca Pharmaceuticals, LP; a nonsteroidal aromatase inhibitor which blocks aromatase, an enzyme needed to make estrogen); Aromasin.RTM. (exemestane, Pfizer Inc., New York, N.Y.; an irreversible, steroidal aromatase inactivator used in the treatment of breast cancer); FEMARA.RTM. (letrozole, Novartis Pharmaceuticals, East Hanover, N.J.; a nonsteroidal aromatase inhibitor approved by the FDA to treat breast cancer); and NOLVADEX.RTM. (tamoxifen, AstraZeneca Pharmaceuticals, LP; a nonsteroidal antiestrogen approved by the FDA to treat breast cancer). Other biologics with which the binding molecules of the invention may be combined include: AVASTIN.RTM. (bevacizumab, Genentech Inc.; the first FDA-approved therapy designed to inhibit angiogenesis); and ZEVALIN.RTM. (ibritumomab tiuxetan, Biogen Idec, Cambridge, Mass.; a radiolabeled monoclonal antibody currently approved for the treatment of B-cell lymphomas).

[1182] In addition, the FDA has approved the following biologics for the treatment of colorectal cancer: AVASTIN.RTM.; ERBITUX.RTM. (cetuximab, ImClone Systems Inc., New York, N.Y., and Bristol-Myers Squibb, New York, N.Y.; is a monoclonal antibody directed against the epidermal growth factor receptor (EGFR)); GLEEVEC.RTM. (imatinib mesylate; a protein kinase inhibitor); and ERGAMISOL.RTM. (levamisole hydrochloride, Janssen Pharmaceutica Products, LP, Titusville, N.J.; an immunomodulator approved by the FDA in 1990 as an adjuvant treatment in combination with 5-fluorouracil after surgical resection in patients with Dukes' Stage C colon cancer).

[1183] For the treatment of lung cancer, exemplary biologics include TARCEVA.RTM. (erlotinib HCL, OSI Pharmaceuticals Inc., Melville, N.Y.; a small molecule designed to target the human epidermal growth factor receptor 1 (HER1) pathway).

[1184] For the treatment of multiple myeloma, exemplary biologics include VELCADE.RTM. Velcade (bortezomib, Millennium Pharmaceuticals, Cambridge Mass.; a proteasome inhibitor). Additional biologics include THALIDOMID.RTM. (thalidomide, Clegene Corporation, Warren, N.J.; an immunomodulatory agent and appears to have multiple actions, including the ability to inhibit the growth and survival of myeloma cells and anti-angiogenesis).

[1185] Additional exemplary cancer therapeutic antibodies include, but are not limited to, 3F8, abagovomab, adecatumumab, afutuzumab, alacizumab pegol, alemtuzumab (CAMPATH.RTM., MABCAMPATH.RTM.), altumomab pentetate (HYBRI-CEAKER.RTM.), anatumomab mafenatox, anrukinzumab (IMA-638), apolizumab, arcitumomab (CEA-SCAN.RTM.), bavituximab, bectumomab (LYMPHOSCAN.RTM.), belimumab (BENLYSTA.RTM., LYMPHOSTAT-B.RTM.), besilesomab (SCINTIMUN.RTM.), bevacizumab (AVASTIN.RTM.), bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, capromab pendetide (PROSTASCINT.RTM.), catumaxomab (REMOVAB.RTM.), CC49, cetuximab (C225, ERBITUX.RTM.), citatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, conatumumab, dacetuzumab, denosumab (PROLIA.RTM.), detumomab, ecromeximab, edrecolomab (PANOREX.RTM.), elotuzumab, epitumomab cituxetan, epratuzumab, ertumaxomab (REXOMUN.RTM.), etaracizumab, farletuzumab, figitumumab, fresolimumab, galiximab, gemtuzumab ozogamicin (MYLOTARG.RTM.), girentuximab, glembatumumab vedotin, ibritumomab (ibritumomab tiuxetan, ZEVALIN.RTM.), igovomab (INDIMACIS-125.RTM.), intetumumab, inotuzumab ozogamicin, ipilimumab, iratumumab, labetuzumab (CEA-CIDE.RTM.), lexatumumab, lintuzumab, lucatumumab, lumiliximab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, nacolomab tafenatox, naptumomab estafenatox, necitumumab, nimotuzumab (THERACIM.RTM., THERALOC.RTM.), nofetumomab merpentan (VERLUMA.RTM.), ofatumumab (ARZERRA.RTM.), olaratumab, oportuzumab monatox, oregovomab (OVAREX.RTM.), panitumumab (VECTIBIX.RTM.), pemtumomab (THERAGYN.RTM.), pertuzumab (OMNITARG.RTM.), pintumomab, pritumumab, ramucirumab, ranibizumab (LUCENTIS.RTM.), rilotumumab, rituximab (MABTHERA.RTM., RITUXAN.RTM.), robatumumab, satumomab pendetide, sibrotuzumab, siltuximab, sontuzumab, tacatuzumab tetraxetan (AFP-CIDE.RTM.), taplitumomab paptox, tenatumomab, TGN1412, ticilimumab (tremelimumab), tigatuzumab, TNX-650, tositumomab (BEXXAR.RTM.), trastuzumab (HERCEPTIN.RTM.), tremelimumab, tucotuzumab celmoleukin, veltuzumab, volociximab, votumumab (HUMASPECT.RTM.), zalutumumab (HUMAX-EGFR.RTM.), and zanolimumab (HUMAX-CD4.RTM.).

[1186] In other embodiments, the multispecific molecule is administered in combination with a viral cancer therapeutic agent. Exemplary viral cancer therapeutic agents include, but not limited to, vaccinia virus (vvDD-CDSR), carcinoembryonic antigen-expressing measles virus, recombinant vaccinia virus (TK-deletion plus GM-CSF), Seneca Valley virus-001, Newcastle virus, coxsackie virus A21, GL-ONC1, EBNA1 C-terminal/LMP2 chimeric protein-expressing recombinant modified vaccinia Ankara vaccine, carcinoembryonic antigen-expressing measles virus, G207 oncolytic virus, modified vaccinia virus Ankara vaccine expressing p53, OncoVEX GM-CSF modified herpes-simplex 1 virus, fowlpox virus vaccine vector, recombinant vaccinia prostate-specific antigen vaccine, human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine, MVA-EBNA1/LMP2 Inj. vaccine, quadrivalent HPV vaccine, quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (GARDASIL.RTM.), recombinant fowlpox-CEA (6D)/TRICOM vaccine; recombinant vaccinia-CEA (6D)-TRICOM vaccine, recombinant modified vaccinia Ankara-5T4 vaccine, recombinant fowlpox-TRICOM vaccine, oncolytic herpes virus NV1020, HPV L1 VLP vaccine V504, human papillomavirus bivalent (types 16 and 18) vaccine (CERVARIX.RTM.), herpes simplex virus HF10, Ad5CMV-p53 gene, recombinant vaccinia DF3/MUC1 vaccine, recombinant vaccinia-MUC-1 vaccine, recombinant vaccinia-TRICOM vaccine, ALVAC MART-1 vaccine, replication-defective herpes simplex virus type I (HSV-1) vector expressing human Preproenkephalin (NP2), wild-type reovirus, reovirus type 3 Dearing (REOLYSIN.RTM.), oncolytic virus HSV1716, recombinant modified vaccinia Ankara (MVA)-based vaccine encoding Epstein-Barr virus target antigens, recombinant fowlpox-prostate specific antigen vaccine, recombinant vaccinia prostate-specific antigen vaccine, recombinant vaccinia-B7.1 vaccine, rAd-p53 gene, Ad5-delta24RGD, HPV vaccine 580299, JX-594 (thymidine kinase-deleted vaccinia virus plus GM-CSF), HPV-16/18 L1/AS04, fowlpox virus vaccine vector, vaccinia-tyrosinase vaccine, MEDI-517 HPV-16/18 VLP AS04 vaccine, adenoviral vector containing the thymidine kinase of herpes simplex virus TK99UN, HspE7, FP253/Fludarabine, ALVAC(2) melanoma multi-antigen therapeutic vaccine, ALVAC-hB7.1, canarypox-hIL-12 melanoma vaccine, Ad-REIC/Dkk-3, rAd-IFN SCH 721015, TIL-Ad-INFg, Ad-ISF35, and coxsackievirus A21 (CVA21, CAVATAK.RTM.).

[1187] In other embodiments, the multispecific molecule is administered in combination with a nanopharmaceutical. Exemplary cancer nanopharmaceuticals include, but not limited to, ABRAXANE.RTM. (paclitaxel bound albumin nanoparticles), CRLX101 (CPT conjugated to a linear cyclodextrin-based polymer), CRLX288 (conjugating docetaxel to the biodegradable polymer poly (lactic-co-glycolic acid)), cytarabine liposomal (liposomal Ara-C, DEPOCYT.TM.) daunorubicin liposomal (DAUNOXOME.RTM.), doxorubicin liposomal (DOXIL.RTM., CAELYX.RTM.), encapsulated-daunorubicin citrate liposome (DAUNOXOME.RTM.), and PEG anti-VEGF aptamer (MACUGEN.RTM.).

[1188] In some embodiments, the multispecific molecule is administered in combination with paclitaxel or a paclitaxel formulation, e.g., TAXOL.RTM., protein-bound paclitaxel (e.g., ABRAXANE.RTM.). Exemplary paclitaxel formulations include, but are not limited to, nanoparticle albumin-bound paclitaxel (ABRAXANE.RTM., marketed by Abraxis Bioscience), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX, marketed by Cell Therapeutic), the tumor-activated prodrug (TAP), ANG105 (Angiopep-2 bound to three molecules of paclitaxel, marketed by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1; see Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620).

[1189] Exemplary RNAi and antisense RNA agents for treating cancer include, but not limited to, CALAA-01, siG12D LODER (Local Drug EluteR), and ALN-VSP02.

[1190] Other cancer therapeutic agents include, but not limited to, cytokines (e.g., aldesleukin (IL-2, Interleukin-2, PROLEUKIN.RTM.), alpha Interferon (IFN-alpha, Interferon alfa, INTRON.RTM. A (Interferon alfa-2b), ROFERON-A.RTM. (Interferon alfa-2a)), Epoetin alfa (PROCRIT.RTM.), filgrastim (G-CSF, Granulocyte--Colony Stimulating Factor, NEUPOGEN.RTM.), GM-CSF (Granulocyte Macrophage Colony Stimulating Factor, sargramostim, LEUKINE.TM.) IL-11 (Interleukin-11, oprelvekin, NEUMEGA.RTM.), Interferon alfa-2b (PEG conjugate) (PEG interferon, PEG-INTRON.TM.), and pegfilgrastim (NEULASTA.TM.)), hormone therapy agents (e.g., aminoglutethimide (CYTADREN.RTM.), anastrozole (ARIMIDEX.RTM.), bicalutamide (CASODEX.RTM.), exemestane (AROMASIN.RTM.), fluoxymesterone (HALOTESTIN.RTM.), flutamide (EULEXIN.RTM.), fulvestrant (FASLODEX.RTM.), goserelin (ZOLADEX.RTM.), letrozole (FEMARA.RTM.), leuprolide (ELIGARD.TM., LUPRON.RTM., LUPRON DEPOT.RTM., VIADUR.TM.), megestrol (megestrol acetate, MEGACE.RTM.), nilutamide (ANANDRON.RTM., NILANDRON.RTM.), octreotide (octreotide acetate, SANDOSTATIN.RTM., SANDOSTATIN LAR.RTM.), raloxifene (EVISTA.RTM.), romiplostim (NPLATE.RTM.), tamoxifen (NOVALDEX.RTM.), and toremifene (FARESTON.RTM.)), phospholipase A2 inhibitors (e.g., anagrelide (AGRYLIN.RTM.)), biologic response modifiers (e.g., BCG (THERACYS.RTM., TICE.RTM.), and Darbepoetin alfa (ARANESP.RTM.)), target therapy agents (e.g., bortezomib (VELCADE.RTM.), dasatinib (SPRYCEL.TM.), denileukin diftitox (ONTAK.RTM.), erlotinib (TARCEVA.RTM.), everolimus (AFINITOR.RTM.), gefitinib (IRESSA.RTM.), imatinib mesylate (STI-571, GLEEVEC.TM.), lapatinib (TYKERB.RTM.), sorafenib (NEXAVAR.RTM.), and SU11248 (sunitinib, SUTENT.RTM.)), immunomodulatory and antiangiogenic agents (e.g., CC-5013 (lenalidomide, REVLIMID.RTM.), and thalidomide (THALOMID.RTM.)), glucocorticosteroids (e.g., cortisone (hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, ALA-CORT.RTM., HYDROCORT ACETATE.RTM., hydrocortone phosphate LANACORT.RTM., SOLU-CORTEF.RTM.), decadron (dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, DEXASONE.RTM., DIODEX.RTM., HEXADROL.RTM., MAXIDEX.RTM.), methylprednisolone (6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, DURALONE.RTM., MEDRALONE.RTM., MEDROL.RTM., M-PREDNISOL.RTM., SOLU-MEDROL.RTM.), prednisolone (DELTA-CORTEF.RTM., ORAPRED.RTM., PEDIAPRED.RTM., PRELONE.RTM.), and prednisone (DELTASONE.RTM., LIQUID PRED.RTM., METICORTEN.RTM., ORASONE.RTM.)), and bisphosphonates (e.g., pamidronate (AREDIA.RTM.), and zoledronic acid (ZOMETA.RTM.))

[1191] In some embodiments, the multispecific molecule is used in combination with a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor). Exemplary tyrosine kinase inhibitor include, but are not limited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., an epidermal growth factor receptor (EGFR) inhibitor), a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., an antibody against VEGF, a VEGF trap, a vascular endothelial growth factor receptor (VEGFR) inhibitor (e.g., a VEGFR-1 inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor)), a platelet derived growth factor (PDGF) pathway inhibitor (e.g., a platelet derived growth factor receptor (PDGFR) inhibitor (e.g., a PDGFR-8 inhibitor)), a RAF-1 inhibitor, a KIT inhibitor and a RET inhibitor. In some embodiments, the anti-cancer agent used in combination with the AHCM agent is selected from the group consisting of: axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN.sup.Tm, AZD2171), dasatinib (SPRYCEL.RTM., BMS-354825), erlotinib (TARCEVA.RTM.), gefitinib (IRESSA.RTM.), imatinib (Gleevec.RTM., CGP57148B, STI-571), lapatinib (TYKERB.RTM., TYVERB.RTM.), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA.RTM.), semaxanib (semaxinib, SU5416), sunitinib (SUTENT.RTM., SU11248), toceranib (PALLADIA.RTM.), vandetanib (ZACTIMA.RTM., ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN.RTM.), bevacizumab (AVASTIN.RTM.), rituximab (RITUXAN.RTM.), cetuximab (ERBITUX.RTM.), panitumumab (VECTIBIX.RTM.), ranibizumab (Lucentis.RTM.), nilotinib (TASIGNA.RTM.), sorafenib (NEXAVAR.RTM.), alemtuzumab (CAMPATH.RTM.), gemtuzumab ozogamicin (MYLOTARG.RTM.), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TK1258, CHIR-258), BIBW 2992 (TOVOK.sup.Tm), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF.RTM.), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228, AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, pelitinib (EKB-569), vandetanib (zactima), WZ3146, WZ4002, WZ8040, ABT-869 (linifanib), AEE788, AP24534 (ponatinib), AV-951 (tivozanib), axitinib, BAY 73-4506 (regorafenib), brivanib alaninate (BMS-582664), brivanib (BMS-540215), cediranib (AZD2171), CHIR-258 (dovitinib), CP 673451, CYC116, E7080, Ki8751, masitinib (AB1010), MGCD-265, motesanib diphosphate (AMG-706), MP-470, OSI-930, Pazopanib Hydrochloride, PD173074, nSorafenib Tosylate (Bay 43-9006), SU 5402, TSU-68 (SU6668), vatalanib, XL880 (GSK1363089, EXEL-2880). Selected tyrosine kinase inhibitors are chosen from sunitinib, erlotinib, gefitinib, or sorafenib. In one embodiment, the tyrosine kinase inhibitor is sunitinib.

[1192] In one embodiment, the multispecific molecule is administered in combination with one of more of: an anti-angiogenic agent, or a vascular targeting agent or a vascular disrupting agent. Exemplary anti-angiogenic agents include, but are not limited to, VEGF inhibitors (e.g., anti-VEGF antibodies (e.g., bevacizumab); VEGF receptor inhibitors (e.g., itraconazole); inhibitors of cell proliferatin and/or migration of endothelial cells (e.g., carboxyamidotriazole, TNP-470); inhibitors of angiogenesis stimulators (e.g., suramin), among others. A vascular-targeting agent (VTA) or vascular disrupting agent (VDA) is designed to damage the vasculature (blood vessels) of cancer tumors causing central necrosis (reviewed in, e.g., Thorpe, P. E. (2004) Clin. Cancer Res. Vol. 10:415-427). VTAs can be small-molecule. Exemplary small-molecule VTAs include, but are not limited to, microtubule destabilizing drugs (e.g., combretastatin A-4 disodium phosphate (CA4P), ZD6126, AVE8062, Oxi 4503); and vadimezan (ASA404).

[1193] Immune Checkpoint Inhibitors

[1194] In other embodiments, methods described herein comprise use of an immune checkpoint inhibitor in combination with the multispecific molecule. The methods can be used in a therapeutic protocol in vivo.

[1195] In embodiments, an immune checkpoint inhibitor inhibits a checkpoint molecule. Exemplary checkpoint molecules include but are not limited to CTLA4, PD1, PD-L1, PD-L2, TIM3, LAG3, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), BTLA, KIR, MHC class I, MHC class II, GAL9, VISTA, BTLA, TIGIT, LAIR1, and A2aR. See, e.g., Pardoll. Nat. Rev. Cancer 12.4(2012):252-64, incorporated herein by reference.

[1196] In embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, e.g., an anti-PD-1 antibody such as Nivolumab, Pembrolizumab or Pidilizumab. Nivolumab (also called MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558) is a fully human IgG4 monoclonal antibody that specifically inhibits PD1. See, e.g., U.S. Pat. No. 8,008,449 and WO2006/121168. Pembrolizumab (also called Lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA.RTM.; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. See, e.g., Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, U.S. Pat. No. 8,354,509 and WO2009/114335. Pidilizumab (also called CT-011 or Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. See, e.g., WO2009/101611. In one embodiment, the inhibitor of PD-1 is an antibody molecule having a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence of Nivolumab, Pembrolizumab or Pidilizumab. Additional anti-PD1 antibodies, e.g., AMP 514 (Amplimmune), are described, e.g., in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649.

[1197] In some embodiments, the PD-1 inhibitor is an immunoadhesin, e.g., an immunoadhesin comprising an extracellular/PD-1 binding portion of a PD-1 ligand (e.g., PD-L1 or PD-L2) that is fused to a constant region (e.g., an Fc region of an immunoglobulin). In embodiments, the PD-1 inhibitor is AMP-224 (B7-DCIg, e.g., described in WO2011/066342 and WO2010/027827), a PD-L2 Fc fusion soluble receptor that blocks the interaction between B7-H1 and PD-1.

[1198] In embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor, e.g., an antibody molecule. In some embodiments, the PD-L1 inhibitor is YW243.55.570, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. In some embodiments, the anti-PD-L1 antibody is MSB0010718C (also called A09-246-2; Merck Serono), which is a monoclonal antibody that binds to PD-L1. Exemplary humanized anti-PD-L1 antibodies are described, e.g., in WO2013/079174. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody, e.g., YW243.55.570. The YW243.55.570 antibody is described, e.g., in WO 2010/077634. In one embodiment, the PD-L1 inhibitor is MDX-1105 (also called BMS-936559), which is described, e.g., in WO2007/005874. In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech/Roche), which is a human Fc-optimized IgG1 monoclonal antibody against PD-L1. See, e.g., U.S. Pat. No. 7,943,743 and U.S Publication No.: 20120039906. In one embodiment, the inhibitor of PD-L1 is an antibody molecule having a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence of YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

[1199] In embodiments, the immune checkpoint inhibitor is a PD-L2 inhibitor, e.g., AMP-224 (which is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1. See, e.g., WO2010/027827 and WO2011/066342.

[1200] In one embodiment, the immune checkpoint inhibitor is a LAG-3 inhibitor, e.g., an anti LAG-3 antibody molecule. In embodiments, the anti-LAG-3 antibody is BMS-986016 (also called BMS986016; Bristol-Myers Squibb). BMS-986016 and other humanized anti-LAG-3 antibodies are described, e.g., in US 2011/0150892, WO2010/019570, and WO2014/008218.

[1201] In embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor, e.g., anti-TIM3 antibody molecule, e.g., described in U.S. Pat. No. 8,552,156, WO 2011/155607, EP 2581113 and U.S Publication No.: 2014/044728.

[1202] In embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, e.g., anti-CTLA-4 antibody molecule. Exemplary anti-CTLA4 antibodies include Tremelimumab (IgG2 monoclonal antibody from Pfizer, formerly known as ticilimumab, CP-675,206); and Ipilimumab (also called MDX-010, CAS No. 477202-00-9). Other exemplary anti-CTLA-4 antibodies are described, e.g., in U.S. Pat. No. 5,811,097.

EXAMPLES

[1203] The following examples are intended to be illustrative, and are not meant in any way to be limiting.

Examples directed to Multispecific Molecules and Uses Thereof

General Methods:

[1204] 1. Construction of the Plasmids.

[1205] The DNA encoding the protein sequences was optimized for expression in Cricetulus griseus, synthesized, and cloned into the pcDNA3.4-TOPO (Life Technologies A14697) using Gateway cloning. All constructs contained an Ig Kappa leader sequence (SEQ ID NO: 84 ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGATCTACA GGA, SEQ ID NO 16: METDTLLLWVLLLWVPGSTG). The nucleic acid sequences used are shown in Table 1.

[1206] 2. Expression and Purification.

[1207] The plasmids were co-transfected into either Expi293 cells (Life Technologies A14527) or ExpiCHO cells (Life Technologies A29127). Transfections were performed using 1 mg of total DNA for a multispecific construct with a 1:1 knob to hole heavy chain ratio and 3:2 light chain to heavy chain ratio. When biotinylation was required, 250 .mu.g of SEQ ID NO: 226 BirA was added per liter in addition to the multispecific construct DNA. Transfection in Expi293 cells was done using linear 25,000 Da polyethylenimine (PEI, Polysciences Inc 23966) in a 3:1 ratio with the total DNA. The DNA and PEI were each added to 50 mL of OptiMem (Life Technologies 31985088) medium and sterile filtered. The DNA and PEI were combined for 10 minutes and added to the Expi293 cells with a cell density of 1.8-2.8.times.10.sup.6 cells/mL and a viability of at least 95%. The ExpiCHO transfection was performed according to the manufacturer's instructions. Expi293 cells were grown in a humidified incubator at 37.degree. C. with 8% CO.sub.2 for 5-7 days after transfection and ExpiCHO cells were grown for 14 days at 32.degree. C. with 5% CO.sub.2. The cells were pelleted by centrifugation at 4500.times.g and the supernatant was filtered through a 0.2 .mu.m membrane. Protein A resin (GE 17-1279-03) was added to the filtered supernatant and incubated for 1-3 hours at room temperature. The resin was packed into a column, washed with 3.times.10 column volumes of Dulbecco's phosphate-buffered saline (DPBS, Life Technologies 14190-144). The bound protein was eluted from the column with 20 mM citrate, 100 mM NaCl, pH 2.9. When necessary, the proteins were further purified using ligand affinity and/or size exclusion chromatography on a Superdex 200 column with a running buffer of DPBS.

[1208] 3. ELISA Assay.

[1209] ELISA assays were performed using either Pierce 96-well streptavidin coated high capacity plates (15500) or Nunc-Immuno 96-well maxisorp plates (Invitrogen 44-2404-21). The plates were washed with 1.times. phosphate buffered saline tween 20 (Pierce 28352) and then coated with 10 .mu.g/mL of the capture protein. After incubating for 2 hours at room temperature with shaking, the plate was washed with 1.times.PBST and the molecule was added in rows A-G using a serial dilution of 1 .mu.M-1 pM. The plate was incubated for 30 minutes, washed, and 100 .mu.L of either peroxidase-conjugated affinipure goat anti-human IgG (109-035-008) or streptavidin-HRP (R&D Systems DY998) was added to each well. The plate was incubated for 30 minutes with shaking, washed, and 100 .mu.L of 1-step Turbo TMB-ELISA substrate solution (Thermo Scientific 34022) was added to each well. The plate was incubated for 5 minutes, the reaction was stopped with 100 .mu.L of 1 M HCl, and the plate was read using the absorbance at 450 nm on a SpectraMax i3x plate reader.

[1210] 4. Cell-Killing Assay.

[1211] To assess the activity of the constructs produced, a BxPC3-luciferase cell-killing assay was performed. BxPC3 cells containing luciferase (Genecopia SCL-C012-HLG) were grown in RPMI 1640 (Gibco 11875119) and 10% fetal bovine serum (Gibco 10082147) with 1 g/mL puromycin (Gibco A1113802). The cells were used to seed a 96-well plate with 15,000 cells per well. After incubating for a day, the media was removed and replaced with the serum-free media RPMI 1640 with 0.5% Pen/Strep (Gibco 15140122). PBMCs (C.T.L. Lot #LP_123) in the serum-free media were added to rows A-G of the 96-well plate at 450,000 cells/well. The compounds were added to columns, in triplicate, with concentrations ranging from 1 .mu.M to 1 pM in rows A-F. The plates were incubated for 6 or 24 hours before measuring. Before proceeding with the cell-killing measurement, 120 .mu.L was removed from each well and added to a 96-well low-binding protein plate. This left 80 .mu.L in the plate, and 80 .mu.L of Bright-Glo (Promega E2610) was added to each well. The plate was then read on a SpectraMax i3x plate reader.

[1212] 5. Cytokine Release Assay.

[1213] For the cytokine release assay, the supernatant removed from the cell-killing plate was diluted 5-fold with the quansys wash buffer. The manufacturer's instructions were followed for the Quansys human IFN.gamma. (Quansys 464649HU) singleplex assay kit. The plates were imaged on a BioRad ChemiDoc XRS+ and analyzed using the Quansys Q-view software.

Example 1

[1214] Multispecific molecule 1 containing a Fab arm targeting mesothelin and an IL2 effector arm, comprising of three distinct protein chains: SEQ ID:168, SEQ ID: 169, and SEQ ID: 170, was expressed by co-transfecting cells with SEQ ID NO: 116, SEQ ID NO: 118, and SEQ ID NO: 119. Multispecific molecule 1 was purified and a SDS-PAGE gel of the final product is shown in FIG. 21. FIG. 43 shows the size exclusion chromatogram of multispecific molecule 1. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 112 pM (FIG. 48). FIG. 53 shows binding with human IL2 receptor a of SEQ ID NO: 182 was assessed and gave an EC.sub.50 of 111 pM. The EC.sub.50 in the cell-killing assay was 79 pM (FIG. 58). FIG. 59 shows the cytokine release data of IFN.gamma. for multispecific molecule 1 in the assay.

Example 2

[1215] Multispecific molecule 2 containing a Fab arm targeting mesothelin, an IL2 effector arm, and an anti-NKp30 NK-cell engager, comprising of: SEQ ID: 174, SEQ ID: 169, SEQ ID: 170, was expressed by co-transfecting cells with SEQ ID NO: 117, SEQ ID NO: 118, and SEQ ID NO: 119. Multispecific molecule 2 was purified and a SDS-PAGE gel of the final product is shown in FIG. 22. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 1.38 nM (FIG. 48). FIG. 53 shows binding with human IL2 receptor a of SEQ ID NO: 182 with an EC.sub.50 of 154 pM. Binding with human NKp30 generated from SEQ ID NO: 180 gave an EC.sub.50 of 230 nM (FIG. 55). The EC.sub.50 in the cell-killing assay was 4.7 pM (FIG. 58). FIG. 59 shows the cytokine release data of IFN.gamma. for multispecific molecule 2 in the assay.

Example 3

[1216] Multispecific molecule 3 containing a mesothelin targeting arm and an anti-NKp30 NK-cell engager, comprising of: SEQ ID NO: 174, SEQ ID NO: 169, and SEQ ID NO: 197, was expressed by co-transfecting cells with SEQ ID NO: 117, SEQ ID NO: 118, and SEQ ID NO: 125. Multispecific molecule 3 was purified and a SDS-PAGE gel of the final product is shown in FIG. 23. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 152 pM (FIG. 48). Binding with human NKp30 generated from SEQ ID NO: 180 gave an EC.sub.50 of 93.4 nM (FIG. 55). The EC.sub.50 in the cell-killing assay was 5.9 pM (FIG. 58). FIG. 59 shows the cytokine release data of IFN.gamma. for multispecific molecule 3 in the assay.

Example 4

[1217] Multispecific molecule 4 containing an IL2 effector arm, comprising of: SEQ ID: 176 and SEQ ID: 170, was expressed by co-transfecting cells with SEQ ID NO: 124 and SEQ ID NO: 119. Multispecific molecule 4 was purified and a SDS-PAGE gel of the final product is shown in FIG. 24. FIG. 53 shows binding with human IL2 receptor at of SEQ ID NO: 182 was assessed and gave an EC.sub.50 of 110 pM. The EC.sub.50 in the cell-killing assay was 41 pM (FIG. 58). FIG. 59 shows the cytokine release data of IFN.gamma. for multispecific molecule 4 in the assay.

Example 5

[1218] Multispecific molecule 5 containing a mesothelin targeting arm and a PDL1 targeting arm, comprising of: SEQ ID: 172, SEQ ID NO: 173, SEQ ID NO: 192, and SEQ ID: 171, was expressed by co-transfecting cells with SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 5 was purified and a SDS-PAGE gel of the final product is shown in FIG. 25. FIG. 44 shows the size exclusion chromatogram of multispecific molecule 5. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 163 nM (FIG. 49). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 250 pM (FIG. 51). Multispecific molecule 5 had no significant effect in the cell-killing assay (FIG. 60).

Example 6

[1219] Multispecific molecule 6 containing a mesothelin targeting arm, a PDL1 targeting arm, and an IL2 effector arm, containing comprising of: SEQ ID: 172, SEQ ID NO: 173, SEQ ID NO: 177, and SEQ ID: 171, was expressed by co-transfecting cells with SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 120, and SEQ ID NO: 121. Multispecific molecule 6 was purified and a SDS-PAGE gel of the final product is shown in FIG. 26. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 13.1 nM (FIG. 49). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 363 pM (FIG. 51). FIG. 54 shows binding with human IL2 receptor at of SEQ ID NO: 182 was assessed and gave an EC.sub.50 of 156 pM. Multispecific molecule 6 displayed an EC.sub.50 of 159 pM in the cell-killing assay shown in FIG. 60.

Example 7

[1220] Multispecific molecule 7 containing a mesothelin targeting arm, a PDL1 targeting arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 193, SEQ ID: 173, SEQ ID NO: 192, and SEQ ID NO: 171, was expressed by co-transfecting cells with SEQ ID NO: 136, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 7 was purified and a SDS-PAGE gel of the final product is shown in FIG. 27. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 2.37 nM (FIG. 49). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 158 pM (FIG. 51). FIG. 56 shows binding with human NKp46 from SEQ ID NO: 179, with an EC.sub.50 of 450 pM. Multispecific molecule 7 showed proliferation of cells in the cell-killing assay with an EC.sub.50 of 15 pM (FIG. 60).

Example 8

[1221] Multispecific molecule 8 containing a mesothelin targeting arm, a PDL1 targeting arm, an IL2 effector arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 193, SEQ ID NO: 173, SEQ ID NO: 192, and SEQ ID: 171, was expressed by co-transfecting cells with SEQ ID NO: 136, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 8 was purified and a SDS-PAGE gel of the final product is shown in FIG. 28. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 1.77 nM (FIG. 49). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 255 pM (FIG. 52). FIG. 54 shows binding with human IL2 receptor a of SEQ ID NO: 182 with an EC.sub.50 of 84 pM. FIG. 57 shows binding with human NKp46 from SEQ ID NO: 179, with an EC.sub.50 of 670 pM. Multispecific molecule 8 showed proliferation of cells in the cell-killing assay with an EC.sub.50 of 44 pM (FIG. 60).

Example 9

[1222] Multispecific molecule 9 containing a mesothelin targeting arm, a PDL1 targeting arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 193, SEQ ID: 173, SEQ ID NO: 192, and SEQ ID NO: 171, was expressed by co-transfecting cells with SEQ ID NO: 136, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 9 was purified and a SDS-PAGE gel of the final product is shown in FIG. 29. An ELISA performed with protein 1 of SEQ ID NO: 181 gave an EC.sub.50 of 275 nM (FIG. 50). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 124 pM (FIG. 51). FIG. 56 shows binding with human NKp46 from SEQ ID NO: 179, with an EC.sub.50 of 6.2 nM. Multispecific molecule 9 showed proliferation of cells in the cell-killing assay with an EC.sub.50 of 84 pM (FIG).

Example 10

[1223] Multispecific molecule 10 containing a mesothelin targeting arm, a PDL1 targeting arm, an IL2 effector arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 193, SEQ ID NO: 173, SEQ ID NO: 192, and SEQ ID: 171, was expressed by co-transfecting cells with SEQ ID NO: 136, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 10 was purified and a SDS-PAGE gel of the final product is shown in FIG. 30. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 263 nM (FIG. 50). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 1.91 nM (FIG. 52). FIG. 54 shows binding with human IL2 receptor a of SEQ ID NO: 182 with an EC.sub.50 of 88 pM. FIG. 57 shows binding with human NKp46 from SEQ ID NO: 179, with an EC.sub.50 of 1.8 nM. Multispecific molecule 10 showed proliferation of cells in the cell-killing assay with an EC.sub.50 of 35 pM (FIG. 61).

Example 11

[1224] Multispecific molecule 11 containing a mesothelin targeting arm, a PDL1 targeting arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 193, SEQ ID: 173, SEQ ID NO: 192, and SEQ ID NO: 171, was expressed by co-transfecting cells with SEQ ID NO: 136, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 11 was purified and a SDS-PAGE gel of the final product is shown in FIG. 31. FIG. 45 shows the size exclusion chromatogram of multispecific molecule 11. An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 206 pM (FIG. 52). FIG. 56 shows binding with human NKp46 from SEQ ID NO: 179, with an EC.sub.50 of 8.7 nM. Multispecific molecule 11 showed proliferation of cells in the cell-killing assay with an EC.sub.50 of 119 pM (FIG. 62).

Example 12

[1225] Multispecific molecule 12 containing a mesothelin targeting arm, a PDL1 targeting arm, an IL2 effector arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 193, SEQ ID NO: 173, SEQ ID NO: 192, and SEQ ID: 171, was expressed by co-transfecting cells with SEQ ID NO: 136, SEQ ID NO: 123, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 12 was purified and a SDS-PAGE gel of the final product is shown in FIG. 32. FIG. 26 shows the size exclusion chromatogram of multispecific molecule 12. An ELISA performed with human mesothelin of SEQ ID NO: 181 gave an EC.sub.50 of 216 nM (FIG. 50). An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 1.82 nM (FIG. 52). FIG. 54 shows binding with human IL2 receptor a of SEQ ID NO: 182 with an EC.sub.50 of 107 pM. FIG. 57 shows binding with human NKp46 from SEQ ID NO: 179, with an EC.sub.50 of 19.3 nM. Multispecific molecule 12 showed proliferation of cells in the cell-killing assay with an EC.sub.50 of 16 pM (FIG. 62).

Example 13

[1226] Multispecific molecule 13 containing a HER3 targeting arm, an IGF1R targeting arm, and an IL2 effector arm, comprising of: SEQ ID: 187, SEQ ID NO: 185, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: DNA BH022, SEQ ID NO: 128, and SEQ ID NO: 127. Multispecific molecule 13 was purified and a SDS-PAGE gel of the final product is shown in FIG. 33. FIG. 47 shows the size exclusion chromatogram of multispecific molecule 13. An ELISA of multispecific molecule 13 with human IL2R.alpha. from SEQ ID NO: 182 gave an EC.sub.50 of 85 pM (FIG. 65). The EC.sub.50 in the cell-killing assay was 14 pM (FIG. 67). FIG. 68 shows the cytokine release data of IFN.gamma. for multispecific molecule 13 in the assay.

Example 14

[1227] Multispecific molecule 14 containing a HER3 targeting arm, an IGF1R targeting arm, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 188, SEQ ID NO: 183, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 131, SEQ ID NO: 126, and SEQ ID NO: 127. Multispecific molecule 14 was purified and a SDS-PAGE gel of the final product is shown in FIG. 34. FIG. 66 shows binding with human NKp46 from SEQ ID NO: 179 with an EC.sub.50 of 2.3 nM. The EC.sub.50 in the cell-killing assay was 100 pM (FIG. 67). FIG. 68 shows the cytokine release data of IFN.gamma. for multispecific molecule 14 in the assay.

Example 15

[1228] Multispecific molecule 15 containing a HER3 targeting arm, an IGF1R targeting arm, and a CD3 targeting arm, comprising of: SEQ ID: 189, SEQ ID NO: 183, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 132, SEQ ID NO: 126, and SEQ ID NO: 127. Multispecific molecule 15 was purified and a SDS-PAGE gel of the final product is shown in FIG. 35. The EC.sub.50 in the cell-killing assay was 277 pM (FIG. 69). FIG. 70 shows the cytokine release data of IFN.gamma. for multispecific molecule 15 in the assay.

Example 16

[1229] Multispecific molecule 16 containing a HER3 targeting arm, an IGF1R targeting arm, an anti-NKp46 NK-cell engager, and an IL2 effector arm, comprising of: SEQ ID: 188, SEQ ID NO: 185, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 131, SEQ ID NO: 128, and SEQ ID NO: 127. Multispecific molecule 16 was purified and a SDS-PAGE gel of the final product is shown in FIG. 36. An ELISA of multispecific molecule 16 with human IL2R.alpha. from SEQ ID NO: 182 gave an EC.sub.50 of 167 pM (FIG. 65). The EC.sub.50 in the cell-killing assay was 330 pM (FIG. 67). FIG. 68 shows the cytokine release data of IFN.gamma. for multispecific molecule 16 in the assay.

Example 17

[1230] Multispecific molecule 17 containing a HER3 targeting arm, an IGF1R targeting arm, a CD3 targeting arm, and an IL2 effector arm, comprising of: SEQ ID: 189, SEQ ID NO: 185, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 132, SEQ ID NO: 128, and SEQ ID NO: 127. Multispecific molecule 17 was purified and a SDS-PAGE gel of the final product is shown in FIG. 37. An ELISA of multispecific molecule 17 with human IL2R.alpha. from SEQ ID NO: 182 gave an EC.sub.50 of 116 pM (FIG. 65). The EC.sub.50 in the cell-killing assay was 18 pM (FIG. 69). FIG. 70 shows the cytokine release data of IFN.gamma. for multispecific molecule 17 in the assay.

Example 18

[1231] Multispecific molecule 18 containing a HER3 targeting arm and an IGF1R targeting arm, comprising of: SEQ ID: 187, SEQ ID NO: 183, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: DNA BH022, SEQ ID NO: 126, and SEQ ID NO: 127. Multispecific molecule 18 was purified and a SDS-PAGE gel of the final product is shown in FIG. 38. The EC.sub.50 in the cell-killing assay was 28 pM (FIG. 67). FIG. 68 shows the cytokine release data of IFN.gamma. for multispecific molecule 18 in the assay.

Example 19

[1232] Multispecific molecule 19 containing a HER3 targeting arm, an IGF1R targeting arm, and an IL7 effector arm, comprising of: SEQ ID: 187, SEQ ID NO: 186, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 130, SEQ ID NO: 129, and SEQ ID NO: 127. Multispecific molecule 19 was purified and a SDS-PAGE gel of the final product is shown in FIG. 39.

Example 20

[1233] Multispecific molecule 20 containing a HER3 targeting arm, an IGF1R targeting arm, a CD3 targeting arm, and an IL7 effector arm, comprising of: SEQ ID: 189, SEQ ID NO: 186, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 132, SEQ ID NO: 129, and SEQ ID NO: 127. Multispecific molecule 20 was purified and a SDS-PAGE gel of the final product is shown in FIG. 40. The EC.sub.50 in the cell-killing assay was 445 pM (FIG. 71). FIG. 72 shows the cytokine release data of IFN.gamma. for multispecific molecule 20 in the assay.

Example 21

[1234] Multispecific molecule 21 containing a HER3 targeting arm, an IGF1R targeting arm, an anti-NKp46 NK-cell engager, and an IL7 effector arm, comprising of: SEQ ID: 190, SEQ ID NO: 169, SEQ ID NO: 186, and SEQ ID: 184, was expressed by co-transfecting cells with SEQ ID NO: 133, SEQ ID NO: 118, SEQ ID NO: 128, and SEQ ID NO: 127. Multispecific molecule 21 was purified and a SDS-PAGE gel of the final product is shown in FIG. 41. FIG. 46 shows binding with human NKp46 from SEQ ID NO: 179 with an EC.sub.50 of 1.3 nM. The EC.sub.50 in the cell-killing assay was 770 pM (FIG. 73). FIG. 74 shows the cytokine release data of IFN.gamma. for multispecific molecule 21 in the assay.

Example 22

[1235] Multispecific molecule 22 containing a mesothelin targeting arm, a PDL1 targeting arm with an IL2 effector, and an anti-NKp46 NK-cell engager, comprising of: SEQ ID: 190, SEQ ID NO: 169, SEQ ID NO: 192, and SEQ ID: 191, was expressed by co-transfecting cells with SEQ ID NO: 133, SEQ ID NO: 118, SEQ ID NO: 135, and SEQ ID NO: 134. Multispecific molecule 22 was purified and a SDS-PAGE gel of the final product is shown in FIG. 42. An ELISA of multispecific molecule 22 with human mesothelin from SEQ ID NO: 181 gave an EC.sub.50 of 310 pM (FIG. 63). FIG. 44 displays the data for multispecific molecule 22 binding to human PDL1 from SEQ ID NO: 178 with an EC.sub.50 of 8 pM. An ELISA of multispecific molecule 22 with human IL2R.alpha. from SEQ ID NO: 182 gave an EC.sub.50 of 8.2 nM (FIG. 65). FIG. 46 shows binding with human NKp46 from SEQ ID NO: 179 with an EC.sub.50 of 2.4 nM. The EC.sub.50 in the cell-killing assay was 995 pM (FIG. 75). FIG. 76 shows the cytokine release data of IFN.gamma. for multispecific molecule 22 in the assay.

Example 23

[1236] Multispecific molecule 23 containing a mesothelin targeting arm and a PDL1 targeting arm comprising of SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 192, and SEQ ID NO: 171, was expressed by co-transfecting cells with SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 135, and SEQ ID NO: 121. Multispecific molecule 23 was purified and used in the cell-killing assay shown in FIG. 75, giving an EC.sub.50 of 250 pM. FIG. 76 shows the cytokine release data of IFN.gamma. for multispecific molecule 23 in the assay.

Examples Directed to Multispecific Molecules Comprising a Stromal Modifying Moiety and Uses Thereof

General Methods:

[1237] 1. Construction of the Plasmids.

[1238] The DNA encoding the protein sequences was optimized for expression in Cricetulus griseus, synthesized, and cloned into the pcDNA3.4-TOPO (Life Technologies A14697) using Gateway cloning. All constructs contained an Ig Kappa leader sequence (SEQ ID NO: 84 ATGGAAACCGACACACTGCTGCTGTGGGTGCTGCTCTTGTGGGTGCCAGGATCTACA GGA, SEQ ID NO: 64 METDTLLLWVLLLWVPGSTG). The nucleic acid sequences used are shown in Table 10.

[1239] 2. Expression and Purification.

[1240] The plasmids were co-transfected into either Expi293 cells (Life Technologies A14527) or ExpiCHO cells (Life Technologies A29127). Transfection were performed using 1 mg of total DNA for a multispecific construct with a 1:1 knob to hole heavy chain ratio and 3:2 light chain to heavy chain ratio. When biotinylation was required, 250 .mu.g of SEQ ID:144 226 BirA was added per liter in addition to the multispecific construct DNA. Transfection in Expi293 cells was done using linear 25,000 Da polyethylenimine (PEI, Polysciences Inc 23966) in a 3:1 ratio with the total DNA. The DNA and PEI were each added to 50 mL of OptiMem (Life Technologies 31985088) medium and sterile filtered. The DNA and PEI were combined for 10 minutes and added to the Expi293 cells with a cell density of 1.8-2.8.times.10.sup.6 cells/mL and a viability of at least 95%. The ExpiCHO transfection was performed according to the manufacturer's instructions. Expi293 cells were grown in a humidified incubator at 37.degree. C. with 8% CO.sub.2 for 5-7 days after transfection and ExpiCHO cells were grown for 14 days at 32.degree. C. with 5% CO.sub.2. The cells were pelleted by centrifugation at 4500.times.g and the supernatant was filtered through a 0.2 .mu.m membrane. Protein A resin (GE 17-1279-03) was added to the filtered supernatant and incubated for 1-3 hours at room temperature. The resin was packed into a column, washed with 3.times.10 column volumes of Dulbecco's phosphate-buffered saline (DPBS, Life Technologies 14190-144). The bound protein was eluted from the column with 20 mM citrate, 100 mM NaCl, pH 2.9. When necessary, the proteins were further purified using ligand affinity and/or size exclusion chromatography on a Superdex 200 column with a running buffer of DPBS.

[1241] 3. ELISA Assay.

[1242] ELISA assays were performed using either Pierce 96-well streptavidin coated high capacity plates (15500) or Nunc-Immuno 96-well maxisorp plates (Invitrogen 44-2404-21). The plates were washed with 1.times. phosphate buffered saline tween 20 (Pierce 28352) and then coated with 10 pg/mL of the capture protein. After incubating for 2 hours at room temperature with shaking, the plate was washed with 1.times.PBST and the molecule was added in rows A-G using a serial dilution of 1 .mu.M-1 pM. The plate was incubated for 30 minutes, washed, and 100 .mu.L of either peroxidase-conjugated affinipure goat anti-human IgG (109-035-008) or streptavidin-HRP (R&D Systems DY998) was added to each well. The plate was incubated for 30 minutes with shaking, washed, and 100 .mu.L of 1-step Turbo TMB-ELISA substrate solution (Thermo Scientific 34022) was added to each well. The plate was incubated for 5 minutes, the reaction was stopped with 100 .mu.L of 1 M HCl, and the plate was read using the absorbance at 450 nm on a SpectraMax i3x plate reader.

[1243] 4. Cell-Killing Assay.

[1244] To assess the activity of the constructs produced, a BxPC3-luciferase cell-killing assay was performed. BxPC3 cells containing luciferase (Genecopia SCL-C012-HLG) were grown in RPMI 1640 (Gibco 11875119) and 10% fetal bovine serum (Gibco 10082147) with 1 g/mL puromycin (Gibco A1113802). The cells were used to seed a 96-well plate with 15,000 cells per well. After incubating for a day, the media was removed and replaced with the serum-free media RPMI 1640 with 0.5% Pen/Strep (Gibco 15140122). PBMCs (C.T.L. Lot #LP_123) in the serum-free media were added to rows A-G of the 96-well plate at 450,000 cells/well. The compounds were added to columns, in triplicate, with concentrations ranging from 1 .mu.M to 10 pM in rows A-F. The plates were incubated for 6 or 24 hours before measuring. Before proceeding with the cell-killing measurement, 120 .mu.L was removed from each well and added to a 96-well low-binding protein plate. This left 80 .mu.L in the plate, and 80 .mu.L of Bright-Glo (Promega E2610) was added to each well. The plate was then read on a SpectraMax i3x plate reader.

[1245] 5. Cytokine Release Assay.

[1246] For the cytokine release assay, the supernatant removed from the cell-killing plate was diluted 5-fold with the quansys wash buffer. The manufacturer's instructions were followed for the Quansys human IFN.gamma. (Quansys 464649HU) singleplex assay kit. The plates were imaged on a BioRad ChemiDoc XRS+ and analyzed using the Quansys Q-view software.

[1247] 6. Turbidimetric Hyaluronidase Enzyme Assay.

[1248] To test hyaluronidase activity, enzyme assays were performed as described previously (Dorfman, A., Ott, M. L. A Turbidimetric Method for the Assay of Hyaluronidase, Journal of Biological Chemistry, 1948.). A stock solution of hyaluronic acid (Sigma 53747) was prepared at 1 mg/mL in 300 mM sodium phosphate, pH 5.35. The hyaluronidase-containing constructs were diluted to 1 mg/mL in 20 mM sodium phosphate, pH 7.0, 77 mM sodium chloride, 0.01% bovine serum albumin (Sigma A6003). Enzyme constructs from 0.01 mg/mL to 1 mg/mL were combined with 1 mg/mL hyaluronic acid and incubated at 37.degree. C. for 45 minutes. An acidified BSA solution (24 mM sodium acetate, 79 mM acetic acid, 0.1% bovine serum albumin, pH 3.75) was then added to the enzyme and substrate. After incubating for 10 minutes at room temperature, the activity was measured with the absorbance at 540 nm. Hyaluronidase activity is seen as a decrease in absorbance, as the enzyme breaks down the hyaluronic acid.

[1249] 7. Hyaluronidase Zymogram.

[1250] To further demonstrate hyaluronidase activity, a 12% SDS-PAGE gel was made containing 0.1 mg/mL hyaluronic acid (Sigma 53747). The constructs were run on the gel and then the gel was incubated in 3% Triton X-100 (Sigma 93443) for one hour. The gel was then incubated in assay buffer (20 mM citrate, 150 mM sodium chloride, pH 3.5) for 16 hours at 37.degree. C. The gel was stained for hyaluronidase activity using 0.5% Alcian Blue (Sigma B8438), which stains hyaluronic acid blue and leaves clear spots where the enzyme degraded hyaluronic acid.

[1251] 8. Gelatinase a Enzyme Assay.

[1252] Enzymatic activity of constructs containing MMP-2 was determined using the EnzChek gelatinase/collagenase assay kit (Molecular Probes E-12055), according to the manufacturer's instructions.

Example 24

[1253] Multispecific molecule 24 containing Fab arms targeting FAP and a hyaluronidase arm, comprising of three distinct protein chains: SEQ ID: 214, SEQ ID: 215, and SEQ ID: 219, was expressed by co-transfecting cells with SEQ ID NO: 202, SEQ ID NO: 203, and SEQ ID NO: 207. Multispecific molecule 23 was purified and a SDS-PAGE gel of the final product is shown in FIG. 77. The size exclusion chromatogram of multispecific molecule 23 is shown in FIG. 86. An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 144 nM (FIG. 94). FIG. 98 demonstrates that multispecific molecule 24 has hyaluronidase activity. The presence of white bands on the blue background in the hyaluronidase zymogram (FIG. 100) further demonstrates hyaluronidase activity of multispecific molecule 24.

Example 25

[1254] Multispecific molecule 25 containing Fab arms targeting FAP, an IL2 effector arm, and a hyaluronidase arm, comprising of: SEQ ID: 218, SEQ ID: 215, SEQ ID: 219, was expressed by co-transfecting cells with SEQ ID NO: 206, SEQ ID NO: 203, and SEQ ID NO: 207. Multispecific molecule 24 was purified and a SDS-PAGE gel of the final product is shown in FIG. 78. The size exclusion chromatogram of multispecific molecule 24 is shown in FIG. 87. An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 128 nM (FIG. 94). FIG. 781 shows binding of multispecific molecule 25 to human IL2R.alpha. (generated from SEQ ID NO: 182) with an EC.sub.50 of 101 nM. FIG. 98 demonstrates that multispecific molecule 25 has hyaluronidase activity. The presence of white bands on the blue background in the hyaluronidase zymogram (FIG. 100) further demonstrates hyaluronidase activity of multispecific molecule 25.

Example 26

[1255] Multispecific molecule 26 containing a FAP targeting arm and a hyaluronidase arm, comprising of: SEQ ID NO: 214, SEQ ID NO: 215, and SEQ ID NO: 224, was expressed by co-transfecting cells with SEQ ID NO: 202, SEQ ID NO: 203, and SEQ ID NO: 212. Multispecific molecule 25 was purified and a SDS-PAGE gel of the final product is shown in FIG. 79. The size exclusion chromatogram of multispecific molecule 25 is shown in FIG. 88. An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 18.5 nM (FIG. 94). FIG. 98 demonstrates that multispecific molecule 26 has hyaluronidase activity. The presence of white bands on the blue background in the hyaluronidase zymogram (FIG. 100) further demonstrates hyaluronidase activity of multispecific molecule 26.

Example 27

[1256] Multispecific molecule 27 containing a PDL1 targeting arm, a FAP targeting arm, and a hyaluronidase arm, comprising of: SEQ ID: 220, SEQ ID: 171, SEQ ID NO: 219, and SEQ ID NO: 215, was expressed by co-transfecting cells with SEQ ID NO: 121, SEQ ID NO: 207, and SEQ ID NO: 208. Multispecific molecule 26 was purified and a SDS-PAGE gel of the final product is shown in FIG. 80. An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 52 pM (FIG. 93). An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 44 nM (FIG. 94). FIG. 99 demonstrates that multispecific molecule 27 has hyaluronidase activity. The presence of white bands on the blue background in the hyaluronidase zymogram (FIG. 100) further demonstrates hyaluronidase activity of multispecific molecule 27.

Example 28

[1257] Multispecific molecule 28 containing a PDL1 targeting arm, a FAP targeting arm, an IL2 effector arm, and a hyaluronidase arm, comprising of: SEQ ID: 221, SEQ ID: 171, SEQ ID NO: 219, and SEQ ID NO: 215, was expressed by co-transfecting cells with SEQ ID NO: 209, SEQ ID NO: 121, SEQ ID NO: 207, and SEQ ID NO: 208. Multispecific molecule 27 was purified and a SDS-PAGE gel of the final product is shown in FIG. 81. The size exclusion chromatogram of multispecific molecule 27 is shown in FIG. 90. An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 0.207 nM (FIG. 93). An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 69 nM (FIG. 95). FIG. 97 shows binding of multispecific molecule 27 to human IL2R.alpha. (generated from SEQ ID NO: 182) with an EC.sub.50 of 97 nM. FIG. 99 demonstrates that multispecific molecule 28 has hyaluronidase activity. The presence of white bands on the blue background in the hyaluronidase zymogram (FIG. 100) further demonstrates hyaluronidase activity of multispecific molecule 28.

Example 29

[1258] Multispecific molecule 29 containing a PDL1 targeting arm, an anti-NKp46 NK-cell engager, an IL2 effector arm, and a hyaluronidase arm, comprising of: SEQ ID: 221, SEQ ID: 171, SEQ ID NO: 222, and SEQ ID NO: 223, was expressed by co-transfecting cells with SEQ ID NO: 209, SEQ ID NO: 121, SEQ ID NO: 210, and SEQ ID NO: 211. Multispecific molecule 28 was purified and a SDS-PAGE gel of the final product is shown in FIG. 82. The size exclusion chromatogram of multispecific molecule 28 is shown in FIG. 91. An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 866 pM (FIG. 93). An ELISA with human NKp46 from SEQ ID NO: 179 gave an EC.sub.50 of 126 pM (FIG. 96). FIG. 97 shows binding of multispecific molecule 6 to human IL2R.alpha. (generated from SEQ ID NO: 182) with an EC.sub.50 of 48 nM. FIG. 99 demonstrates that multispecific molecule 29 has hyaluronidase activity. The presence of white bands on the blue background in the hyaluronidase zymogram (FIG. 100) further demonstrates hyaluronidase activity of multispecific molecule 29.

Example 30

[1259] Multispecific molecule 30 containing FAP targeting arms and a gelatinase arm, comprising of: SEQ ID: 214, SEQ ID: 215, and SEQ ID NO: 216, was expressed by co-transfecting cells with SEQ ID NO: 202, SEQ ID NO: 203, and SEQ ID NO: 207. Multispecific molecule 29 was purified and a SDS-PAGE gel of the final product is shown in FIG. 83. The size exclusion chromatogram of multispecific molecule 30 is shown in FIG. 92. An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 385 nM (FIG. 95). FIG. 101 demonstrates that multispecific molecule 30 has collagenase activity.

Example 31

[1260] Multispecific molecule 31 containing a FAP targeting arm and a gelatinase arm, comprising of: SEQ ID: 214, SEQ ID: 215, and SEQ ID NO: 217, was expressed by co-transfecting cells with SEQ ID NO: 202, SEQ ID NO: 203, and SEQ ID NO: D205. Multispecific molecule 30 was purified and a SDS-PAGE gel of the final product is shown in FIG. 84. The size exclusion chromatogram of multispecific molecule 31 is shown in FIG. 93. An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 466 nM (FIG. 95). FIG. 101 demonstrates that multispecific molecule 31 has collagenase activity.

Example 32

[1261] Multispecific molecule 32 containing a PDL1 targeting arm, a FAP targeting arm, an IL2 effector arm, and a gelatinase arm, comprising of: SEQ ID: 221, SEQ ID: 171, SEQ ID NO: 216, and SEQ ID NO: 215, was expressed by co-transfecting cells with SEQ ID NO: 209, SEQ ID NO: 121, SEQ ID NO: 204, and SEQ ID NO: 203. Multispecific molecule 31 was purified and a SDS-PAGE gel of the final product is shown in FIG. 85. An ELISA performed with human PDL1 of SEQ ID NO: 178 gave an EC.sub.50 of 155 pM (FIG. 93). An ELISA was performed with human FAP generated from SEQ ID NO: 225 and gave an EC.sub.50 of 85 nM (FIG. 95). FIG. 97 shows binding of multispecific molecule 32 to human IL2R.alpha. (generated from SEQ ID NO: 182) with an EC.sub.50 of 36 nM. FIG. 101 demonstrates that multispecific molecule 32 has collagenase activity.

INCORPORATION BY REFERENCE

[1262] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

EQUIVALENTS

[1263] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 242 <210> SEQ ID NO 1 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 1 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> SEQ ID NO 2 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 2 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn 1 5 10 <210> SEQ ID NO 3 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 3 Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe Arg 1 5 10 15 Gly <210> SEQ ID NO 4 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 4 Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr 1 5 10 <210> SEQ ID NO 5 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 5 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 100 105 <210> SEQ ID NO 6 <211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 6 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys <210> SEQ ID NO 7 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 7 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 8 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 8 Ser Ala Ser Ser Ser Val Ser Tyr Met His 1 5 10 <210> SEQ ID NO 9 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 9 Asp Thr Ser Lys Leu Ala Ser 1 5 <210> SEQ ID NO 10 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 10 Gln Gln Trp Ser Gly Tyr Pro Leu Thr 1 5 <210> SEQ ID NO 11 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 11 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> SEQ ID NO 12 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 12 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala 20 <210> SEQ ID NO 13 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 13 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 14 <211> LENGTH: 103 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 14 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys Ser Cys 100 <210> SEQ ID NO 15 <211> LENGTH: 21 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 15 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val 20 <210> SEQ ID NO 16 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 16 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly 20 <210> SEQ ID NO 17 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 18 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu 65 70 75 <210> SEQ ID NO 19 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 19 Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly 1 5 10 15 Gly Ser Leu Gln 20 <210> SEQ ID NO 20 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 21 <211> LENGTH: 157 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn 1 5 10 15 Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp 20 25 30 Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile 35 40 45 Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile 50 55 60 Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile 65 70 75 80 Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys 85 90 95 Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys 100 105 110 Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu 115 120 125 Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu 130 135 140 Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 145 150 155 <210> SEQ ID NO 22 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> SEQ ID NO 23 <211> LENGTH: 138 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Gln Asp Pro Tyr Val Lys Glu Ala Glu Asn Leu Lys Lys Tyr Phe Asn 1 5 10 15 Ala Gly His Ser Asp Val Ala Asp Asn Gly Thr Leu Phe Leu Gly Ile 20 25 30 Leu Lys Asn Trp Lys Glu Glu Ser Asp Arg Lys Ile Met Gln Ser Gln 35 40 45 Ile Val Ser Phe Tyr Phe Lys Leu Phe Lys Asn Phe Lys Asp Asp Gln 50 55 60 Ser Ile Gln Lys Ser Val Glu Thr Ile Lys Glu Asp Met Asn Val Lys 65 70 75 80 Phe Phe Asn Ser Asn Lys Lys Lys Arg Asp Asp Phe Glu Lys Leu Thr 85 90 95 Asn Tyr Ser Val Thr Asp Leu Asn Val Gln Arg Lys Ala Ile His Glu 100 105 110 Leu Ile Gln Val Met Ala Glu Leu Ser Pro Ala Ala Lys Thr Gly Lys 115 120 125 Arg Lys Arg Ser Gln Met Leu Phe Arg Gly 130 135 <210> SEQ ID NO 24 <211> LENGTH: 238 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 24 Asp Leu Lys Val Glu Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu 1 5 10 15 Asn Asp Asn Val Thr Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu 20 25 30 Asn Ile Thr Ser Met Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe 35 40 45 Asp Lys Glu Val Lys Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala 50 55 60 Phe Arg Pro Gly Ala Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp 65 70 75 80 Ala Ser Leu Arg Leu Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr 85 90 95 Arg Cys Glu Val Val Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln 100 105 110 Leu Glu Val Val Ala Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val 115 120 125 Gly Met Lys Glu Asn Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe 130 135 140 Tyr Pro Glu Ala Ile Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe 145 150 155 160 Pro His Pro Ile Glu Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile 165 170 175 Lys Asn Met Asp Gly Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn 180 185 190 Ser Ser Gln Glu Asp Pro Gly Thr Val Tyr Gln Cys Val Val Arg His 195 200 205 Ala Ser Leu His Thr Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala 210 215 220 Arg His Ser Leu Ser Glu Thr Glu Lys Thr Asp Asn Phe Ser 225 230 235 <210> SEQ ID NO 25 <211> LENGTH: 284 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 25 Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly 1 5 10 15 Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro 20 25 30 Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln 35 40 45 Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg 50 55 60 Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile 65 70 75 80 Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys 85 90 95 Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr 100 105 110 Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr 115 120 125 Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn 130 135 140 Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met 145 150 155 160 His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val 165 170 175 Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu 180 185 190 Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr 195 200 205 Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser 210 215 220 His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr 225 230 235 240 Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg 245 250 255 Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val 260 265 270 Pro Ser Gly Lys Val Leu Val Leu Gln Ser His Trp 275 280 <210> SEQ ID NO 26 <211> LENGTH: 287 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 26 Ala Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp 1 5 10 15 Glu Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln 20 25 30 Pro Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly 35 40 45 Gln Trp Ala Glu Asp Val Leu Gly Ala Lys Thr Trp Asp Thr Glu Thr 50 55 60 Glu Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His 65 70 75 80 Ile Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val 85 90 95 Cys Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr 100 105 110 Tyr Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser 115 120 125 Thr Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr 130 135 140 Asn Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala 145 150 155 160 Met Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly 165 170 175 Val Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Cys Ser 180 185 190 Glu Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe 195 200 205 Tyr Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu 210 215 220 Ser His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly 225 230 235 240 Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln 245 250 255 Arg Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro 260 265 270 Val Pro Ser Gly Lys Val Leu Val Leu Gln Ser Gln Arg Thr Asp 275 280 285 <210> SEQ ID NO 27 <211> LENGTH: 191 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 27 Gly Trp Val Asp Thr His Cys Leu Cys Tyr Asp Phe Ile Ile Thr Pro 1 5 10 15 Lys Ser Arg Pro Glu Pro Gln Trp Cys Glu Val Gln Gly Leu Val Asp 20 25 30 Glu Arg Pro Phe Leu His Tyr Asp Cys Val Asn His Lys Ala Lys Ala 35 40 45 Phe Ala Ser Leu Gly Lys Lys Val Asn Val Thr Lys Thr Trp Glu Glu 50 55 60 Gln Thr Glu Thr Leu Arg Asp Val Val Asp Phe Leu Lys Gly Gln Leu 65 70 75 80 Leu Asp Ile Gln Val Glu Asn Leu Ile Pro Ile Glu Pro Leu Thr Leu 85 90 95 Gln Ala Arg Met Ser Cys Glu His Glu Ala His Gly His Gly Arg Gly 100 105 110 Ser Trp Gln Phe Leu Phe Asn Gly Gln Lys Phe Leu Leu Phe Asp Ser 115 120 125 Asn Asn Arg Lys Trp Thr Ala Leu His Pro Gly Ala Lys Lys Met Thr 130 135 140 Glu Lys Trp Glu Lys Asn Arg Asp Val Thr Met Phe Phe Gln Lys Ile 145 150 155 160 Ser Leu Gly Asp Cys Lys Met Trp Leu Glu Glu Phe Leu Met Tyr Trp 165 170 175 Glu Gln Met Leu Asp Pro Thr Lys Pro Pro Ser Leu Ala Pro Gly 180 185 190 <210> SEQ ID NO 28 <211> LENGTH: 329 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 28 Gln Asp Val Arg Val Gln Val Leu Pro Glu Val Arg Gly Gln Leu Gly 1 5 10 15 Gly Thr Val Glu Leu Pro Cys His Leu Leu Pro Pro Val Pro Gly Leu 20 25 30 Tyr Ile Ser Leu Val Thr Trp Gln Arg Pro Asp Ala Pro Ala Asn His 35 40 45 Gln Asn Val Ala Ala Phe His Pro Lys Met Gly Pro Ser Phe Pro Ser 50 55 60 Pro Lys Pro Gly Ser Glu Arg Leu Ser Phe Val Ser Ala Lys Gln Ser 65 70 75 80 Thr Gly Gln Asp Thr Glu Ala Glu Leu Gln Asp Ala Thr Leu Ala Leu 85 90 95 His Gly Leu Thr Val Glu Asp Glu Gly Asn Tyr Thr Cys Glu Phe Ala 100 105 110 Thr Phe Pro Lys Gly Ser Val Arg Gly Met Thr Trp Leu Arg Val Ile 115 120 125 Ala Lys Pro Lys Asn Gln Ala Glu Ala Gln Lys Val Thr Phe Ser Gln 130 135 140 Asp Pro Thr Thr Val Ala Leu Cys Ile Ser Lys Glu Gly Arg Pro Pro 145 150 155 160 Ala Arg Ile Ser Trp Leu Ser Ser Leu Asp Trp Glu Ala Lys Glu Thr 165 170 175 Gln Val Ser Gly Thr Leu Ala Gly Thr Val Thr Val Thr Ser Arg Phe 180 185 190 Thr Leu Val Pro Ser Gly Arg Ala Asp Gly Val Thr Val Thr Cys Lys 195 200 205 Val Glu His Glu Ser Phe Glu Glu Pro Ala Leu Ile Pro Val Thr Leu 210 215 220 Ser Val Arg Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asp Asn 225 230 235 240 Trp Tyr Leu Gly Arg Thr Asp Ala Thr Leu Ser Cys Asp Val Arg Ser 245 250 255 Asn Pro Glu Pro Thr Gly Tyr Asp Trp Ser Thr Thr Ser Gly Thr Phe 260 265 270 Pro Thr Ser Ala Val Ala Gln Gly Ser Gln Leu Val Ile His Ala Val 275 280 285 Asp Ser Leu Phe Asn Thr Thr Phe Val Cys Thr Val Thr Asn Ala Val 290 295 300 Gly Met Gly Arg Ala Glu Gln Val Ile Phe Val Arg Glu Thr Pro Asn 305 310 315 320 Thr Ala Gly Ala Gly Ala Thr Gly Gly 325 <210> SEQ ID NO 29 <211> LENGTH: 323 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 29 Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln Ala Pro Thr Gln 1 5 10 15 Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro Cys Tyr Leu Gln 20 25 30 Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu Thr Trp Ala Arg 35 40 45 His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln Thr Gln Gly Pro 50 55 60 Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala Ala Arg Leu Gly 65 70 75 80 Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly Leu Arg Val Glu 85 90 95 Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe Pro Gln Gly Ser 100 105 110 Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys Pro Gln Asn Thr 115 120 125 Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro Val Pro Met Ala 130 135 140 Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln Ile Thr Trp His 145 150 155 160 Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val Pro Gly Phe Leu 165 170 175 Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu Val Pro Ser Ser 180 185 190 Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu His Glu Ser Phe 195 200 205 Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val Tyr Tyr Pro Pro 210 215 220 Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr Leu Gly Gln Asn 225 230 235 240 Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro Glu Pro Thr Gly 245 250 255 Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro Phe Ala Val Ala 260 265 270 Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys Pro Ile Asn Thr 275 280 285 Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala Arg Gln Ala Glu 290 295 300 Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu His Ser Gly Ile 305 310 315 320 Ser Arg Asn <210> SEQ ID NO 30 <211> LENGTH: 330 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 30 Gln Asn Leu Phe Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala 1 5 10 15 Thr Ile Ser Cys Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu 20 25 30 Leu Asn Pro Asn Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu 35 40 45 Lys Asp Ser Arg Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys 50 55 60 Val Ser Leu Thr Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys 65 70 75 80 Gln Leu Tyr Thr Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val 85 90 95 Leu Val Pro Pro Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala 100 105 110 Val Glu Gly Glu Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys 115 120 125 Pro Ala Thr Thr Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly 130 135 140 Lys Ser Glu Val Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln 145 150 155 160 Leu Met Leu Lys Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys 165 170 175 Gln Val Glu His Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr 180 185 190 Leu Glu Val Gln Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro 195 200 205 Leu Gln Gly Leu Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu 210 215 220 Ala Ile Gly Lys Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp 225 230 235 240 Asp Glu Met Pro Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile 245 250 255 Asn Asn Leu Asn Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser 260 265 270 Asn Ile Val Gly Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp 275 280 285 Pro Pro Thr Thr Ile Pro Pro Pro Thr Thr Thr Thr Thr Thr Thr Thr 290 295 300 Thr Thr Thr Thr Thr Ile Leu Thr Ile Ile Thr Asp Ser Arg Ala Gly 305 310 315 320 Glu Glu Gly Ser Ile Arg Ala Val Asp His 325 330 <210> SEQ ID NO 31 <211> LENGTH: 155 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 31 Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu Pro Leu Glu Ser Leu Gly 1 5 10 15 Trp Asp Val Ala Glu Leu Gln Leu Asn His Thr Gly Pro Gln Gln Asp 20 25 30 Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala Leu Gly Arg Ser Phe Leu 35 40 45 His Gly Pro Glu Leu Asp Lys Gly Gln Leu Arg Ile His Arg Asp Gly 50 55 60 Ile Tyr Met Val His Ile Gln Val Thr Leu Ala Ile Cys Ser Ser Thr 65 70 75 80 Thr Ala Ser Arg His His Pro Thr Thr Leu Ala Val Gly Ile Cys Ser 85 90 95 Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg Leu Ser Phe His Gln Gly 100 105 110 Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro Leu Ala Arg Gly Asp Thr 115 120 125 Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu Pro Ser Arg Asn Thr Asp 130 135 140 Glu Thr Phe Phe Gly Val Gln Trp Val Arg Pro 145 150 155 <210> SEQ ID NO 32 <211> LENGTH: 294 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 32 Trp Thr Tyr His Tyr Ser Glu Lys Pro Met Asn Trp Gln Arg Ala Arg 1 5 10 15 Arg Phe Cys Arg Asp Asn Tyr Thr Asp Leu Val Ala Ile Gln Asn Lys 20 25 30 Ala Glu Ile Glu Tyr Leu Glu Lys Thr Leu Pro Phe Ser Arg Ser Tyr 35 40 45 Tyr Trp Ile Gly Ile Arg Lys Ile Gly Gly Ile Trp Thr Trp Val Gly 50 55 60 Thr Asn Lys Ser Leu Thr Glu Glu Ala Glu Asn Trp Gly Asp Gly Glu 65 70 75 80 Pro Asn Asn Lys Lys Asn Lys Glu Asp Cys Val Glu Ile Tyr Ile Lys 85 90 95 Arg Asn Lys Asp Ala Gly Lys Trp Asn Asp Asp Ala Cys His Lys Leu 100 105 110 Lys Ala Ala Leu Cys Tyr Thr Ala Ser Cys Gln Pro Trp Ser Cys Ser 115 120 125 Gly His Gly Glu Cys Val Glu Ile Ile Asn Asn Tyr Thr Cys Asn Cys 130 135 140 Asp Val Gly Tyr Tyr Gly Pro Gln Cys Gln Phe Val Ile Gln Cys Glu 145 150 155 160 Pro Leu Glu Ala Pro Glu Leu Gly Thr Met Asp Cys Thr His Pro Leu 165 170 175 Gly Asn Phe Ser Phe Ser Ser Gln Cys Ala Phe Ser Cys Ser Glu Gly 180 185 190 Thr Asn Leu Thr Gly Ile Glu Glu Thr Thr Cys Gly Pro Phe Gly Asn 195 200 205 Trp Ser Ser Pro Glu Pro Thr Cys Gln Val Ile Gln Cys Glu Pro Leu 210 215 220 Ser Ala Pro Asp Leu Gly Ile Met Asn Cys Ser His Pro Leu Ala Ser 225 230 235 240 Phe Ser Phe Thr Ser Ala Cys Thr Phe Ile Cys Ser Glu Gly Thr Glu 245 250 255 Leu Ile Gly Lys Lys Lys Thr Ile Cys Glu Ser Ser Gly Ile Trp Ser 260 265 270 Asn Pro Ser Pro Ile Cys Gln Lys Leu Asp Lys Ser Phe Ser Met Ile 275 280 285 Lys Glu Gly Asp Tyr Asn 290 <210> SEQ ID NO 33 <211> LENGTH: 243 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 33 Arg Tyr Leu Gln Val Ser Gln Gln Leu Gln Gln Thr Asn Arg Val Leu 1 5 10 15 Glu Val Thr Asn Ser Ser Leu Arg Gln Gln Leu Arg Leu Lys Ile Thr 20 25 30 Gln Leu Gly Gln Ser Ala Glu Asp Leu Gln Gly Ser Arg Arg Glu Leu 35 40 45 Ala Gln Ser Gln Glu Ala Leu Gln Val Glu Gln Arg Ala His Gln Ala 50 55 60 Ala Glu Gly Gln Leu Gln Ala Cys Gln Ala Asp Arg Gln Lys Thr Lys 65 70 75 80 Glu Thr Leu Gln Ser Glu Glu Gln Gln Arg Arg Ala Leu Glu Gln Lys 85 90 95 Leu Ser Asn Met Glu Asn Arg Leu Lys Pro Phe Phe Thr Cys Gly Ser 100 105 110 Ala Asp Thr Cys Cys Pro Ser Gly Trp Ile Met His Gln Lys Ser Cys 115 120 125 Phe Tyr Ile Ser Leu Thr Ser Lys Asn Trp Gln Glu Ser Gln Lys Gln 130 135 140 Cys Glu Thr Leu Ser Ser Lys Leu Ala Thr Phe Ser Glu Ile Tyr Pro 145 150 155 160 Gln Ser His Ser Tyr Tyr Phe Leu Asn Ser Leu Leu Pro Asn Gly Gly 165 170 175 Ser Gly Asn Ser Tyr Trp Thr Gly Leu Ser Ser Asn Lys Asp Trp Lys 180 185 190 Leu Thr Asp Asp Thr Gln Arg Thr Arg Thr Tyr Ala Gln Ser Ser Lys 195 200 205 Cys Asn Lys Val His Lys Thr Trp Ser Trp Trp Thr Leu Glu Ser Glu 210 215 220 Ser Cys Arg Ser Ser Leu Pro Tyr Ile Cys Glu Met Thr Ala Phe Arg 225 230 235 240 Phe Pro Asp <210> SEQ ID NO 34 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 34 Lys Leu Thr Arg Asp Ser Gln Ser Leu Cys Pro Tyr Asp Trp Ile Gly 1 5 10 15 Phe Gln Asn Lys Cys Tyr Tyr Phe Ser Lys Glu Glu Gly Asp Trp Asn 20 25 30 Ser Ser Lys Tyr Asn Cys Ser Thr Gln His Ala Asp Leu Thr Ile Ile 35 40 45 Asp Asn Ile Glu Glu Met Asn Phe Leu Arg Arg Tyr Lys Cys Ser Ser 50 55 60 Asp His Trp Ile Gly Leu Lys Met Ala Lys Asn Arg Thr Gly Gln Trp 65 70 75 80 Val Asp Gly Ala Thr Phe Thr Lys Ser Phe Gly Met Arg Gly Ser Glu 85 90 95 Gly Cys Ala Tyr Leu Ser Asp Asp Gly Ala Ala Thr Ala Arg Cys Tyr 100 105 110 Thr Glu Arg Lys Trp Ile Cys Arg Lys Arg Ile His 115 120 <210> SEQ ID NO 35 <211> LENGTH: 194 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 35 Gln Gly His Leu Val His Met Thr Val Val Ser Gly Ser Asn Val Thr 1 5 10 15 Leu Asn Ile Ser Glu Ser Leu Pro Glu Asn Tyr Lys Gln Leu Thr Trp 20 25 30 Phe Tyr Thr Phe Asp Gln Lys Ile Val Glu Trp Asp Ser Arg Lys Ser 35 40 45 Lys Tyr Phe Glu Ser Lys Phe Lys Gly Arg Val Arg Leu Asp Pro Gln 50 55 60 Ser Gly Ala Leu Tyr Ile Ser Lys Val Gln Lys Glu Asp Asn Ser Thr 65 70 75 80 Tyr Ile Met Arg Val Leu Lys Lys Thr Gly Asn Glu Gln Glu Trp Lys 85 90 95 Ile Lys Leu Gln Val Leu Asp Pro Val Pro Lys Pro Val Ile Lys Ile 100 105 110 Glu Lys Ile Glu Asp Met Asp Asp Asn Cys Tyr Leu Lys Leu Ser Cys 115 120 125 Val Ile Pro Gly Glu Ser Val Asn Tyr Thr Trp Tyr Gly Asp Lys Arg 130 135 140 Pro Phe Pro Lys Glu Leu Gln Asn Ser Val Leu Glu Thr Thr Leu Met 145 150 155 160 Pro His Asn Tyr Ser Arg Cys Tyr Thr Cys Gln Val Ser Asn Ser Val 165 170 175 Ser Ser Lys Asn Gly Thr Val Cys Leu Ser Pro Pro Cys Thr Leu Ala 180 185 190 Arg Ser <210> SEQ ID NO 36 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 36 Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val Gln Phe 1 5 10 15 Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln Lys Glu 20 25 30 Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn Cys Asp 35 40 45 Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu Val Asn 50 55 60 Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln Leu Lys 65 70 75 80 Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr Tyr Lys 85 90 95 Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu Asp Asp 100 105 110 Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn Pro Gly 115 120 125 Glu Phe Cys Val Leu 130 <210> SEQ ID NO 37 <211> LENGTH: 149 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 37 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 1 5 10 15 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 20 25 30 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 35 40 45 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 50 55 60 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 65 70 75 80 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 85 90 95 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 100 105 110 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 115 120 125 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 130 135 140 Gly Leu Leu Lys Leu 145 <210> SEQ ID NO 38 <211> LENGTH: 205 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 38 Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser Ala 1 5 10 15 Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp Pro 20 25 30 Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala 35 40 45 Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro 50 55 60 Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp 65 70 75 80 Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe 85 90 95 Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val 100 105 110 Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala 115 120 125 Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg 130 135 140 Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly 145 150 155 160 Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala 165 170 175 Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Thr 180 185 190 Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu 195 200 205 <210> SEQ ID NO 39 <211> LENGTH: 455 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 39 Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp 1 5 10 15 Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro 20 25 30 Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala 35 40 45 Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr 50 55 60 Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro 65 70 75 80 Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile 85 90 95 Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp 100 105 110 Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val 115 120 125 Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu 130 135 140 Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala 145 150 155 160 Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg 165 170 175 Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His 180 185 190 His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile 195 200 205 Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu 210 215 220 Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr 225 230 235 240 Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile 245 250 255 Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val 260 265 270 Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr 275 280 285 Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp 290 295 300 Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp 305 310 315 320 Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu 325 330 335 Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys 340 345 350 Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp 355 360 365 Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly 370 375 380 Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys 385 390 395 400 Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp 405 410 415 Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala 420 425 430 Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn 435 440 445 Ala Ser Pro Ser Thr Leu Ser 450 455 <210> SEQ ID NO 40 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu 65 70 75 <210> SEQ ID NO 41 <211> LENGTH: 157 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 41 Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn 1 5 10 15 Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp 20 25 30 Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile 35 40 45 Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile 50 55 60 Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile 65 70 75 80 Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys 85 90 95 Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys 100 105 110 Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu 115 120 125 Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu 130 135 140 Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 145 150 155 <210> SEQ ID NO 42 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 42 Gly Gly Gly Gly Ser 1 5 <210> SEQ ID NO 43 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 43 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> SEQ ID NO 44 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 44 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> SEQ ID NO 45 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 45 Asp Val Pro Ser Gly Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly 1 5 10 15 Ser <210> SEQ ID NO 46 <211> LENGTH: 356 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 46 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp 245 250 255 Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp 260 265 270 Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu 275 280 285 Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr 290 295 300 Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly 305 310 315 320 Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys 325 330 335 Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe 340 345 350 Ile Asn Thr Ser 355 <210> SEQ ID NO 47 <211> LENGTH: 379 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 47 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys Asp Val Pro Ser Gly Pro Gly Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile 225 230 235 240 Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu 245 250 255 Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr 260 265 270 Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr 275 280 285 Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln 290 295 300 Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu 305 310 315 320 Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys 325 330 335 Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly 340 345 350 Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly 355 360 365 Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu 370 375 <210> SEQ ID NO 48 <211> LENGTH: 454 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 48 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> SEQ ID NO 49 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 49 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 50 <211> LENGTH: 346 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 50 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 115 120 125 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 130 135 140 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 145 150 155 160 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 165 170 175 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 180 185 190 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 195 200 205 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 210 215 220 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 225 230 235 240 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu 245 250 255 Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 260 265 270 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 275 280 285 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 290 295 300 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 305 310 315 320 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 325 330 335 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> SEQ ID NO 51 <211> LENGTH: 500 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 51 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 115 120 125 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 130 135 140 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 145 150 155 160 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 165 170 175 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 180 185 190 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 195 200 205 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 210 215 220 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 225 230 235 240 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu 245 250 255 Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 260 265 270 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 275 280 285 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 290 295 300 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 305 310 315 320 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 325 330 335 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Met 340 345 350 Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser Glu 355 360 365 Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly Tyr 370 375 380 Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln Leu 385 390 395 400 Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr Phe 405 410 415 Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser Leu 420 425 430 Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala Ala 435 440 445 Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His Leu 450 455 460 Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn Val 465 470 475 480 Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe Gly 485 490 495 Leu Leu Lys Leu 500 <210> SEQ ID NO 52 <211> LENGTH: 697 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 52 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Asp Leu Lys Val Glu 450 455 460 Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu Asn Asp Asn Val Thr 465 470 475 480 Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu Asn Ile Thr Ser Met 485 490 495 Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe Asp Lys Glu Val Lys 500 505 510 Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala Phe Arg Pro Gly Ala 515 520 525 Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp Ala Ser Leu Arg Leu 530 535 540 Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr Arg Cys Glu Val Val 545 550 555 560 Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln Leu Glu Val Val Ala 565 570 575 Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val Gly Met Lys Glu Asn 580 585 590 Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe Tyr Pro Glu Ala Ile 595 600 605 Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe Pro His Pro Ile Glu 610 615 620 Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile Lys Asn Met Asp Gly 625 630 635 640 Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn Ser Ser Gln Glu Asp 645 650 655 Pro Gly Thr Val Tyr Gln Cys Val Val Arg His Ala Ser Leu His Thr 660 665 670 Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala Arg His Ser Leu Ser 675 680 685 Glu Thr Glu Lys Thr Asp Asn Phe Ser 690 695 <210> SEQ ID NO 53 <211> LENGTH: 459 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 53 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 450 455 <210> SEQ ID NO 54 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 54 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 55 <211> LENGTH: 475 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 55 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 35 40 45 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 50 55 60 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 65 70 75 80 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 115 120 125 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 145 150 155 160 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 165 170 175 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 210 215 220 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 225 230 235 240 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> SEQ ID NO 56 <211> LENGTH: 379 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 56 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys Asp Val Pro Ser Gly Pro Gly Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile 225 230 235 240 Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu 245 250 255 Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr 260 265 270 Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr 275 280 285 Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln 290 295 300 Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu 305 310 315 320 Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys 325 330 335 Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly 340 345 350 Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly 355 360 365 Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu 370 375 <210> SEQ ID NO 57 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 57 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 58 <211> LENGTH: 519 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 58 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 20 25 30 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 35 40 45 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 50 55 60 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 65 70 75 80 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 85 90 95 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 100 105 110 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 115 120 125 Phe Ile Asn Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 130 135 140 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 145 150 155 160 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 165 170 175 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 180 185 190 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 195 200 205 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 210 215 220 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 225 230 235 240 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 245 250 255 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys 260 265 270 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys 275 280 285 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 290 295 300 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 305 310 315 320 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 325 330 335 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 340 345 350 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly 355 360 365 Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val 370 375 380 Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu 385 390 395 400 Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly 405 410 415 Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln 420 425 430 Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile 435 440 445 Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu 450 455 460 Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser 465 470 475 480 Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe 485 490 495 Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr 500 505 510 Ser Phe Gly Leu Leu Lys Leu 515 <210> SEQ ID NO 59 <211> LENGTH: 718 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 59 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 35 40 45 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 50 55 60 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 65 70 75 80 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 115 120 125 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 145 150 155 160 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 165 170 175 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 210 215 220 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 225 230 235 240 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 465 470 475 480 Asp Leu Lys Val Glu Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu 485 490 495 Asn Asp Asn Val Thr Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu 500 505 510 Asn Ile Thr Ser Met Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe 515 520 525 Asp Lys Glu Val Lys Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala 530 535 540 Phe Arg Pro Gly Ala Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp 545 550 555 560 Ala Ser Leu Arg Leu Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr 565 570 575 Arg Cys Glu Val Val Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln 580 585 590 Leu Glu Val Val Ala Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val 595 600 605 Gly Met Lys Glu Asn Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe 610 615 620 Tyr Pro Glu Ala Ile Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe 625 630 635 640 Pro His Pro Ile Glu Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile 645 650 655 Lys Asn Met Asp Gly Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn 660 665 670 Ser Ser Gln Glu Asp Pro Gly Thr Val Tyr Gln Cys Val Val Arg His 675 680 685 Ala Ser Leu His Thr Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala 690 695 700 Arg His Ser Leu Ser Glu Thr Glu Lys Thr Asp Asn Phe Ser 705 710 715 <210> SEQ ID NO 60 <211> LENGTH: 242 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 60 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala Asp Ile Val Met Thr Gln Ser Pro Asp Ser 20 25 30 Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser 35 40 45 Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr 50 55 60 Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser 65 70 75 80 Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly 85 90 95 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala 100 105 110 Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln 115 120 125 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe 130 135 140 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 145 150 155 160 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 165 170 175 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 180 185 190 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 195 200 205 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 210 215 220 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 225 230 235 240 Glu Cys <210> SEQ ID NO 61 <211> LENGTH: 455 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 61 Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp 1 5 10 15 Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro 20 25 30 Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala 35 40 45 Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr 50 55 60 Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro 65 70 75 80 Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile 85 90 95 Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp 100 105 110 Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val 115 120 125 Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu 130 135 140 Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala 145 150 155 160 Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg 165 170 175 Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His 180 185 190 His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile 195 200 205 Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu 210 215 220 Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr 225 230 235 240 Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile 245 250 255 Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val 260 265 270 Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr 275 280 285 Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp 290 295 300 Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp 305 310 315 320 Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu 325 330 335 Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys 340 345 350 Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp 355 360 365 Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly 370 375 380 Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys 385 390 395 400 Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp 405 410 415 Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala 420 425 430 Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn 435 440 445 Ala Ser Pro Ser Thr Leu Ser 450 455 <210> SEQ ID NO 62 <211> LENGTH: 413 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 62 Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp Asn 1 5 10 15 Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp Val 20 25 30 Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly Pro 35 40 45 Asp Met Thr Ile Phe Tyr Ser Ser Gln Gly Thr Tyr Pro Tyr Tyr Thr 50 55 60 Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala Ser Leu 65 70 75 80 Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala Ile Pro 85 90 95 Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala Trp Arg 100 105 110 Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg Gln Arg 115 120 125 Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala Pro Gln 130 135 140 Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg Ala Trp 145 150 155 160 Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg Gly Leu 165 170 175 Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe Leu Ser 180 185 190 Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln Asn Asp 195 200 205 Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro Ser Ile 210 215 220 Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met Tyr Val 225 230 235 240 Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala Gly Asp 245 250 255 Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp Thr Thr 260 265 270 Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly Glu Ser 275 280 285 Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp Glu Asn 290 295 300 Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met Asp Thr 305 310 315 320 Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu Leu Cys 325 330 335 Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg Thr Ser 340 345 350 His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser Ile Gln 355 360 365 Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu Ser Leu 370 375 380 Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys Tyr Pro 385 390 395 400 Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp 405 410 <210> SEQ ID NO 63 <211> LENGTH: 551 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 63 Tyr Asn Phe Phe Pro Arg Lys Pro Lys Trp Asp Lys Asn Gln Ile Thr 1 5 10 15 Tyr Arg Ile Ile Gly Tyr Thr Pro Asp Leu Asp Pro Glu Thr Val Asp 20 25 30 Asp Ala Phe Ala Arg Ala Phe Gln Val Trp Ser Asp Val Thr Pro Leu 35 40 45 Arg Phe Ser Arg Ile His Asp Gly Glu Ala Asp Ile Met Ile Asn Phe 50 55 60 Gly Arg Trp Glu His Gly Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly 65 70 75 80 Leu Leu Ala His Ala Phe Ala Pro Gly Thr Gly Val Gly Gly Asp Ser 85 90 95 His Phe Asp Asp Asp Glu Leu Trp Thr Leu Gly Glu Gly Gln Val Val 100 105 110 Arg Val Lys Tyr Gly Asn Ala Asp Gly Glu Tyr Cys Lys Phe Pro Phe 115 120 125 Leu Phe Asn Gly Lys Glu Tyr Asn Ser Cys Thr Asp Thr Gly Arg Ser 130 135 140 Asp Gly Phe Leu Trp Cys Ser Thr Thr Tyr Asn Phe Glu Lys Asp Gly 145 150 155 160 Lys Tyr Gly Phe Cys Pro His Glu Ala Leu Phe Thr Met Gly Gly Asn 165 170 175 Ala Glu Gly Gln Pro Cys Lys Phe Pro Phe Arg Phe Gln Gly Thr Ser 180 185 190 Tyr Asp Ser Cys Thr Thr Glu Gly Arg Thr Asp Gly Tyr Arg Trp Cys 195 200 205 Gly Thr Thr Glu Asp Tyr Asp Arg Asp Lys Lys Tyr Gly Phe Cys Pro 210 215 220 Glu Thr Ala Met Ser Thr Val Gly Gly Asn Ser Glu Gly Ala Pro Cys 225 230 235 240 Val Phe Pro Phe Thr Phe Leu Gly Asn Lys Tyr Glu Ser Cys Thr Ser 245 250 255 Ala Gly Arg Ser Asp Gly Lys Met Trp Cys Ala Thr Thr Ala Asn Tyr 260 265 270 Asp Asp Asp Arg Lys Trp Gly Phe Cys Pro Asp Gln Gly Tyr Ser Leu 275 280 285 Phe Leu Val Ala Ala His Glu Phe Gly His Ala Met Gly Leu Glu His 290 295 300 Ser Gln Asp Pro Gly Ala Leu Met Ala Pro Ile Tyr Thr Tyr Thr Lys 305 310 315 320 Asn Phe Arg Leu Ser Gln Asp Asp Ile Lys Gly Ile Gln Glu Leu Tyr 325 330 335 Gly Ala Ser Pro Asp Ile Asp Leu Gly Thr Gly Pro Thr Pro Thr Leu 340 345 350 Gly Pro Val Thr Pro Glu Ile Cys Lys Gln Asp Ile Val Phe Asp Gly 355 360 365 Ile Ala Gln Ile Arg Gly Glu Ile Phe Phe Phe Lys Asp Arg Phe Ile 370 375 380 Trp Arg Thr Val Thr Pro Arg Asp Lys Pro Met Gly Pro Leu Leu Val 385 390 395 400 Ala Thr Phe Trp Pro Glu Leu Pro Glu Lys Ile Asp Ala Val Tyr Glu 405 410 415 Ala Pro Gln Glu Glu Lys Ala Val Phe Phe Ala Gly Asn Glu Tyr Trp 420 425 430 Ile Tyr Ser Ala Ser Thr Leu Glu Arg Gly Tyr Pro Lys Pro Leu Thr 435 440 445 Ser Leu Gly Leu Pro Pro Asp Val Gln Arg Val Asp Ala Ala Phe Asn 450 455 460 Trp Ser Lys Asn Lys Lys Thr Tyr Ile Phe Ala Gly Asp Lys Phe Trp 465 470 475 480 Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro Gly Phe Pro Lys Leu 485 490 495 Ile Ala Asp Ala Trp Asn Ala Ile Pro Asp Asn Leu Asp Ala Val Val 500 505 510 Asp Leu Gln Gly Gly Gly His Ser Tyr Phe Phe Lys Gly Ala Tyr Tyr 515 520 525 Leu Lys Leu Glu Asn Gln Ser Leu Lys Ser Val Lys Phe Gly Ser Ile 530 535 540 Lys Ser Asp Trp Leu Gly Cys 545 550 <210> SEQ ID NO 64 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 64 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly 20 <210> SEQ ID NO 65 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 65 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 66 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 66 Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His 1 5 10 <210> SEQ ID NO 67 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 67 Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> SEQ ID NO 68 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 68 Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr 1 5 10 15 <210> SEQ ID NO 69 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 69 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys <210> SEQ ID NO 70 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 70 Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <210> SEQ ID NO 71 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 71 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> SEQ ID NO 72 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 72 Gln Gln Tyr Phe Ser Tyr Pro Leu Thr 1 5 <210> SEQ ID NO 73 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 73 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu 65 70 75 <210> SEQ ID NO 74 <211> LENGTH: 157 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 74 Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn 1 5 10 15 Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp 20 25 30 Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile 35 40 45 Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile 50 55 60 Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile 65 70 75 80 Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys 85 90 95 Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys 100 105 110 Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu 115 120 125 Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu 130 135 140 Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 145 150 155 <210> SEQ ID NO 75 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 75 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala Ala 1 5 10 <210> SEQ ID NO 76 <211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 76 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Ala Ala Ala <210> SEQ ID NO 77 <211> LENGTH: 24 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 77 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Glu Ala Ala Ala Lys Ala Ala Ala 20 <210> SEQ ID NO 78 <211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 78 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala Ala 20 25 <210> SEQ ID NO 79 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 79 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr 225 <210> SEQ ID NO 80 <211> LENGTH: 213 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 80 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 81 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 81 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys 225 <210> SEQ ID NO 82 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 83 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 83 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 84 <211> LENGTH: 60 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 84 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 <210> SEQ ID NO 85 <211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 85 caggtccagc tgcaggaaag cggccctgga ctggtcaagc ctagccagac cctgagcctg 60 acctgtaccg tgtccggcgg cagcatcaac aacaacaatt actactggac atggatccgg 120 cagcaccccg gcaagggcct ggaatggatc ggctacatct actacagcgg ctccaccttc 180 tacaacccca gcctgaagtc cagagtgacc atcagcgtgg acaccagcaa gacccagttc 240 tccctgaagc tgagcagcgt gacagccgcc gacacagccg tgtactactg cgccagagaa 300 gataccatga ccggcctgga tgtgtggggc cagggcacca cagtgacagt gtctagc 357 <210> SEQ ID NO 86 <211> LENGTH: 318 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 86 gatatccaga tgacacagag ccctagcagc ctgagcgcca gcgtgggcga tagagtgacc 60 atcacctgtc gggccagcca gagcatcaac aactacctga actggtatca gcagaagccc 120 ggcaaggccc ctaccctgct gatctatgcc gcttctagcc tgcagagcgg cgtgcccagc 180 agattttctg gcagcagatc cggcaccgac ttcaccctga caatcagcag cctgcagccc 240 gaggacttcg ccgcctactt ctgccagcag acctacagca atcccacctt cggccagggc 300 accaaggtgg aagtgaag 318 <210> SEQ ID NO 87 <211> LENGTH: 399 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 87 gcccctacca gcagcagcac caagaaaacc cagctccagc tcgagcacct cctgctggac 60 ctgcagatga tcctgaacgg catcaacaac tacaagaacc ccaagctgac ccggatgctg 120 accttcaagt tctacatgcc caagaaggcc accgagctga agcacctcca gtgcctggaa 180 gaggaactga agcccctgga agaagtgctg aacctggccc agagcaagaa cttccacctg 240 aggcccaggg acctgatcag caacatcaac gtgatcgtgc tggaactgaa aggcagcgag 300 acaaccttca tgtgcgagta cgccgacgag acagccacca tcgtggaatt tctgaaccgg 360 tggatcacct tctgccagag catcatcagc accctgaca 399 <210> SEQ ID NO 88 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 88 ggcggcggag gatctggcgg aggcggcagc 30 <210> SEQ ID NO 89 <211> LENGTH: 687 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 89 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 60 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 360 ggccagcccc gcgaacctca ggtgtacaca ctgcctccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg cctggtcaag ggcttctacc cctccgatat cgccgtggaa 480 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 540 gacggcagct tcttcctgta ctccaaactg accgtggaca agagccggtg gcagcagggc 600 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctgagcctga gccccggcaa gtaatga 687 <210> SEQ ID NO 90 <211> LENGTH: 687 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 60 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 360 ggccagccta gagagcctca ggtctgcacc ctgcctccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg cgccgtgaag ggcttctacc cctccgatat cgccgtggaa 480 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 540 gacggcagct tcttcctggt gtccaaactg accgtggaca agagccggtg gcagcagggc 600 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctgagcctga gccccggcaa gtaatga 687 <210> SEQ ID NO 91 <211> LENGTH: 309 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 91 gccagcacca agggccctag cgtgttccct ctggccccta gctctaagag cacatctggc 60 ggaacagccg ccctgggctg cctggtcaag gattactttc ctgagcccgt gaccgtgtcc 120 tggaactctg gtgctctgac cagcggcgtg cacacctttc cagctgtgct gcagagcagc 180 ggcctgtaca gcctgtctag cgtggtcaca gtgcctagca gcagcctggg cacacagacc 240 tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagcg ggtggaaccc 300 aagagctgc 309 <210> SEQ ID NO 92 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 92 agaacagtgg ccgctcccag cgtgttcatc ttcccaccca gcgacgagca gctgaagtct 60 ggcacagcca gcgtcgtgtg cctgctgaac aacttctacc ccagagaagc caaggtgcag 120 tggaaggtgg acaacgccct gcagtccggc aacagccagg aaagcgtcac cgagcaggac 180 agcaaggact ccacctacag cctgtccagc accctgaccc tgagcaaggc cgactacgag 240 aagcacaaag tgtacgcctg cgaagtgacc caccagggcc tgagcagccc cgtgaccaag 300 agcttcaata gaggcgagtg ctaatga 327 <210> SEQ ID NO 93 <211> LENGTH: 324 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 93 ggccagccca aggccaaccc caccgtgacc ctgttccctc catcctccga ggaactgcag 60 gctaacaagg ccaccctcgt gtgcctgatc tccgacttct accctggcgc cgtgaccgtg 120 gcttggaagg ctgatggctc tcctgtgaag gccggcgtgg aaaccaccaa gccctccaag 180 cagtccaaca acaaatacgc cgcctccagc tacctgtccc tgacccctga gcagtggaag 240 tcccaccggt cctacagctg ccaggtcaca catgagggct ccaccgtgga aaagaccgtg 300 gcccctaccg agtgctccta atga 324 <210> SEQ ID NO 94 <211> LENGTH: 360 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 94 gaggtgcagc tgctggaatc tggcggagga ctggtgcagc ctggcggctc tctgagactg 60 tcttgtgccg cctccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 120 cctggcaagg gcctggaatg ggtgtcctct atctacccct ccggcggcat caccttttac 180 gccgacaccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc tagaatcaag 300 ctgggcaccg tgaccaccgt ggactattgg ggccagggca ccctggtcac cgtgtcctct 360 <210> SEQ ID NO 95 <211> LENGTH: 330 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 95 cagtctgctc tgacccagcc tgcctctgtg tctggctccc ctggccagtc catcaccatc 60 agctgtaccg gcacctcctc cgacgtgggc ggctacaact acgtgtcctg gtatcagcag 120 catcccggca aggcccctaa gctgatgatc tacgacgtgt ccaaccggcc ctccggcgtg 180 tccaatcggt tctctggctc caagtccggc aacaccgcct ccctgacaat cagcggactg 240 caggccgagg acgaggccga ctactactgc tcctcctaca cctccagctc tacccgggtg 300 ttcggcaccg gcaccaaagt gacagtgctg 330 <210> SEQ ID NO 96 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 96 ggcggcggag gatctggcgg aggtggaagc ggaggcggtg gatct 45 <210> SEQ ID NO 97 <211> LENGTH: 360 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 97 caggttcagt tgcagcagtc cggacctgag ctggttaagc ctggcgcttc cgtgaagatg 60 tcctgcaagg cttccggcta caccttcacc gactacgtga tcaactgggg caagcagaga 120 tctggccagg gactcgagtg gatcggcgag atctatcctg gctccggcac caattactac 180 aacgagaagt tcaaggctaa ggctaccctg accgccgaca agtcctccaa tatcgcctac 240 atgcagctgt ccagcctgac ctctgaggac tccgctgtgt acttctgcgc tcggagaggc 300 agatacggcc tgtatgccat ggattactgg ggacagggaa ccagtgtgac agtgtcaagt 360 <210> SEQ ID NO 98 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 98 gatattcaga tgacccagac cacctccagc ctgtccgctt ctctgggcga cagagtgaca 60 atcagctgca gagccagcca ggacatcagc aactacctga actggtatca acagaaaccc 120 gacggcaccg tgaagctgct gatctactac acctctcggc tgcactctgg cgtgccctct 180 agattttctg gcagcggaag cggcaccgac tattccctga ccatcaacaa cctggaacaa 240 gaggatatcg ctacctactt ctgccagcaa ggcaacaccc ggccttggac atttggcggc 300 ggaacaaagc tggaaatcaa gtgatga 327 <210> SEQ ID NO 99 <211> LENGTH: 60 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 99 ggtggcggag gaagcggcgg aggcggctct ggtggtggtg gttctggtgg cggtggctcc 60 <210> SEQ ID NO 100 <211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 100 caggtccagc tgcaggaatc tggccctggc ctggtcaagc cctccgagac actgtctctg 60 acctgcaccg tgtccggcgg ctctgtgtcc tccggctcct actactggtc ctggatccgg 120 cagcctccag gcaagggact ggaatggatc ggctacatct actactccgg cagcaccaac 180 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 240 tccctgaagc tgtcctccgt gaccgccgct gacaccgccg tgtactactg tgccagagag 300 ggcaagaacg gcgccttcga tatctggggc cagggcacca tggtcaccgt gtctagc 357 <210> SEQ ID NO 101 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 101 gacatccaga tgacccagag cccttccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacctgtc gggcctccca gtccatctcc tcctacctga actggtatca gcagaagccc 120 ggcaaggccc ctaagctgct gatctacgcc gcctccagtc tgcagtctgg cgtgccatct 180 ggcttctccg gctctggctc tggcaccgac ttcaccctga ccatctccag cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag tcctactcca cccctctgac cttcggcgga 300 ggcaccaagg tggaaatcaa g 321 <210> SEQ ID NO 102 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 102 ggcggcggag gctcc 15 <210> SEQ ID NO 103 <400> SEQUENCE: 103 000 <210> SEQ ID NO 104 <211> LENGTH: 456 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104 gactgtgaca tcgaaggcaa ggacggcaag cagtacgaga gcgtgctgat ggtgtccatc 60 gaccagctgc tggacagcat gaaggaaatc ggctccaact gcctgaacaa cgagttcaac 120 ttcttcaagc ggcacatctg cgacgccaac aaagaaggca tgttcctgtt cagagccgcc 180 agaaagctgc ggcagttcct gaagatgaac tccaccggcg acttcgacct gcatctgctg 240 aaagtgtctg agggcaccac catcctgctg aactgtaccg gccaagtgaa gggcagaaag 300 cctgctgctc tgggcgaagc ccagcctacc aagtctctgg aagagaacaa gagcctgaaa 360 gagcagaaga agctgaacga cctctgcttc ctgaagcggc tgctgcaaga gatcaagacc 420 tgctggaaca agattctgat ggggaccaaa gagcac 456 <210> SEQ ID NO 105 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 105 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 60 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 120 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 180 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 300 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 360 tcctct 366 <210> SEQ ID NO 106 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 106 gacatccaga tgacccagtc tccatcctct ctgtctgcca gcctgggcga cagagtgacc 60 atcacctgta gagcctctca gggcatctcc tcctacctgg cctggtatca gcagaagcct 120 ggcaaggctc ccaagctgct gatctacgcc aagagcacac tgcagtctgg cgtgccctct 180 agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 240 gaggactccg ccacctacta ctgtcagcag tactggacct ttccactgac cttcggcgga 300 ggcaccaagg tggaaatcaa g 321 <210> SEQ ID NO 107 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 107 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 60 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 120 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 180 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 240 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 300 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 360 tctagt 366 <210> SEQ ID NO 108 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 108 tcttacgagc tgacccagga tccagccgtg tctgttgctc tgggccagac agtgcggatt 60 acctgccagg gcgactccct gagatcctac tacgcctcct ggtatcagca gaagccaggc 120 caggctcctg tgctggtcat ctacggcaag aacaaccggc ctagcggcat ccctgacaga 180 ttctccggct ctacctccgg caactctgcc agcctgacaa ttactggcgc ccaggctgag 240 gacgaggccg actactactg caactccaga gacagccctg gcaatcagtg ggttttcggc 300 ggaggcacca aagtgacagt tcttggt 327 <210> SEQ ID NO 109 <211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 109 caagttcagt tggttcaaag cggtggcggc gtggtgcagc ctggaagatc tctcagactg 60 tcctgcaagg cctccggcta caccttcacc agatacacca tgcattgggt tcgacaagca 120 ccaggcaagg gcctcgagtg gatcggctac atcaaccctt ccagaggcta caccaactac 180 aaccagaaag tgaaggaccg gttcaccatc agcagagaca acagcaagaa taccgccttt 240 ctgcagatgg actccctgcg gcctgaagat accggcgtgt acttttgcgc ccggtactac 300 gacgaccact actccctgga ttactgggga cagggaacac ccgtgacagt gtctagc 357 <210> SEQ ID NO 110 <211> LENGTH: 324 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 110 gatattcaga tgacccagtc tccttccagc ctgtccgctt ctgtgggcga cagagtgact 60 attacctgct ccgcctcttc ctccgtgtcc tacatgaact ggtatcaaca aacacccggc 120 aaggccccta agagatggat ctacgacacc agcaagctgg cctctggcgt gccctctaga 180 ttttctggct ctggctccgg caccgactat acctttacaa tctccagcct gcagcctgag 240 gatatcgcca cctactactg tcagcagtgg tctagcaacc ccttcacctt tggacagggc 300 accaagctgc agatcacctg atga 324 <210> SEQ ID NO 111 <211> LENGTH: 399 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 111 gctcctacct cctccagcac caagaaaacc cagctgcagt tggagcatct gctgctggac 60 ctccagatga tcctgaatgg catcaacaat tacaagaacc ccaagctcac ccggatgctg 120 accgccaagt ttgccatgcc taagaaggcc accgagctga aacatctgca gtgcctggaa 180 gaggaactga agcccctgga agaagtgctg aatctggccc agtccaagaa cttccacctg 240 aggcctcggg acctgatctc caacatcaac gtgatcgtgc tcgagctgaa gggctccgag 300 acaaccttca tgtgcgagta cgccgacgag acagctacca tcgtggaatt tctgaaccgg 360 tggatcacct tctgtcagtc catcatcagc accctgacc 399 <210> SEQ ID NO 112 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 112 gaagtgcagc tccaagaatc tggacccggg ctcgtgaagc ccagccagtc tctgagtctg 60 acctgtacag tgaccggcta ctccatcacc tccgactacg cttggaactg gatccggcag 120 ttccccggca acaagttgga gtggatgggc tatatcacct acagcggcag cacctcttac 180 aacccttctc tggaatcccg gatcagcatc acccgggaca cctctaccaa tcagttcttt 240 ctgcagctga acagcgtgac caccgaggac accgccacct actattgtgc tagaggcggc 300 tactacggct cctcctgggg agtgtttgct tactggggac agggaaccct cgtgactgtt 360 tctgct 366 <210> SEQ ID NO 113 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 113 gacatccaga tgacccagtc tccagccagc ctgtctgctt ctgtgggcga gacagtgacc 60 attacctgcc gggtgtccga gaacatctac tcctacctgg cctggtatca acagaaacag 120 ggcaagtccc ctcagctgct ggtgtacaat gctaagaccc tggctgaggg cgtgccctct 180 agattttctg gctctggcag cggcacccag tttagcctga agatcaactc cctgcagcct 240 gaggacttcg gcagctacta ctgccagcac cactatggca ccccttggac atttggcgga 300 ggcaccaagc tggaaatcaa g 321 <210> SEQ ID NO 114 <211> LENGTH: 351 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 114 caggttcagt tgcagcagtc tgccgtggaa ctggctagac ctggcgcttc cgtgaagatg 60 tcctgcaagg cctccggcta caccttcacc agcttcacca tgcactgggt caagcagagg 120 cctggacaag gcttggagtg gattggatat atcaacccta gctctggcta caccgagtac 180 aaccagaagt tcaaggacaa gaccactctg accgccgaca agtcctccag caccgcttac 240 atgcagctcg actccctgac ctctgacgac tctgctgtgt actattgcgt gcggggctcc 300 tccagaggct tcgattattg gggacaaggc acactcgtga cagtgtcagc t 351 <210> SEQ ID NO 115 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 115 gatatccaga tgatccagtc tcctgccagc ctgtccgtgt ctgtgggaga gactgtgacc 60 atcacctgtc gggcctccga gaacatctac tccaacctgg cctggttcca gcagaagcag 120 ggaaagtctc ctcagctgct ggtgtacgcc gccaccaatt tggctgatgg cgtgccctct 180 cggttctccg gatctggatc tggcacacag tattccctga agatcaactc cctgcagtcc 240 gaggacttcg gcatctacta ttgccagcac ttctggggca cccctagaac ctttggcggc 300 ggaacaaagc tggaaatcaa g 321 <210> SEQ ID NO 116 <211> LENGTH: 1176 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 116 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 gcccctacca gcagcagcac caagaaaacc cagctccagc tcgagcacct cctgctggac 120 ctgcagatga tcctgaacgg catcaacaac tacaagaacc ccaagctgac ccggatgctg 180 accttcaagt tctacatgcc caagaaggcc accgagctga agcacctcca gtgcctggaa 240 gaggaactga agcccctgga agaagtgctg aacctggccc agagcaagaa cttccacctg 300 aggcccaggg acctgatcag caacatcaac gtgatcgtgc tggaactgaa aggcagcgag 360 acaaccttca tgtgcgagta cgccgacgag acagccacca tcgtggaatt tctgaaccgg 420 tggatcacct tctgccagag catcatcagc accctgacag gcggcggagg atctggcgga 480 ggcggcagcg ataagaccca cacctgtcct ccatgtcccg cccctgaact gctgggcgga 540 cctagcgtgt tcctgttccc tccaaagccc aaggacaccc tgatgatcag ccggacccct 600 gaagtgacct gcgtggtggt ggatgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 660 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 720 agcacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaatggcaaa 780 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ctatcgagaa aaccatcagc 840 aaggccaagg gccagcctag agagcctcag gtctgcaccc tgcctcccag ccgggaagag 900 atgaccaaga accaggtgtc cctgagctgc gccgtgaagg gcttctaccc ctccgatatc 960 gccgtggaat gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcccgtg 1020 ctggacagcg acggcagctt cttcctggtg tccaaactga ccgtggacaa gagccggtgg 1080 cagcagggca atgtgttcag ctgtagcgtg atgcacgagg ccctgcacaa ccactacacc 1140 cagaagtctc tgagcctgag ccccggcaag taatga 1176 <210> SEQ ID NO 117 <211> LENGTH: 1452 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 117 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 caggtccagc tgcaggaaag cggccctgga ctggtcaagc ctagccagac cctgagcctg 120 acctgtaccg tgtccggcgg cagcatcaac aacaacaatt actactggac atggatccgg 180 cagcaccccg gcaagggcct ggaatggatc ggctacatct actacagcgg ctccaccttc 240 tacaacccca gcctgaagtc cagagtgacc atcagcgtgg acaccagcaa gacccagttc 300 tccctgaagc tgagcagcgt gacagccgcc gacacagccg tgtactactg cgccagagaa 360 gataccatga ccggcctgga tgtgtggggc cagggcacca cagtgacagt gtctagcgcc 420 agcaccaagg gccctagcgt gttccctctg gcccctagct ctaagagcac atctggcgga 480 acagccgccc tgggctgcct ggtcaaggat tactttcctg agcccgtgac cgtgtcctgg 540 aactctggtg ctctgaccag cggcgtgcac acctttccag ctgtgctgca gagcagcggc 600 ctgtacagcc tgtctagcgt ggtcacagtg cctagcagca gcctgggcac acagacctac 660 atctgcaacg tgaaccacaa gcccagcaac accaaggtgg acaagcgggt ggaacccaag 720 agctgcgaca agacccacac ctgtcctccc tgtcctgccc ctgaactgct gggcggacct 780 tccgtgttcc tgttccctcc aaagcccaag gacaccctga tgatcagccg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtcccac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gtacaacagc 960 acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg ccagccccta tcgagaaaac catcagcaag 1080 gccaagggcc agccccgcga acctcaggtg tacacactgc ctccctgccg ggaagagatg 1140 accaagaacc aggtgtccct gtggtgtctc gtgaagggct tctacccctc cgatatcgcc 1200 gtggaatggg agagcaacgg ccagcccgag aacaactaca agaccacccc tcccgtgctg 1260 gacagcgacg gcagcttctt cctgtactcc aaactgaccg tggacaagag ccggtggcag 1320 cagggcaatg tgttcagctg tagcgtgatg cacgaggccc tgcacaacca ctacacccag 1380 aagtccctgt ccctgagccc tggaaaaggt ggcggaggaa gcggaggcgg aggttctggc 1440 ggcggaggat ct 1452 <210> SEQ ID NO 118 <211> LENGTH: 705 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 118 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg cagcaccggc 60 gatatccaga tgacacagag ccctagcagc ctgagcgcca gcgtgggcga tagagtgacc 120 atcacctgtc gggccagcca gagcatcaac aactacctga actggtatca gcagaagccc 180 ggcaaggccc ctaccctgct gatctatgcc gcttctagcc tgcagagcgg cgtgcccagc 240 agattttctg gcagcagatc cggcaccgac ttcaccctga caatcagcag cctgcagccc 300 gaggacttcg ccgcctactt ctgccagcag acctacagca atcccacctt cggccagggc 360 accaaggtgg aagtgaagag aacagtggcc gctcccagcg tgttcatctt cccacccagc 420 gacgagcagc tgaagtctgg cacagccagc gtcgtgtgcc tgctgaacaa cttctacccc 480 agagaagcca aggtgcagtg gaaggtggac aacgccctgc agtccggcaa cagccaggaa 540 agcgtcaccg agcaggacag caaggactcc acctacagcc tgtccagcac cctgaccctg 600 agcaaggccg actacgagaa gcacaaagtg tacgcctgcg aagtgaccca ccagggcctg 660 agcagccccg tgaccaagag cttcaataga ggcgagtgct aatga 705 <210> SEQ ID NO 119 <211> LENGTH: 1176 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 119 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 gcccctacca gcagcagcac caagaaaacc cagctccagc tcgagcacct cctgctggac 120 ctgcagatga tcctgaacgg catcaacaac tacaagaacc ccaagctgac ccggatgctg 180 accttcaagt tctacatgcc caagaaggcc accgagctga agcacctcca gtgcctggaa 240 gaggaactga agcccctgga agaagtgctg aacctggccc agagcaagaa cttccacctg 300 aggcccaggg acctgatcag caacatcaac gtgatcgtgc tggaactgaa aggcagcgag 360 acaaccttca tgtgcgagta cgccgacgag acagccacca tcgtggaatt tctgaaccgg 420 tggatcacct tctgccagag catcatcagc accctgacag gcggcggagg atctggcgga 480 ggcggcagcg ataagaccca cacctgtcct ccatgtcccg cccctgaact gctgggcgga 540 cctagcgtgt tcctgttccc tccaaagccc aaggacaccc tgatgatcag ccggacccct 600 gaagtgacct gcgtggtggt ggatgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 660 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 720 agcacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaatggcaaa 780 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ctatcgagaa aaccatcagc 840 aaggccaagg gccagcctag agagcctcag gtctgcaccc tgcctcccag ccgggaagag 900 atgaccaaga accaggtgtc cctgagctgc gccgtgaagg gcttctaccc ctccgatatc 960 gccgtggaat gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcccgtg 1020 ctggacagcg acggcagctt cttcctggtg tccaaactga ccgtggacaa gagccggtgg 1080 cagcagggca atgtgttcag ctgtagcgtg atgcacgagg ccctgcacaa ccactacacc 1140 cagaagtctc tgagcctgag ccccggcaag taatga 1176 <210> SEQ ID NO 120 <400> SEQUENCE: 120 000 <210> SEQ ID NO 121 <211> LENGTH: 714 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 121 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg ctctaccggc 60 cagtctgctc tgacccagcc tgcctctgtg tctggctccc ctggccagtc catcaccatc 120 agctgtaccg gcacctcctc cgacgtgggc ggctacaact acgtgtcctg gtatcagcag 180 catcccggca aggcccctaa gctgatgatc tacgacgtgt ccaaccggcc ctccggcgtg 240 tccaatcggt tctctggctc caagtccggc aacaccgcct ccctgacaat cagcggactg 300 caggccgagg acgaggccga ctactactgc tcctcctaca cctccagctc tacccgggtg 360 ttcggcaccg gcaccaaagt gacagtgctg ggccagccca aggccaaccc caccgtgacc 420 ctgttccctc catcctccga ggaactgcag gctaacaagg ccaccctcgt gtgcctgatc 480 tccgacttct accctggcgc cgtgaccgtg gcttggaagg ctgatggctc tcctgtgaag 540 gccggcgtgg aaaccaccaa gccctccaag cagtccaaca acaaatacgc cgcctccagc 600 tacctgtccc tgacccctga gcagtggaag tcccaccggt cctacagctg ccaggtcaca 660 catgagggct ccaccgtgga aaagaccgtg gcccctaccg agtgctccta atga 714 <210> SEQ ID NO 122 <211> LENGTH: 1413 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 122 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg ctctacagga 60 caggtccagc tgcaggaatc tggccctggc ctggtcaagc cctccgagac actgtctctg 120 acctgcaccg tgtccggcgg ctctgtgtcc tccggctcct actactggtc ctggatccgg 180 cagcctccag gcaagggact ggaatggatc ggctacatct actactccgg cagcaccaac 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 300 tccctgaagc tgtcctccgt gaccgccgct gacaccgccg tgtactactg tgccagagag 360 ggcaagaacg gcgccttcga tatctggggc cagggcacca tggtcaccgt gtctagcgct 420 tccaccaagg gcccctccgt gttccctctg gccccttcca gcaagtccac ctctggcgga 480 accgctgctc tgggctgcct cgtgaaggac tacttccccg agcctgtgac cgtgtcctgg 540 aactctggcg ccctgacatc cggcgtgcac acctttccag ccgtgctgca gtccagcggc 600 ctgtactctc tgtccagcgt cgtgaccgtg ccttccagct ctctgggcac acagacctac 660 atctgcaacg tgaaccacaa gccttccaac accaaggtgg acaagcgggt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctccc tgtcctgccc ctgaactgct gggcggaccc 780 agcgtgttcc tgttccctcc aaagcccaag gacaccctga tgatctcccg gacccctgaa 840 gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctaccggg tggtgtccgt gctgacagtg ctgcaccagg actggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg ccagccccta tcgaaaagac catcagcaag 1080 gctaagggcc agccccgcga gccccaggtt tacacactgc ctccctgccg ggaagagatg 1140 accaagaatc aggtgtccct gtggtgtctg gtcaagggct tctacccctc cgatatcgcc 1200 gtggaatggg agtccaacgg ccagcccgag aacaactaca agaccacccc tcccgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgaccg tggacaagtc ccggtggcag 1320 cagggcaacg tgttctcctg ctctgtgatg cacgaggccc tgcacaacca ctacacccag 1380 aagtccctgt ccctgagccc cggcaagtaa tga 1413 <210> SEQ ID NO 123 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 123 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg ctctaccggc 60 gacatccaga tgacccagag cccttccagc ctgtccgcct ctgtgggcga cagagtgacc 120 atcacctgtc gggcctccca gtccatctcc tcctacctga actggtatca gcagaagccc 180 ggcaaggccc ctaagctgct gatctacgcc gcctccagtc tgcagtctgg cgtgccatct 240 ggcttctccg gctctggctc tggcaccgac ttcaccctga ccatctccag cctgcagccc 300 gaggacttcg ccacctacta ctgccagcag tcctactcca cccctctgac cttcggcgga 360 ggcaccaagg tggaaatcaa gcggaccgtg gccgctccct ccgtgttcat cttcccacct 420 tccgacgagc agctgaagtc cggcaccgct tctgtcgtgt gcctgctgaa caacttctac 480 cctcgggaag ccaaggtgca gtggaaggtg gacaatgccc tgcagtccgg caactcccag 540 gaatccgtca ccgagcagga ctccaaggac agcacctact ccctgtcctc taccctgacc 600 ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 660 ctgagcagcc ccgtgaccaa gtccttcaac agaggcgagt gctaatga 708 <210> SEQ ID NO 124 <211> LENGTH: 747 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 124 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg cagcaccggc 60 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 120 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 180 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 240 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 300 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 360 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 420 ggccagcccc gcgaacctca ggtgtacaca ctgcctccct gccgggaaga gatgaccaag 480 aaccaggtgt ccctgtggtg cctggtcaag ggcttctacc cctccgatat cgccgtggaa 540 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 600 gacggcagct tcttcctgta ctccaaactg accgtggaca agagccggtg gcagcagggc 660 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 720 ctgagcctga gccccggcaa gtaatga 747 <210> SEQ ID NO 125 <211> LENGTH: 747 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 125 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg cagcaccggc 60 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 120 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 180 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 240 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 300 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 360 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 420 ggccagccta gagagcctca ggtctgcacc ctgcctccca gccgggaaga gatgaccaag 480 aaccaggtgt ccctgtcctg cgccgtgaag ggcttctacc cctccgatat cgccgtggaa 540 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 600 gacggcagct tcttcctggt gtccaaactg accgtggaca agagccggtg gcagcagggc 660 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 720 ctgagcctga gccccggcaa gtaatga 747 <210> SEQ ID NO 126 <211> LENGTH: 1422 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 126 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 120 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 180 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 240 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 360 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 420 tcctctgctt ctaccaaggg acccagcgtg ttccctctgg ctccttccag caagtctacc 480 tctggcggaa cagctgctct gggctgcctg gtcaaggact actttcctga gcctgtgaca 540 gtgtcctgga actctggcgc tctgacatcc ggcgtgcaca cctttccagc tgtgctgcaa 600 tccagcggcc tgtactctct gtcctccgtc gtgacagtgc cttccagctc tctgggaacc 660 cagacctaca tctgcaatgt gaaccacaag ccttccaaca ccaaggtgga caagagagtg 720 gaacccaagt cctgcgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 780 ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatctctcgg 840 acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggatcccga agtgaagttc 900 aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 960 tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 1020 ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 1080 atctccaagg ccaagggcca gcctcgggaa cctcaagtct gtaccctgcc tcctagccgg 1140 gaagagatga ccaagaacca ggtgtccctg tcctgtgccg tgaagggctt ctacccttcc 1200 gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1260 cctgtgctgg actccgacgg ctcattcttc ctggtgtcca agctgacagt ggacaagtcc 1320 agatggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaatcac 1380 tacacccaga agtccctgtc tctgagcccc ggcaagtgat ga 1422 <210> SEQ ID NO 127 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 127 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 gacatccaga tgacccagtc tccatcctct ctgtctgcca gcctgggcga cagagtgacc 120 atcacctgta gagcctctca gggcatctcc tcctacctgg cctggtatca gcagaagcct 180 ggcaaggctc ccaagctgct gatctacgcc aagagcacac tgcagtctgg cgtgccctct 240 agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 300 gaggactccg ccacctacta ctgtcagcag tactggacct ttccactgac cttcggcgga 360 ggcaccaagg tggaaatcaa gagaaccgtg gccgctcctt ccgtgttcat cttcccacct 420 tccgacgagc agctgaagtc cggcacagct tctgtcgtgt gcctgctgaa caacttctac 480 cctcgggaag ccaaagtgca gtggaaggtg gacaacgctc tgcagtccgg caactcccaa 540 gagtctgtga ccgagcagga ctccaaggac agcacctaca gcctgtcctc cacactgacc 600 ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccatcagggc 660 ctgtctagcc ctgtgaccaa gtctttcaac cggggcgagt gctgatga 708 <210> SEQ ID NO 128 <211> LENGTH: 1866 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 128 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 120 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 180 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 240 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 360 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 420 tcctctgctt ctaccaaggg acccagcgtg ttccctctgg ctccttccag caagtctacc 480 tctggcggaa cagctgctct gggctgcctg gtcaaggact actttcctga gcctgtgaca 540 gtgtcctgga actctggcgc tctgacatcc ggcgtgcaca cctttccagc tgtgctgcaa 600 tccagcggcc tgtactctct gtcctccgtc gtgacagtgc cttccagctc tctgggaacc 660 cagacctaca tctgcaatgt gaaccacaag ccttccaaca ccaaggtgga caagagagtg 720 gaacccaagt cctgcgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 780 ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatctctcgg 840 acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggatcccga agtgaagttc 900 aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 960 tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 1020 ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 1080 atctccaagg ccaagggcca gcctcgggaa cctcaagtct gtaccctgcc tcctagccgg 1140 gaagagatga ccaagaacca ggtgtccctg tcctgtgccg tgaagggctt ctacccttcc 1200 gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1260 cctgtgctgg actccgacgg ctcattcttc ctggtgtcca agctgacagt ggacaagtcc 1320 agatggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaatcac 1380 tacacccaga agtccctgtc tctgagccct ggcaaaggcg gaggcggatc tggtggtggc 1440 ggttctggcg gcggtggatc tgctcctaca tcctccagca ccaagaaaac ccagctgcag 1500 ttggagcatc tgctgctgga cctccagatg atcctgaatg gcatcaacaa ttacaagaac 1560 cccaagctca cccggatgct gaccttcaag ttctacatgc ccaagaaggc caccgagctg 1620 aaacatctgc agtgcctgga agaggaactg aagcctctgg aagaagtgct gaatctggcc 1680 cagtccaaga acttccacct gaggcctcgg gacctgatct ccaacatcaa cgtgatcgtg 1740 ctcgagctga agggctccga gactaccttc atgtgcgagt acgccgacga gacagctacc 1800 atcgtggaat ttctgaaccg gtggatcacc ttctgccagt ccatcatcag caccctgacc 1860 tgatga 1866 <210> SEQ ID NO 129 <211> LENGTH: 1923 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 129 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 120 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 180 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 240 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 360 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 420 tcctctgctt ctaccaaggg acccagcgtg ttccctctgg ctccttccag caagtctacc 480 tctggcggaa cagctgctct gggctgcctg gtcaaggact actttcctga gcctgtgaca 540 gtgtcctgga actctggcgc tctgacatcc ggcgtgcaca cctttccagc tgtgctgcaa 600 tccagcggcc tgtactctct gtcctccgtc gtgacagtgc cttccagctc tctgggaacc 660 cagacctaca tctgcaatgt gaaccacaag ccttccaaca ccaaggtgga caagagagtg 720 gaacccaagt cctgcgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 780 ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatctctcgg 840 acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggatcccga agtgaagttc 900 aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 960 tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 1020 ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 1080 atctccaagg ccaagggcca gcctcgggaa cctcaagtct gtaccctgcc tcctagccgg 1140 gaagagatga ccaagaacca ggtgtccctg tcctgtgccg tgaagggctt ctacccttcc 1200 gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1260 cctgtgctgg actccgacgg ctcattcttc ctggtgtcca agctgacagt ggacaagtcc 1320 agatggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaatcac 1380 tacacccaga agtccctgtc tctgagccct ggcaaaggcg gaggcggatc tggtggtggc 1440 ggttctggcg gcggtggatc tgactgtgat atcgaaggca aggacggcaa gcagtacgag 1500 tccgtcctga tggtgtccat cgaccagctg ctggacagca tgaaggaaat cggctccaac 1560 tgcctgaaca acgagttcaa cttcttcaag cggcacatct gcgacgccaa caaagaaggc 1620 atgtttctgt tccgggctgc cagaaagctg cggcagttcc tgaagatgaa cagcaccggc 1680 gacttcgacc tgcacctgtt gaaagtgtct gagggcacca ccatcctgct gaactgtacc 1740 ggccaagtga agggaagaaa gcctgccgct ctgggcgaag cccagcctac aaagtctctg 1800 gaagagaaca agtccctgaa agagcagaag aagctgaacg acctctgttt cctgaagcgg 1860 ctgctgcaag agatcaagac ctgctggaac aagatcctga tgggcaccaa agagcactga 1920 tag 1923 <210> SEQ ID NO 130 <211> LENGTH: 1539 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 130 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 120 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 180 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 240 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 300 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 360 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 420 tctagtgctt ctactggtgg tggcggatct ggcggcggag gaagcggagg cggaggtagt 480 ggtggcggtg gatcttctta cgagctgacc caggatccag ccgtgtctgt tgctctgggc 540 cagacagtgc ggattacctg ccagggcgac tccctgagat cctactacgc ctcctggtat 600 cagcagaagc caggccaggc tcctgtgctg gtcatctacg gcaagaacaa ccggcctagc 660 ggcatccctg acagattctc cggctctacc tccggcaact ctgccagcct gacaattact 720 ggcgcccagg ctgaggacga ggccgactac tactgcaact ccagagacag ccctggcaat 780 cagtgggttt tcggcggagg caccaaagtg acagttcttg gtggcggagg tggaagtggc 840 ggaggcggtt ctgataagac ccacacctgt ccaccttgtc ctgctccaga actgctcggc 900 ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat ctctcggacc 960 cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg atcccgaagt gaagttcaat 1020 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcctagaga ggaacagtac 1080 aactccacct atagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 1140 aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga aaagaccatc 1200 tccaaggcca agggccagcc tagggaaccc caggtttaca ccctgcctcc atgccgggaa 1260 gagatgacca agaaccaggt gtccctgtgg tgcctggtca agggcttcta cccttccgat 1320 atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac cacacctcca 1380 gtgctggact ccgacggctc attcttcctg tactccaagc tgacagtgga caagtccaga 1440 tggcagcagg gcaacgtgtt ctcctgctcc gtgatgcacg aggccctgca caatcactac 1500 acccagaagt ccctgtctct gagccccggc aagtgatga 1539 <210> SEQ ID NO 131 <211> LENGTH: 2325 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 131 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 120 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 180 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 240 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 300 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 360 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 420 tctagtgctt ctactggtgg tggcggatct ggcggcggag gaagcggagg cggaggtagt 480 ggtggcggtg gatcttctta cgagctgacc caggatccag ccgtgtctgt tgctctgggc 540 cagacagtgc ggattacctg ccagggcgac tccctgagat cctactacgc ctcctggtat 600 cagcagaagc caggccaggc tcctgtgctg gtcatctacg gcaagaacaa ccggcctagc 660 ggcatccctg acagattctc cggctctacc tccggcaact ctgccagcct gacaattact 720 ggcgcccagg ctgaggacga ggccgactac tactgcaact ccagagacag ccctggcaat 780 cagtgggttt tcggcggagg caccaaagtg acagttcttg gtggcggagg tggaagtggc 840 ggaggcggtt ctgataagac ccacacctgt ccaccttgtc ctgctccaga actgctcggc 900 ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat ctctcggacc 960 cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg atcccgaagt gaagttcaat 1020 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcctagaga ggaacagtac 1080 aactccacct atagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 1140 aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga aaagaccatc 1200 tccaaggcca agggccagcc tagggaaccc caggtttaca ccctgcctcc atgccgggaa 1260 gagatgacca agaaccaggt gtccctgtgg tgcctggtca agggcttcta cccttccgat 1320 atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac cacacctcca 1380 gtgctggact ccgacggctc attcttcctg tactccaagc tgacagtgga caagtccaga 1440 tggcagcagg gcaacgtgtt ctcctgctcc gtgatgcacg aggccctgca caatcactac 1500 acccagaagt ccctgtctct gtctcccgga aaaggcggtg gtggatcagg tggcggaggc 1560 tcaggcggag gcggatctca agttcagttg cagcagagcg gacccgagct ggtcaaacct 1620 ggcgcttccg tgaagatgtc ctgcaaggcc tccggctaca ccttcaccga ttacgtgatc 1680 aactggggca agcagcgctc tggccaaggc ctggaatgga tcggcgagat ctatcctggc 1740 tccggcacca actactacaa cgagaagttc aaggctaagg ctaccctgac cgccgacaag 1800 tcctccaata tcgcctacat gcagctgtct agcctgacct ccgaggactc tgccgtgtac 1860 ttctgcgcca gaagaggcag atacggcctg tacgccatgg actactgggg acagggaacc 1920 tccgtgacag ttagtagcgg tggcggcggt agcggcggtg gtggttctgg cggtggtggt 1980 agtggcggcg gaggatctga tatccagatg acccagacca ccagcagcct gtctgcttcc 2040 ctgggcgata gagtgaccat ctcttgcaga gccagccagg acatcagcaa ctacctgaac 2100 tggtatcaac aaaaacccga cggcaccgtg aagctgctga tctactacac ctctcggctg 2160 cactctggcg tgccctctag attttctggc agcggctctg gaaccgacta ctccctgacc 2220 atcaacaacc tggaacaaga ggatatcgct acctacttct gccagcaagg caacacccgg 2280 ccttggacat ttggaggcgg caccaagctg gaaatcaagt gatga 2325 <210> SEQ ID NO 132 <211> LENGTH: 2319 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 132 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 120 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 180 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 240 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 300 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 360 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 420 tctagtgctt ctactggtgg tggcggatct ggcggcggag gaagcggagg cggaggtagt 480 ggtggcggtg gatcttctta cgagctgacc caggatccag ccgtgtctgt tgctctgggc 540 cagacagtgc ggattacctg ccagggcgac tccctgagat cctactacgc ctcctggtat 600 cagcagaagc caggccaggc tcctgtgctg gtcatctacg gcaagaacaa ccggcctagc 660 ggcatccctg acagattctc cggctctacc tccggcaact ctgccagcct gacaattact 720 ggcgcccagg ctgaggacga ggccgactac tactgcaact ccagagacag ccctggcaat 780 cagtgggttt tcggcggagg caccaaagtg acagttcttg gtggcggagg tggaagtggc 840 ggaggcggtt ctgataagac ccacacctgt ccaccttgtc ctgctccaga actgctcggc 900 ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat ctctcggacc 960 cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg atcccgaagt gaagttcaat 1020 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcctagaga ggaacagtac 1080 aactccacct atagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 1140 aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga aaagaccatc 1200 tccaaggcca agggccagcc tagggaaccc caggtttaca ccctgcctcc atgccgggaa 1260 gagatgacca agaaccaggt gtccctgtgg tgcctggtca agggcttcta cccttccgat 1320 atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac cacacctcca 1380 gtgctggact ccgacggctc attcttcctg tactccaagc tgacagtgga caagtccaga 1440 tggcagcagg gcaacgtgtt ctcctgctcc gtgatgcacg aggccctgca caatcactac 1500 acccagaagt ccctgtctct gtctcccgga aaaggcggtg gtggatcagg tggcggaggc 1560 tcaggcggag gcggatctca agttcagttg gttcaaagcg gtggcggcgt ggtgcagcct 1620 ggaagatctc tcagactgtc ctgcaaggcc tccggctaca ccttcaccag atacaccatg 1680 cattgggttc gacaagcacc aggcaagggc ctcgagtgga tcggctacat caacccttcc 1740 agaggctaca ccaactacaa ccagaaagtg aaggaccggt tcaccatcag cagagacaac 1800 agcaagaata ccgcctttct gcagatggac tccctgcggc ctgaagatac cggcgtgtac 1860 ttttgcgccc ggtactacga cgaccactac tccctggatt actggggaca gggaacaccc 1920 gtgacagtgt ctagcggtgg cggtggttca ggcggcggtg gtagtggcgg cggaggtagc 1980 ggcggtggcg gatctgatat tcagatgacc cagtctcctt ccagcctgtc cgcttctgtg 2040 ggcgacagag tgactattac ctgctccgcc tcttcctccg tgtcctacat gaactggtat 2100 caacaaacac ccggcaaggc ccctaagaga tggatctacg acaccagcaa gctggcctct 2160 ggcgtgccct ctagattttc tggctctggc tccggcaccg actatacctt tacaatctcc 2220 agcctgcagc ctgaggatat cgccacctac tactgtcagc agtggtctag caaccccttc 2280 acctttggac agggcaccaa gctgcagatc acctgatga 2319 <210> SEQ ID NO 133 <211> LENGTH: 2199 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 133 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcaagagtc tggccctgga ctggtcaagc cctctcagac cctgtctctg 120 acctgtaccg tgtccggcgg ctccatcaac aacaacaatt actactggac ctggatccgg 180 cagcaccctg gcaaaggact ggaatggatc ggctacatct actactccgg ctccaccttc 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acaccagcaa gacccagttc 300 tccctgaagc tgtcctctgt gaccgccgct gataccgccg tgtactactg cgccagagaa 360 gataccatga ccggcctgga tgtgtggggc cagggaacaa cagtgaccgt gtcctccgct 420 tccaccaagg gaccttccgt gtttcctctg gctccctcca gcaagtctac ctctggtgga 480 acagctgccc tgggctgcct ggtcaaggat tactttcctg agcctgtgac agtgtcctgg 540 aactctggcg ctctgacatc cggcgtgcac acctttccag ctgtgctgca atcctccggc 600 ctgtactctc tgtcctccgt cgtgaccgtg ccttctagct ctctgggcac ccagacctac 660 atctgcaatg tgaaccacaa gccttccaac accaaggtgg acaagagagt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctcca tgtcctgctc cagaactgct cggcggaccc 780 tctgtgttcc tgtttccacc taagcctaag gacaccctga tgatctctcg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtctcac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctacagag tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg cctgctccta tcgaaaagac catcagcaag 1080 gccaagggcc agcctaggga accccaggtt tacaccctgc ctccatgccg ggaagagatg 1140 accaagaacc aggtgtccct gtggtgcctc gtgaagggct tctacccttc cgatatcgcc 1200 gtggaatggg agagcaatgg ccagcctgag aacaactaca agacaacccc tcctgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc cagatggcag 1320 cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaatca ctacacccag 1380 aagagtctgt ctctgtctcc cggcaaaggc ggcggaggat ctggcggagg cggtagcggt 1440 ggtggcggat ctcaggttca gttgcagcag tccggacctg agctggttaa gcctggcgcc 1500 tccgtgaaga tgtcctgcaa ggcttctggc tacaccttca ccgactacgt gatcaactgg 1560 ggcaagcaga gatctggcca gggactcgag tggatcggag agatctatcc tggctccggc 1620 accaactact acaatgagaa gttcaaggct aaggctaccc tgaccgccga caagtcctcc 1680 aatatcgcct acatgcagct gtccagcctg acctctgagg actccgctgt gtacttctgt 1740 gctcggagag gcagatacgg cctgtatgcc atggattact ggggacaggg cacctccgtg 1800 actgtctcta gcggtggcgg aggtagcgga ggcggtggtt caggcggagg cggctctggt 1860 ggcggtggat ctgatattca gatgacccag accacctcca gcctgtccgc ttctctgggc 1920 gacagagtga caatcagctg cagagccagc caggacatca gcaactacct gaactggtat 1980 cagcagaaac ccgacggcac cgtgaagctg ctgatctact acacctctcg gctgcactct 2040 ggcgtgccct ctagattttc tggcagcgga agcggcaccg attactccct gacaatcaac 2100 aacctcgagc aagaggatat cgctacctac ttctgccagc aaggcaacac ccggccttgg 2160 acatttggcg gcggaacaaa gctggaaatc aagtgatga 2199 <210> SEQ ID NO 134 <211> LENGTH: 1158 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 134 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccgga 60 cagtctgctc tgacccagcc tgcttctgtg tctggctctc ccggccagtc catcaccatc 120 tcttgtaccg gcacctcctc tgacgtcggc ggctacaact acgtgtcctg gtatcagcag 180 catcccggca aggcccctaa gctgatgatc tacgacgtgt ccaaccggcc ttccggcgtg 240 tccaatagat tctccggctc caagtccggc aacaccgctt ctctgacaat cagcggactg 300 caggccgagg acgaggccga ctactactgt tcctcctaca cctcctccag caccagagtg 360 tttggcaccg gcaccaaagt gaccgtgctg ggacagccta aggccaatcc taccgtgaca 420 ctgttccctc catcctccga ggaactgcag gctaacaagg ctaccctcgt gtgcctgatc 480 tccgactttt accctggcgc tgtgaccgtg gcctggaagg ctgatggatc tcctgtgaag 540 gctggcgtgg aaaccaccaa gccttccaag cagtccaaca acaaatacgc cgcctcctcc 600 tacctgtctc tgacccctga acagtggaag tcccaccggt cctacagctg ccaagtgacc 660 catgagggct ccaccgtgga aaagaccgtg gctcctactg agtgttctgg cggcggagga 720 tctggcggag gtggaagcgg aggcggtgga tctgctccta cctccagctc caccaagaaa 780 acccagctgc agttggagca tctgctgctg gacctgcaga tgatcctgaa cggcatcaac 840 aactacaaga accccaagct gacccggatg ctgaccgcca agtttgccat gcctaagaag 900 gccaccgagc tgaaacatct gcagtgcctg gaagaggaac tgaagcccct ggaagaagtg 960 ctgaatctgg cccagtccaa gaacttccac ctgaggcctc gggacctgat cagcaacatc 1020 aacgtgatcg tgctcgagct gaagggctcc gagacaacct tcatgtgcga gtacgccgac 1080 gagacagcta ccatcgtgga atttctgaac cggtggatca ccttctgcca gagcatcatc 1140 agcaccctga cctgatga 1158 <210> SEQ ID NO 135 <211> LENGTH: 1416 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 135 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 gaggtgcagc tgctggaatc tggcggagga ctggtgcagc ctggcggctc tctgagactg 120 tcttgtgccg cctccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 180 cctggcaagg gcctggaatg ggtgtcctct atctacccct ccggcggcat caccttttac 240 gccgacaccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc tagaatcaag 360 ctgggcaccg tgaccaccgt ggactattgg ggccagggca ccctggtcac cgtgtcctct 420 gcttctacca agggcccctc cgtgttccct ctggcccctt ccagcaagtc cacctctggc 480 ggaaccgctg ctctgggctg cctggtcaag gactacttcc ccgagcccgt gaccgtgtct 540 tggaactctg gcgccctgac cagcggcgtg cacacatttc cagccgtgct gcagtccagc 600 ggcctgtact ctctgtcctc cgtcgtgaca gtgccctcca gctctctggg cacacagacc 660 tacatctgca acgtgaacca caagccctcc aacaccaagg tggacaagcg ggtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccctgtcctg cccctgaact gctgggcgga 780 cccagcgtgt tcctgttccc tccaaagcct aaggacaccc tgatgatctc ccggacccct 840 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctacc gggtggtgtc cgtgctgaca gtgctgcatc aggactggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgccagccc ctatcgaaaa gaccatctcc 1080 aaggccaagg gccagccaag agagcctcaa gtctgcacac tgcctcccag ccgggaagag 1140 atgaccaaga accaggtgtc cctgagctgc gctgtgaagg gcttctaccc ttccgatatc 1200 gccgtggaat gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcccgtg 1260 ctggactccg acggctcatt cttcctggtg tccaagctga ccgtggacaa gtcccggtgg 1320 cagcagggca acgtgttctc ctgctctgtg atgcacgagg ccctgcacaa ccactacacc 1380 cagaagtccc tgtccctgtc tcccggcaag taatga 1416 <210> SEQ ID NO 136 <400> SEQUENCE: 136 000 <210> SEQ ID NO 137 <211> LENGTH: 2205 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 137 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcaagagtc tggccctgga ctggtcaagc cttccgagac actgtctctg 120 acctgcaccg tgtctggcgg ctctgtgtcc tctggctcct actactggtc ctggatcaga 180 cagcctcctg gcaaaggcct ggaatggatc ggctacatct actactccgg ctccaccaac 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 300 tccctgaagc tgtcctccgt gaccgctgct gataccgccg tgtactactg tgccagagag 360 ggcaagaacg gcgccttcga tatttggggc cagggcacca tggtcaccgt gtccagtgct 420 tctaccaagg gacccagcgt gttcccactg gctcccagct ctaagtctac ctctggcgga 480 acagctgccc tgggctgtct ggtcaaggat tacttccctg agcctgtgac cgtgtcctgg 540 aattctggcg ctctgacatc cggcgtgcac acctttccag ctgtgctgca atcctccggc 600 ctgtactctc tgtccagcgt cgtgaccgtg ccttctagct ctctgggcac ccagacctac 660 atctgcaatg tgaaccacaa gcctagcaac accaaggtgg acaagagagt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctcca tgtcctgctc cagaactgct cggcggacct 780 tccgtgttcc tgtttcctcc aaagcctaag gacaccctga tgatctctcg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtctcac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctacagag tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg cctgctccta tcgaaaagac catcagcaag 1080 gccaagggcc agcctaggga accccaggtt tacaccctgc ctccatgccg ggaagagatg 1140 accaagaatc aggtgtccct gtggtgcctc gtgaagggct tctacccttc cgatatcgcc 1200 gtggaatggg agagcaatgg ccagcctgag aacaactaca agacaacccc tcctgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc cagatggcag 1320 cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaatca ctacacccag 1380 aagtccctgt ctctgtcccc tggaaaaggc ggcggaggat ctggcggagg tggaagcgga 1440 ggcggtggat ctgaagtgca gctccaagaa tctggacccg ggctcgtgaa gcccagccag 1500 tctctgagtc tgacctgtac agtgaccggc tactccatca cctccgacta cgcttggaac 1560 tggatccggc agttccccgg caacaagttg gagtggatgg gctatatcac ctacagcggc 1620 agcacctctt acaacccttc tctggaatcc cggatcagca tcacccggga cacctctacc 1680 aatcagttct ttctgcagct gaacagcgtg accaccgagg acaccgccac ctactattgt 1740 gctagaggcg gctactacgg ctcctcctgg ggagtgtttg cttactgggg acagggaacc 1800 ctcgtgactg tttctgctgg tggcggagga agcggcggag gcggctctgg tggtggtggt 1860 tctggtggcg gcggatctga catccagatg acccagtctc cagccagcct gtctgcttct 1920 gtgggcgaga cagtgaccat tacctgccgg gtgtccgaga acatctactc ctacctggcc 1980 tggtatcaac agaaacaggg caagtcccct cagctgctgg tgtacaatgc taagaccctg 2040 gctgagggcg tgccctctag attttctggc tctggcagcg gcacccagtt tagcctgaag 2100 atcaactccc tgcagcctga ggacttcggc agctactact gccagcacca ctatggcacc 2160 ccttggacat ttggcggagg caccaagctg gaaatcaagt gatga 2205 <210> SEQ ID NO 138 <211> LENGTH: 2190 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 138 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcaagagtc tggccctgga ctggtcaagc cttccgagac actgtctctg 120 acctgcaccg tgtctggcgg ctctgtgtcc tctggctcct actactggtc ctggatcaga 180 cagcctcctg gcaaaggcct ggaatggatc ggctacatct actactccgg ctccaccaac 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 300 tccctgaagc tgtcctccgt gaccgctgct gataccgccg tgtactactg tgccagagag 360 ggcaagaacg gcgccttcga tatttggggc cagggcacca tggtcaccgt gtccagtgct 420 tctaccaagg gacccagcgt gttcccactg gctcccagct ctaagtctac ctctggcgga 480 acagctgccc tgggctgtct ggtcaaggat tacttccctg agcctgtgac cgtgtcctgg 540 aattctggcg ctctgacatc cggcgtgcac acctttccag ctgtgctgca atcctccggc 600 ctgtactctc tgtccagcgt cgtgaccgtg ccttctagct ctctgggcac ccagacctac 660 atctgcaatg tgaaccacaa gcctagcaac accaaggtgg acaagagagt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctcca tgtcctgctc cagaactgct cggcggacct 780 tccgtgttcc tgtttcctcc aaagcctaag gacaccctga tgatctctcg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtctcac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctacagag tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg cctgctccta tcgaaaagac catcagcaag 1080 gccaagggcc agcctaggga accccaggtt tacaccctgc ctccatgccg ggaagagatg 1140 accaagaatc aggtgtccct gtggtgcctc gtgaagggct tctacccttc cgatatcgcc 1200 gtggaatggg agagcaatgg ccagcctgag aacaactaca agacaacccc tcctgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc cagatggcag 1320 cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaatca ctacacccag 1380 aagtccctgt ctctgtcccc tggaaaaggc ggcggaggat ctggcggagg tggaagcgga 1440 ggcggtggat ctcaggttca gttgcagcag tctgccgtgg aactggctag acctggcgct 1500 tccgtgaaga tgtcctgcaa ggcctccggc tacaccttca ccagcttcac catgcactgg 1560 gtcaagcaga ggcctggaca aggcttggag tggattggat atatcaaccc tagctctggc 1620 tacaccgagt acaaccagaa gttcaaggac aagaccactc tgaccgccga caagtcctcc 1680 agcaccgctt acatgcagct cgactccctg acctctgacg actctgctgt gtactattgc 1740 gtgcggggct cctccagagg cttcgattat tggggacaag gcacactcgt gacagtgtca 1800 gctggtggtg gcggtagtgg cggtggcggt tcaggtggcg gaggaagcgg cggaggcgga 1860 tctgatatcc agatgatcca gtctcctgcc agcctgtccg tgtctgtggg agagactgtg 1920 accatcacct gtcgggcctc cgagaacatc tactccaacc tggcctggtt ccagcagaag 1980 cagggaaagt ctcctcagct gctggtgtac gccgccacca atttggctga tggcgtgccc 2040 tctcggttct ccggatctgg atctggcaca cagtattccc tgaagatcaa ctccctgcag 2100 tccgaggact tcggcatcta ctattgccag cacttctggg gcacccctag aacctttggc 2160 ggcggaacaa agctggaaat caagtgatga 2190 <210> SEQ ID NO 139 <211> LENGTH: 675 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 139 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gagctgtgcg acgatgaccc tcctgagatc cctcacgcca ccttcaaggc catggcttac 120 aaagagggca ccatgctgaa ctgcgagtgc aagcggggct tcagacggat caagtccggc 180 agcctgtaca tgctgtgcac cggcaactcc tctcactcct cctgggacaa ccagtgccag 240 tgcacctcct ctgccaccag aaacaccacc aagcaagtga cccctcagcc tgaggaacag 300 aaagagcgca agaccaccga gatgcagagc cccatgcagc ctgtggatca ggcttctctg 360 cctggccact gtagagagcc tccaccttgg gagaatgagg ccaccgagcg gatctaccac 420 tttgtcgtgg gccagatggt gtactaccag tgcgtgcagg gatacagagc cctgcataga 480 ggccctgctg agtccgtgtg caagatgacc catggcaaga ccagatggac ccagcctcag 540 ctgatctgta caggcggagg cggaggatct ggtggtggtg gatctggcct gaacgacatc 600 ttcgaggccc agaaaatcga gtggcacgaa ggcggtggcg gctcccacca tcatcatcac 660 caccatcact gatga 675 <210> SEQ ID NO 140 <211> LENGTH: 1734 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 140 atggaaaccg acaccctgct gctgtgggtg ctgctgctct gggtcccagg ctccaccggc 60 ggactgaacg acatcttcga ggcccagaaa atcgagtggc acgagggcgg aggcggctcc 120 gagcctagaa ccgacaccga cacctgtccc aacccccccg acccctgccc tacctgtcct 180 acccctgatc tgctgggcgg accctccgtg ttcatcttcc cacccaagcc taaggacgtg 240 ctgatgatct ccctgacccc caagatcacc tgtgtggtgg tggacgtgtc cgaagaggaa 300 cccgacgtgc agttcaattg gtacgtgaac aacgtggaag ataagaccgc ccagaccgag 360 acacggcagc ggcagtacaa ctccacctac cgggtggtgt ccgtgctgcc catcaagcac 420 caggactgga tgtccggcaa ggtgttcaag tgcaaagtga acaacaacgc cctgcccagc 480 cccatcgaaa agaccatctc caagcctcgg ggccaagtcc gagtgcccca gatctacacc 540 ttcccacccc ctatcgagca gaccgtgaag aaagacgtgt ccgtgacctg cctcgtgacc 600 ggattcctgc cacaagacat ccacgtggaa tgggagtcca acggccagcc ccagcccgag 660 cagaactaca agaacaccca gcccgtgctg gactccgacg gctcctactt cctgtactcc 720 aagctgaacg tgcccaagtc cagatgggac cagggcgact ccttcacctg ttccgtgatc 780 cacgaggccc tgcacaacca ccacatgacc aagaccatca gccggtccct gggcaatggc 840 ggcggaggct ccgaggtgga aaagaccgcc tgcccctccg gcaagaaggc cagagagatc 900 gacgagtccc tgatcttcta caagaagtgg gagctggaag cctgcgtgga cgccgccctg 960 ctggccaccc agatggacag agtgaacgcc atccccttca cctacgagca gctggatgtg 1020 ctgaagcaca agctggacga gctgtacccc cagggctacc ccgagagcgt gatccagcac 1080 ctgggctacc tgtttctgaa gatgtccccc gaggacatcc ggaagtggaa cgtgacctcc 1140 ctggaaaccc tgaaggccct gctggaagtg aacaagggcc acgagatgag cccccaggcc 1200 cccagacgac ctctgcctca ggtggcaacc ctgatcgata gattcgtgaa gggcagaggc 1260 cagctggaca aggacaccct ggacacactg accgccttct accccggcta cctgtgctcc 1320 ctgtcccctg aggaactgtc ctccgtgccc ccctcctcta tctgggccgt gcggcctcag 1380 gatctggaca cctgtgaccc tcggcagctg gatgtcctgt atcccaaggc ccggctggcc 1440 ttccagaaca tgaacggctc cgagtacttc gtgaagatcc agtccttcct gggcggagcc 1500 cccaccgagg acctgaaggc tctgtcccag cagaacgtgt ccatggacct ggccaccttc 1560 atgaagctgc ggaccgacgc cgtgctgcct ctgaccgtgg ctgaggtgca gaagctgctg 1620 ggcccccacg tggaaggcct gaaggccgag gaacggcaca gacccgtgcg ggactggatc 1680 ctgcggcaga gacaggacga cctggatacc ctgggcctgg gcctgcagta atga 1734 <210> SEQ ID NO 141 <211> LENGTH: 822 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 141 atgagaatct tcgccgtgtt catcttcatg acctactggc atctgctgaa cgccttcacc 60 gtgaccgtgc ccaaggacct gtacgtggtg gaatacggct ccaacatgac catcgagtgc 120 aagttccccg tggaaaagca gctggacctg gccgccctga tcgtgtactg ggagatggaa 180 gataagaaca tcatccagtt cgtgcacggg gaagaggacc tgaaggtgca gcactcctcc 240 taccggcaga gagccagact gctgaaggac cagctgtccc tgggcaatgc cgccctgcag 300 atcaccgacg tgaagctgca ggatgccggc gtgtaccggt gcatgatctc ttacggcgga 360 gccgactaca agcggatcac cgtgaaagtg aacgccccct acaacaagat caaccagcgg 420 atcctggtgg tggaccccgt gacctctgag cacgagctga cctgtcaggc cgagggctac 480 cctaaggccg aagtgatctg gacctcctcc gaccaccagg tgctgtccgg caagaccacc 540 accacaaact ccaagcggga agagaagctg ttcaacgtga cctccaccct gcggatcaac 600 acaaccacca acgagatctt ctactgtacc ttccggcggc tggaccccga ggaaaatcac 660 accgctgagc tcgtgatccc cgagctgcct ctggcccacc ctcctaatga gagaacaggc 720 ggcggaggct ccggcctgaa cgacatcttt gaggcccaga aaatcgagtg gcacgagggc 780 ggaggcggct cccaccatca tcaccaccac catcactgat ga 822 <210> SEQ ID NO 142 <211> LENGTH: 1182 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 142 atggcttgga tgctgctgct gatcctgatc atggtgcacc ccggctcttg cgccctgtgg 60 gtgtcccagc ctcctgagat cagaaccctg gaaggctcct ccgccttcct gccctgctcc 120 ttcaatgcct ctcagggcag actggccatc ggctccgtga cctggttcag ggatgaggtg 180 gtgcccggca aagaagtgcg gaacggcaca cctgagttca gaggcagact cgcccctctg 240 gcctcctcta gattcctgca cgatcaccag gccgagctgc acatcagaga tgtgcggggc 300 cacgacgcct ccatctacgt gtgcagagtg gaagtgctgg gcctgggcgt gggcaccggc 360 aatggaacac ggctggtggt ggaaaaagag ggcggaggcg gatctggcgg cggaggctct 420 gataagaccc acacctgtcc tccctgtcct gcccctgaac tgctgggcgg accttccgtg 480 ttcctgttcc ctccaaagcc caaggacacc ctgatgatct cccggacccc tgaagtgacc 540 tgcgtggtgg tggacgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 600 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 660 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 720 tgcaaggtgt ccaacaaggc cctgccagcc ccaatcgaaa agaccatctc caaggccaag 780 ggccagcccc gcgagcctca ggtgtacaca ctgcctccca gccgggaaga gatgaccaag 840 aaccaggtgt ccctgacctg tctggtcaag ggcttctacc cctccgatat cgccgtggaa 900 tgggagtcca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggactcc 960 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 1020 aacgtgttct cctgctctgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1080 ctgtccctga gccctggcaa aggtggtggt ggtagcggtg gcggaggcag cggcctgaac 1140 gatatcttcg aggcccagaa aatcgagtgg cacgagtaat ga 1182 <210> SEQ ID NO 143 <211> LENGTH: 1587 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 143 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 cagcagcaga cactgcccaa gccttttatc tgggccgagc ctcacttcat ggtgcccaaa 120 gaaaagcaag tgaccatctg ctgccagggc aactacggcg ctgtggaata ccagctgcac 180 ttcgagggct ccctgttcgc cgtggataga cctaagcctc ctgagcggat caacaaagtg 240 aagttctaca tccccgacat gaactcccgg atggctggcc agtactcctg catctataga 300 gtgggcgagc tttggagcga gccctccaat ctgctggatc tggtggtcac cgagatgtac 360 gacaccccta cactgagcgt gcaccccgga cctgaagtga tctctggcga gaaagtgacc 420 ttctactgca gactggatac cgccacctcc atgtttctgc tgctcaaaga gggcagatcc 480 tctcacgtgc agcgcggcta tggaaaggtg caggctgagt ttcctctggg ccctgtgacc 540 accgctcaca gaggcaccta cagatgcttc ggctcctaca acaaccacgc ctggtctttc 600 ccatccgagc ctgtgaagct gctggtcacc ggcgacatcg agaacacatc tctggcccct 660 gaggacccca cctttcctga tacctggggc acctatctgc tgaccaccga gacaggcctg 720 cagaaagatc acgccctgtg ggatcacacc gctcagaatg gtggcggagg atctggcgga 780 ggcggatctg aacctagaac cgacaccgac acctgtccta atcctccaga tccttgtcct 840 acctgtccaa cacctgacct gctcggcgga ccttccgtgt tcatcttccc acctaagcca 900 aaggacgtgc tgatgatctc tctgacccct aagatcacct gtgtggtggt ggacgtgtcc 960 gaagaggaac ccgacgtgca gttcaattgg tacgtgaaca acgtcgagga caagacagcc 1020 cagaccgaga cacggcagcg gcagtacaac tctacctaca gagtggtgtc cgtgctgccc 1080 atcaagcacc aggattggat gtccggcaag gtgttcaagt gcaaagtgaa caacaacgcc 1140 ctgccttctc caatcgaaaa gaccatctcc aagcctcggg gccaagtgcg agtgccccag 1200 atctatacct ttccacctcc tatcgagcag accgtgaaga aagatgtgtc cgtgacctgc 1260 ctcgtgaccg gcttcctgcc tcaagacatc catgtggaat gggagtccaa cggccagcct 1320 cagcctgagc agaactacaa gaacacccag cctgtgctgg actccgacgg cagctacttc 1380 ctgtactcca agctgaacgt gcccaagtcc agatgggacc agggcgactc cttcacctgt 1440 tccgtgatcc acgaggccct gcacaaccac cacatgacca agaccatcag cagatccctc 1500 ggcaatggcg gtggtggttc tggcggcgga ggttccggac tgaacgatat cttcgaggcc 1560 cagaaaatcg agtggcacga gtgatga 1587 <210> SEQ ID NO 144 <211> LENGTH: 1041 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 144 atggaaactg acaccctcct cctttgggtg ctgctgcttt gggtgcctgg atcgaccggg 60 atgaaggaca ataccgtgcc tctgaagctc attgccctgc tggccaacgg agaattccat 120 tccggcgaac agctggggga gactctcggg atgtcccggg ccgccatcaa caagcacatc 180 cagactttgc gcgactgggg agtcgacgtg ttcacggtgc cggggaaggg ctactcgctc 240 ccggaaccga tccagctgct gaacgccaag cagattctgg gacagctgga tggcggaagc 300 gtggcagtgc tgcccgtgat cgactcaacc aaccagtatc tgctggatag aatcggtgaa 360 ctgaaatccg gcgacgcttg cattgccgag taccaacagg ccggaagggg acggcgcggc 420 aggaagtggt tctctccatt cggcgcgaac ctctacctga gcatgttctg gagattggag 480 cagggtcccg ccgcggccat cggcctctcc ctggtcatcg gcattgtgat ggctgaagtg 540 ctgaggaagt tgggtgccga caaggtccgc gtgaagtggc cgaacgacct gtacctccaa 600 gaccggaaat tggcggggat tctcgtcgag cttaccggaa agactggcga tgccgcacaa 660 attgtgatcg gggcgggaat caacatggcg atgcgacggg tggaagagag cgtcgtgaac 720 cagggatgga tcaccctgca agaggccgga atcaacctgg atcgcaacac cctggctgcc 780 atgctcattc gcgaactgag agccgcactg gagctgtttg agcaggaggg tctggccccc 840 tacctgtcac gctgggaaaa gcttgataac ttcatcaatc ggcctgtgaa gctgatcatc 900 ggagacaagg agattttcgg catctcgaga ggcatcgaca aacaaggagc cctcctgctg 960 gaacaggacg gaatcattaa gccctggatg ggtggagaga tctccctgcg gtccgccgaa 1020 aagtccggga aggatgaact c 1041 <210> SEQ ID NO 145 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 145 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> SEQ ID NO 146 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 146 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Thr Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ala Tyr Phe Cys Gln Gln Thr Tyr Ser Asn Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Val Lys 100 105 <210> SEQ ID NO 147 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 147 Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> SEQ ID NO 148 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 148 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 149 <211> LENGTH: 110 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 149 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 <210> SEQ ID NO 150 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 150 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 50 55 60 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 151 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 151 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 152 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 152 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> SEQ ID NO 153 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 153 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> SEQ ID NO 154 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 154 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> SEQ ID NO 155 <400> SEQUENCE: 155 000 <210> SEQ ID NO 156 <211> LENGTH: 152 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 156 Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu 1 5 10 15 Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser 20 25 30 Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp 35 40 45 Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg 50 55 60 Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu 65 70 75 80 Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val 85 90 95 Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser 100 105 110 Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu 115 120 125 Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys 130 135 140 Ile Leu Met Gly Thr Lys Glu His 145 150 <210> SEQ ID NO 157 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 157 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 158 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 158 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Lys Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> SEQ ID NO 159 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 159 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 160 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 160 Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn Gln 85 90 95 Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 <210> SEQ ID NO 161 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 161 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> SEQ ID NO 162 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 162 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr 100 105 <210> SEQ ID NO 163 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 163 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 164 <211> LENGTH: 140 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 164 Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser Leu 1 5 10 15 Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr Ala 20 25 30 Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met Gly 35 40 45 Tyr Ile Thr Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Glu Ser 50 55 60 Arg Ile Ser Ile Thr Arg Asp Thr Ser Thr Asn Gln Phe Phe Leu Gln 65 70 75 80 Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 85 90 95 Gly Gly Tyr Tyr Gly Ser Ser Trp Gly Val Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 <210> SEQ ID NO 165 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 165 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Val Ser Glu Asn Ile Tyr Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 166 <211> LENGTH: 117 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 166 Gln Val Gln Leu Gln Gln Ser Ala Val Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Asp Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Ser Arg Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <210> SEQ ID NO 167 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 167 Asp Ile Gln Met Ile Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn 20 25 30 Leu Ala Trp Phe Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Gly Ile Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 168 <211> LENGTH: 449 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 168 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> SEQ ID NO 169 <211> LENGTH: 213 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 169 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Thr Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ala Tyr Phe Cys Gln Gln Thr Tyr Ser Asn Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Val Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 170 <211> LENGTH: 370 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 170 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 130 135 140 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 145 150 155 160 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 165 170 175 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 180 185 190 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 195 200 205 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 210 215 220 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 225 230 235 240 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 245 250 255 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 260 265 270 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 275 280 285 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 290 295 300 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 305 310 315 320 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 325 330 335 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 340 345 350 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 355 360 365 Gly Lys 370 <210> SEQ ID NO 171 <211> LENGTH: 216 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 171 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> SEQ ID NO 172 <211> LENGTH: 449 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 172 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> SEQ ID NO 173 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 173 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 174 <211> LENGTH: 464 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 174 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 <210> SEQ ID NO 175 <400> SEQUENCE: 175 000 <210> SEQ ID NO 176 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 176 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 177 <211> LENGTH: 598 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 177 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu 465 470 475 480 His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr 485 490 495 Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro 500 505 510 Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu 515 520 525 Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His 530 535 540 Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu 545 550 555 560 Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr 565 570 575 Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser 580 585 590 Ile Ile Ser Thr Leu Thr 595 <210> SEQ ID NO 178 <211> LENGTH: 254 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 178 Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser 1 5 10 15 Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu 20 25 30 Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln 35 40 45 Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg 50 55 60 Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala 65 70 75 80 Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys 85 90 95 Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val 100 105 110 Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro 115 120 125 Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys 130 135 140 Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys 145 150 155 160 Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr 165 170 175 Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr 180 185 190 Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile 195 200 205 Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr Gly Gly Gly 210 215 220 Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His 225 230 235 240 Glu Gly Gly Gly Gly Ser His His His His His His His His 245 250 <210> SEQ ID NO 179 <211> LENGTH: 411 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 179 Thr Glu Met Tyr Asp Thr Pro Thr Leu Ser Val His Pro Gly Pro Glu 1 5 10 15 Val Ile Ser Gly Glu Lys Val Thr Phe Tyr Cys Arg Leu Asp Thr Ala 20 25 30 Thr Ser Met Phe Leu Leu Leu Lys Glu Gly Arg Ser Ser His Val Gln 35 40 45 Arg Gly Tyr Gly Lys Val Gln Ala Glu Phe Pro Leu Gly Pro Val Thr 50 55 60 Thr Ala His Arg Gly Thr Tyr Arg Cys Phe Gly Ser Tyr Asn Asn His 65 70 75 80 Ala Trp Ser Phe Pro Ser Glu Pro Val Lys Leu Leu Val Thr Gly Asp 85 90 95 Ile Glu Asn Thr Ser Leu Ala Pro Glu Asp Pro Thr Phe Pro Asp Thr 100 105 110 Trp Gly Thr Tyr Leu Leu Thr Thr Glu Thr Gly Leu Gln Lys Asp His 115 120 125 Ala Leu Trp Asp His Thr Ala Gln Asn Gly Gly Gly Gly Ser Gly Gly 130 135 140 Gly Gly Ser Glu Pro Arg Thr Asp Thr Asp Thr Cys Pro Asn Pro Pro 145 150 155 160 Asp Pro Cys Pro Thr Cys Pro Thr Pro Asp Leu Leu Gly Gly Pro Ser 165 170 175 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Met Ile Ser Leu 180 185 190 Thr Pro Lys Ile Thr Cys Val Val Val Asp Val Ser Glu Glu Glu Pro 195 200 205 Asp Val Gln Phe Asn Trp Tyr Val Asn Asn Val Glu Asp Lys Thr Ala 210 215 220 Gln Thr Glu Thr Arg Gln Arg Gln Tyr Asn Ser Thr Tyr Arg Val Val 225 230 235 240 Ser Val Leu Pro Ile Lys His Gln Asp Trp Met Ser Gly Lys Val Phe 245 250 255 Lys Cys Lys Val Asn Asn Asn Ala Leu Pro Ser Pro Ile Glu Lys Thr 260 265 270 Ile Ser Lys Pro Arg Gly Gln Val Arg Val Pro Gln Ile Tyr Thr Phe 275 280 285 Pro Pro Pro Ile Glu Gln Thr Val Lys Lys Asp Val Ser Val Thr Cys 290 295 300 Leu Val Thr Gly Phe Leu Pro Gln Asp Ile His Val Glu Trp Glu Ser 305 310 315 320 Asn Gly Gln Pro Gln Pro Glu Gln Asn Tyr Lys Asn Thr Gln Pro Val 325 330 335 Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val Pro 340 345 350 Lys Ser Arg Trp Asp Gln Gly Asp Ser Phe Thr Cys Ser Val Ile His 355 360 365 Glu Ala Leu His Asn His His Met Thr Lys Thr Ile Ser Arg Ser Leu 370 375 380 Gly Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Leu Asn Asp 385 390 395 400 Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu 405 410 <210> SEQ ID NO 180 <211> LENGTH: 374 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 180 Leu Trp Val Ser Gln Pro Pro Glu Ile Arg Thr Leu Glu Gly Ser Ser 1 5 10 15 Ala Phe Leu Pro Cys Ser Phe Asn Ala Ser Gln Gly Arg Leu Ala Ile 20 25 30 Gly Ser Val Thr Trp Phe Arg Asp Glu Val Val Pro Gly Lys Glu Val 35 40 45 Arg Asn Gly Thr Pro Glu Phe Arg Gly Arg Leu Ala Pro Leu Ala Ser 50 55 60 Ser Arg Phe Leu His Asp His Gln Ala Glu Leu His Ile Arg Asp Val 65 70 75 80 Arg Gly His Asp Ala Ser Ile Tyr Val Cys Arg Val Glu Val Leu Gly 85 90 95 Leu Gly Val Gly Thr Gly Asn Gly Thr Arg Leu Val Val Glu Lys Glu 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 115 120 125 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 130 135 140 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 145 150 155 160 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 165 170 175 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 180 185 190 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 195 200 205 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 210 215 220 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 225 230 235 240 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 245 250 255 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 260 265 270 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 275 280 285 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 290 295 300 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 305 310 315 320 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 325 330 335 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly 340 345 350 Gly Ser Gly Gly Gly Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln 355 360 365 Lys Ile Glu Trp His Glu 370 <210> SEQ ID NO 181 <211> LENGTH: 556 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 181 Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu Gly 1 5 10 15 Gly Gly Gly Ser Glu Pro Arg Thr Asp Thr Asp Thr Cys Pro Asn Pro 20 25 30 Pro Asp Pro Cys Pro Thr Cys Pro Thr Pro Asp Leu Leu Gly Gly Pro 35 40 45 Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Met Ile Ser 50 55 60 Leu Thr Pro Lys Ile Thr Cys Val Val Val Asp Val Ser Glu Glu Glu 65 70 75 80 Pro Asp Val Gln Phe Asn Trp Tyr Val Asn Asn Val Glu Asp Lys Thr 85 90 95 Ala Gln Thr Glu Thr Arg Gln Arg Gln Tyr Asn Ser Thr Tyr Arg Val 100 105 110 Val Ser Val Leu Pro Ile Lys His Gln Asp Trp Met Ser Gly Lys Val 115 120 125 Phe Lys Cys Lys Val Asn Asn Asn Ala Leu Pro Ser Pro Ile Glu Lys 130 135 140 Thr Ile Ser Lys Pro Arg Gly Gln Val Arg Val Pro Gln Ile Tyr Thr 145 150 155 160 Phe Pro Pro Pro Ile Glu Gln Thr Val Lys Lys Asp Val Ser Val Thr 165 170 175 Cys Leu Val Thr Gly Phe Leu Pro Gln Asp Ile His Val Glu Trp Glu 180 185 190 Ser Asn Gly Gln Pro Gln Pro Glu Gln Asn Tyr Lys Asn Thr Gln Pro 195 200 205 Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val 210 215 220 Pro Lys Ser Arg Trp Asp Gln Gly Asp Ser Phe Thr Cys Ser Val Ile 225 230 235 240 His Glu Ala Leu His Asn His His Met Thr Lys Thr Ile Ser Arg Ser 245 250 255 Leu Gly Asn Gly Gly Gly Gly Ser Glu Val Glu Lys Thr Ala Cys Pro 260 265 270 Ser Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys 275 280 285 Lys Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln 290 295 300 Met Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val 305 310 315 320 Leu Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser 325 330 335 Val Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp 340 345 350 Ile Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu 355 360 365 Glu Val Asn Lys Gly His Glu Met Ser Pro Gln Ala Pro Arg Arg Pro 370 375 380 Leu Pro Gln Val Ala Thr Leu Ile Asp Arg Phe Val Lys Gly Arg Gly 385 390 395 400 Gln Leu Asp Lys Asp Thr Leu Asp Thr Leu Thr Ala Phe Tyr Pro Gly 405 410 415 Tyr Leu Cys Ser Leu Ser Pro Glu Glu Leu Ser Ser Val Pro Pro Ser 420 425 430 Ser Ile Trp Ala Val Arg Pro Gln Asp Leu Asp Thr Cys Asp Pro Arg 435 440 445 Gln Leu Asp Val Leu Tyr Pro Lys Ala Arg Leu Ala Phe Gln Asn Met 450 455 460 Asn Gly Ser Glu Tyr Phe Val Lys Ile Gln Ser Phe Leu Gly Gly Ala 465 470 475 480 Pro Thr Glu Asp Leu Lys Ala Leu Ser Gln Gln Asn Val Ser Met Asp 485 490 495 Leu Ala Thr Phe Met Lys Leu Arg Thr Asp Ala Val Leu Pro Leu Thr 500 505 510 Val Ala Glu Val Gln Lys Leu Leu Gly Pro His Val Glu Gly Leu Lys 515 520 525 Ala Glu Glu Arg His Arg Pro Val Arg Asp Trp Ile Leu Arg Gln Arg 530 535 540 Gln Asp Asp Leu Asp Thr Leu Gly Leu Gly Leu Gln 545 550 555 <210> SEQ ID NO 182 <211> LENGTH: 203 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 182 Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro His Ala Thr Phe Lys 1 5 10 15 Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn Cys Glu Cys Lys Arg 20 25 30 Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr Met Leu Cys Thr Gly 35 40 45 Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys Gln Cys Thr Ser Ser 50 55 60 Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro Gln Pro Glu Glu Gln 65 70 75 80 Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro Met Gln Pro Val Asp 85 90 95 Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro Pro Pro Trp Glu Asn 100 105 110 Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val Gly Gln Met Val Tyr 115 120 125 Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His Arg Gly Pro Ala Glu 130 135 140 Ser Val Cys Lys Met Thr His Gly Lys Thr Arg Trp Thr Gln Pro Gln 145 150 155 160 Leu Ile Cys Thr Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 165 170 175 Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu Gly Gly 180 185 190 Gly Gly Ser His His His His His His His His 195 200 <210> SEQ ID NO 183 <211> LENGTH: 452 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 183 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys 450 <210> SEQ ID NO 184 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 184 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Lys Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 185 <211> LENGTH: 600 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 185 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln 465 470 475 480 Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn 485 490 495 Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr 500 505 510 Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu 515 520 525 Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn 530 535 540 Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val 545 550 555 560 Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp 565 570 575 Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys 580 585 590 Gln Ser Ile Ile Ser Thr Leu Thr 595 600 <210> SEQ ID NO 186 <211> LENGTH: 619 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 186 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu 465 470 475 480 Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu 485 490 495 Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His 500 505 510 Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg 515 520 525 Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu 530 535 540 His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr 545 550 555 560 Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro 565 570 575 Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu 580 585 590 Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys 595 600 605 Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His 610 615 <210> SEQ ID NO 187 <211> LENGTH: 491 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 187 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly 145 150 155 160 Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr 165 170 175 Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile 180 185 190 Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 195 200 205 Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala 210 215 220 Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn 225 230 235 240 Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 260 265 270 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 275 280 285 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 290 295 300 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 305 310 315 320 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 325 330 335 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 340 345 350 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 355 360 365 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 370 375 380 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu 385 390 395 400 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 405 410 415 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 420 425 430 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 435 440 445 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 450 455 460 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 465 470 475 480 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 <210> SEQ ID NO 188 <211> LENGTH: 753 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 188 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly 145 150 155 160 Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr 165 170 175 Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile 180 185 190 Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 195 200 205 Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala 210 215 220 Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn 225 230 235 240 Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 260 265 270 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 275 280 285 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 290 295 300 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 305 310 315 320 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 325 330 335 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 340 345 350 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 355 360 365 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 370 375 380 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu 385 390 395 400 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 405 410 415 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 420 425 430 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 435 440 445 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 450 455 460 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 465 470 475 480 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 485 490 495 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln 500 505 510 Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys 515 520 525 Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Val Ile Asn Trp Gly Lys 530 535 540 Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Gly 545 550 555 560 Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe Lys Ala Lys Ala Thr Leu 565 570 575 Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr Met Gln Leu Ser Ser Leu 580 585 590 Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg Gly Arg Tyr 595 600 605 Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val 610 615 620 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 625 630 635 640 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser 645 650 655 Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser 660 665 670 Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly 675 680 685 Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val 690 695 700 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr 705 710 715 720 Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln 725 730 735 Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 740 745 750 Lys <210> SEQ ID NO 189 <211> LENGTH: 751 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 189 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly 145 150 155 160 Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr 165 170 175 Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile 180 185 190 Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 195 200 205 Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala 210 215 220 Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn 225 230 235 240 Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 260 265 270 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 275 280 285 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 290 295 300 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 305 310 315 320 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 325 330 335 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 340 345 350 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 355 360 365 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 370 375 380 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu 385 390 395 400 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 405 410 415 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 420 425 430 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 435 440 445 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 450 455 460 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 465 470 475 480 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 485 490 495 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln 500 505 510 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 515 520 525 Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg 530 535 540 Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser 545 550 555 560 Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys Asp Arg Phe Thr Ile 565 570 575 Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu 580 585 590 Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp 595 600 605 His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser 610 615 620 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 625 630 635 640 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 645 650 655 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser 660 665 670 Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro 675 680 685 Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser 690 695 700 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser 705 710 715 720 Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 725 730 735 Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr 740 745 750 <210> SEQ ID NO 190 <211> LENGTH: 711 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 190 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 465 470 475 480 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 485 490 495 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 500 505 510 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 515 520 525 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 530 535 540 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 545 550 555 560 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 565 570 575 Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 595 600 605 Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr 610 615 620 Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr 625 630 635 640 Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser 645 650 655 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 660 665 670 Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala 675 680 685 Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly 690 695 700 Gly Thr Lys Leu Glu Ile Lys 705 710 <210> SEQ ID NO 191 <211> LENGTH: 364 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 191 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys 225 230 235 240 Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu 245 250 255 Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 260 265 270 Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 275 280 285 Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala 290 295 300 Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile 305 310 315 320 Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 325 330 335 Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 340 345 350 Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr 355 360 <210> SEQ ID NO 192 <211> LENGTH: 450 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 192 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> SEQ ID NO 193 <211> LENGTH: 711 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 193 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 465 470 475 480 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 485 490 495 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 500 505 510 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 515 520 525 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 530 535 540 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 545 550 555 560 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 565 570 575 Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 595 600 605 Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr 610 615 620 Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr 625 630 635 640 Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser 645 650 655 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 660 665 670 Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala 675 680 685 Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly 690 695 700 Gly Thr Lys Leu Glu Ile Lys 705 710 <210> SEQ ID NO 194 <211> LENGTH: 713 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 194 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 465 470 475 480 Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp 485 490 495 Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp 500 505 510 Met Gly Tyr Ile Thr Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 515 520 525 Glu Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Thr Asn Gln Phe Phe 530 535 540 Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys 545 550 555 560 Ala Arg Gly Gly Tyr Tyr Gly Ser Ser Trp Gly Val Phe Ala Tyr Trp 565 570 575 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly 580 585 590 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 595 600 605 Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly Glu Thr 610 615 620 Val Thr Ile Thr Cys Arg Val Ser Glu Asn Ile Tyr Ser Tyr Leu Ala 625 630 635 640 Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val Tyr Asn 645 650 655 Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 660 665 670 Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro Glu Asp 675 680 685 Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Trp Thr Phe 690 695 700 Gly Gly Gly Thr Lys Leu Glu Ile Lys 705 710 <210> SEQ ID NO 195 <211> LENGTH: 708 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 195 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gln Val Gln Leu Gln Gln Ser Ala Val Glu Leu Ala Arg Pro Gly Ala 465 470 475 480 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe 485 490 495 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 500 505 510 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe 515 520 525 Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 530 535 540 Met Gln Leu Asp Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 545 550 555 560 Val Arg Gly Ser Ser Arg Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 565 570 575 Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 580 585 590 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Ile Gln Ser 595 600 605 Pro Ala Ser Leu Ser Val Ser Val Gly Glu Thr Val Thr Ile Thr Cys 610 615 620 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Phe Gln Gln Lys 625 630 635 640 Gln Gly Lys Ser Pro Gln Leu Leu Val Tyr Ala Ala Thr Asn Leu Ala 645 650 655 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr 660 665 670 Ser Leu Lys Ile Asn Ser Leu Gln Ser Glu Asp Phe Gly Ile Tyr Tyr 675 680 685 Cys Gln His Phe Trp Gly Thr Pro Arg Thr Phe Gly Gly Gly Thr Lys 690 695 700 Leu Glu Ile Lys 705 <210> SEQ ID NO 196 <400> SEQUENCE: 196 000 <210> SEQ ID NO 197 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 197 Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> SEQ ID NO 198 <211> LENGTH: 1653 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 198 tacaacttct tcccacggaa acccaagtgg gacaagaacc agatcaccta ccggatcatc 60 ggctacaccc ctgacctgga tcctgagaca gtggacgatg ccttcgccag agccttccaa 120 gtttggagcg acgtgacccc tctgcggttc tccagaatcc atgatggcga ggccgacatc 180 atgatcaact tcggcagatg ggagcacggc gacggctacc cttttgatgg caaggatggc 240 ctgctggccc acgcttttgc ccctggaaca ggtgttggcg gcgactctca cttcgacgac 300 gatgagttgt ggaccctcgg cgaaggacag gtcgtcagag tgaagtacgg caacgccgat 360 ggcgagtact gcaagttccc cttcctgttc aacggcaaag agtacaactc ctgcaccgac 420 accggcagat ctgacggctt cctgtggtgc tccaccacct acaactttga gaaggacggc 480 aaatacggct tctgccctca cgaggccctg tttaccatgg gcggaaatgc tgagggccag 540 ccatgcaagt ttccattccg gttccaaggg acctcctacg acagctgtac caccgaggga 600 agaaccgatg gctatcgttg gtgcggcacc acagaggact acgacagaga caagaagtat 660 ggcttctgtc ccgagacagc catgtctacc gtcggcggca attctgaagg cgccccttgt 720 gtgttccctt tcaccttcct gggcaacaaa tacgagtcct gcacctccgc tggccgctct 780 gatggaaaaa tgtggtgcgc taccaccgcc aactacgacg acgacagaaa gtggggcttt 840 tgtcctgacc agggctactc cctgtttctg gtggccgctc acgagtttgg ccatgctatg 900 ggcctcgagc actctcaaga tcccggtgca ctgatggccc ctatctacac ctacaccaag 960 aacttccggc tgtcccagga cgacatcaag ggcatccaag agctgtacgg cgcctctcct 1020 gatatcgatc tcggcaccgg acctactcct acactgggac ctgtgacacc cgagatctgc 1080 aagcaggaca tcgtgttcga cggaatcgcc cagatccggg gcgagatctt cttttttaag 1140 gaccggttca tctggcggac agtgacccct agagacaagc ctatgggacc tctgctggtg 1200 gctaccttct ggcctgagct gcctgagaag atcgacgccg tgtacgaggc ccctcaagag 1260 gaaaaggccg tctttttcgc cggcaacgag tactggatct actccgcttc taccctggaa 1320 cggggctacc ccaagcctct gacatctctg ggactgcctc cagacgtgca gagagtggac 1380 gccgccttca actggtccaa gaacaagaaa acctacatct tcgccgggga caagttctgg 1440 cggtacaacg aagtgaagaa aaagatggac cctggcttcc ccaagctgat cgccgatgcc 1500 tggaacgcta tccccgataa cctggacgct gtggtggatc tccaaggcgg cggacactcc 1560 tactttttca agggcgccta ctacctgaag ctggaaaacc agagcctgaa gtccgtgaag 1620 ttcggctcca tcaagtccga ctggctcgga tgt 1653 <210> SEQ ID NO 199 <211> LENGTH: 1242 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 199 ttcagaggcc ctctgctgcc caacagaccc ttcaccaccg tgtggaacgc caacacccag 60 tggtgcctgg aaagacacgg cgtggacgtg gacgtgtccg tgttcgatgt ggtggccaac 120 cccggccaga ccttcagggg ccctgacatg accatcttct actccagcca gctgggcacc 180 tacccctact acacccctac aggcgagcct gtgtttggcg gcctgcctca gaacgcctct 240 ctgatcgctc acctggcccg gaccttccag gacatcctgg ctgctatccc tgcccccgac 300 ttttctggcc tggccgtgat cgattgggag gcctggcgac ctagatgggc cttcaactgg 360 gacaccaagg acatctaccg gcagcggtcc agagccctgg tgcaggctca gcatcctgat 420 tggcctgccc ctcaggtgga agccgtggcc caggatcagt ttcagggcgc tgccagagct 480 tggatggctg gcacactgca gctgggaagg gccctgaggc ctagaggact gtggggcttc 540 tacggcttcc ccgactgcta caactacgac ttcctgtccc ccaactacac cggccagtgc 600 ccctctggaa tccgggccca gaatgatcag ctgggctggc tgtggggcca gtctagagcc 660 ctgtacccct ccatctacat gcccgccgtg ctggaaggca ccggcaagtc ccagatgtac 720 gtgcagcaca gagtggccga ggccttcagg gtggcagtgg ctgctggcga tcctaacctg 780 cccgtgctgc cctacgtgca gatcttctac gataccacca accactttct gcccctggac 840 gagctggaac actccctggg agagtctgct gctcagggtg ctgcaggcgt ggtgctgtgg 900 gtgtcctggg agaacacccg gaccaaagag tcctgccagg ccatcaaaga gtacatggac 960 accaccctgg gccccttcat cctgaacgtg acctctggcg ccctgctgtg tagccaggct 1020 ctgtgttctg gccacggcag atgcgtgcgg agaacctctc accctaaggc tctgctgctg 1080 ctgaaccccg cctccttcag catccagctg acacctggcg gcggacccct gtctctgaga 1140 ggtgctctgt ccctggaaga tcaggcccag atggccgtgg aattcaagtg ccggtgctac 1200 cctggctggc aggccccttg gtgcgagcgg aaatctatgt gg 1242 <210> SEQ ID NO 200 <211> LENGTH: 372 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 200 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 120 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 180 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 240 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 300 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 360 accgtgtcct ct 372 <210> SEQ ID NO 201 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 201 gacatcgtga tgacccagtc tccagactct ctggccgtgt ctctgggcga gagagccacc 60 atcaactgca agtcctctca gtccctgctg tactcccgga accagaagaa ctacctggcc 120 tggtatcagc agaagcccgg ccagcctcct aagctgctga tcttctgggc ctccaccaga 180 gaatctggcg tgcccgatag attctccggc tctggctttg gcaccgactt taccctgacc 240 atcagctccc tgcaggccga ggatgtggcc gtgtactact gccagcagta cttcagctac 300 cctctgacct ttggccaggg caccaaggtg gaaatcaag 339 <210> SEQ ID NO 202 <211> LENGTH: 1428 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 202 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct agggaacccc aggtttacac cctgcctcca 1140 tgccgggaag agatgaccaa gaaccaggtg tccctgtggt gcctcgtgaa gggcttctac 1200 ccttccgata tcgccgtgga atgggagagc aatggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgt acagcaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca agtgatga 1428 <210> SEQ ID NO 203 <211> LENGTH: 726 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 203 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 gacatcgtga tgacccagtc tccagactct ctggccgtgt ctctgggcga gagagccacc 120 atcaactgca agtcctctca gtccctgctg tactcccgga accagaagaa ctacctggcc 180 tggtatcagc agaagcccgg ccagcctcct aagctgctga tcttctgggc ctccaccaga 240 gaatctggcg tgcccgatag attctccggc tctggctttg gcaccgactt taccctgacc 300 atcagctccc tgcaggccga ggatgtggcc gtgtactact gccagcagta cttcagctac 360 cctctgacct ttggccaggg caccaaggtg gaaatcaagc ggacagtggc cgctccttcc 420 gtgttcatct tcccaccttc cgacgagcag ctgaagtctg gcacagcctc tgtcgtgtgc 480 ctgctgaaca acttctaccc tcgggaagcc aaggtgcagt ggaaggtgga caatgccctg 540 cagtccggca actcccaaga gtctgtgacc gagcaggact ccaaggacag cacctacagc 600 ctgtcctcca cactgaccct gtccaaggcc gactacgaga agcacaaggt gtacgcctgc 660 gaagtgaccc atcagggcct gtctagccct gtgaccaagt ctttcaaccg gggcgagtgc 720 tgatga 726 <210> SEQ ID NO 204 <211> LENGTH: 3126 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 204 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct cgggaacctc aagtctgtac cctgcctcct 1140 agccgggaag agatgaccaa gaaccaggtg tccctgagct gcgccgtgaa gggcttctac 1200 ccttctgata tcgccgtgga atgggagagc aacggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca aaggtggcgg aggatctggc 1440 ggaggtggaa gcggcggagg cggctcttac aacttcttcc cacggaaacc caagtgggat 1500 aagaaccaga tcacctaccg gatcatcggc tacacccctg acctggatcc tgagactgtg 1560 gacgatgcct tcgccagggc cttccaagtt tggagcgacg tgacccctct gcggttctcc 1620 agaatccatg atggcgaggc cgacatcatg atcaacttcg gcagatggga gcacggcgac 1680 ggctaccctt ttgatggcaa ggatggcctg ctggcccacg cttttgcccc tggaacaggt 1740 gttggcggcg actctcactt cgacgacgat gagttgtgga ccctcggcga aggacaggtc 1800 gtcagagtga agtacggcaa cgccgatggc gagtactgca agttcccctt cctgttcaat 1860 gggaaagagt ataactcctg caccgacacc ggcagatctg acggcttcct gtggtgctcc 1920 accacctaca acttcgagaa ggacggcaaa tacggcttct gccctcacga ggctctgttc 1980 accatgggcg gaaatgctga gggacagccc tgcaagtttc cattcagatt ccaagggacc 2040 tcctacgact cttgcaccac cgagggaaga accgatggct atcgttggtg cggcaccaca 2100 gaggactacg accgggacaa gaagtatggc ttctgtcccg agacagccat gtctaccgtc 2160 ggcggcaatt ctgagggtgc cccttgcgtg ttccctttca ccttcctggg caacaaatac 2220 gagtcctgca cctccgctgg cagatccgat ggaaagatgt ggtgcgctac caccgccaac 2280 tacgacgacg acagaaagtg gggcttttgt cctgaccagg gctacagcct gtttctggtg 2340 gccgctcacg agttcggcca tgctatggga ctcgagcact ctcaagatcc cggcgcactg 2400 atggccccta tctacaccta caccaagaac ttccggctgt cccaggacga catcaagggc 2460 atccaagagc tgtacggcgc ctctcctgat atcgatctcg gcaccggacc tactcctaca 2520 ctgggacctg tgacacccga gatctgcaag caggatatcg tgttcgacgg aatcgcccag 2580 atccggggcg agatcttctt ttttaaggac cgcttcattt ggcggaccgt gactcctcgg 2640 gacaagccta tgggacctct gctggtggct accttctggc ctgaactgcc cgagaagatc 2700 gatgccgtgt acgaggcccc tcaagaggaa aaggccgtct ttttcgccgg caacgagtac 2760 tggatctact ccgctagcac cctggaacgg ggctacccta agcctctgac ttctctggga 2820 ctgccacctg acgtgcagcg agtggatgcc gccttcaact ggtccaagaa caagaaaacc 2880 tatatcttcg ccggggacaa gttctggcgg tacaacgaag tcaagaaaaa gatggaccct 2940 ggcttcccca agctgatcgc cgatgcctgg aacgctatcc ccgataacct ggacgctgtg 3000 gtggacttgc aaggcggcgg acactcctac tttttcaagg gcgcctacta cctgaagctg 3060 gaaaaccaga gcctgaagtc cgtgaagttc ggctccatca agtccgactg gctgggctgc 3120 tgatga 3126 <210> SEQ ID NO 205 <211> LENGTH: 2445 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 205 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg ctctaccggc 60 tacaacttct tcccacggaa acccaagtgg gacaagaacc agatcaccta ccggatcatc 120 ggctacaccc ctgacctgga tcctgagaca gtggacgatg ccttcgccag agccttccaa 180 gtttggagcg acgtgacccc tctgcggttc tccagaatcc atgatggcga ggccgacatc 240 atgatcaact tcggcagatg ggagcacggc gacggctacc cttttgatgg caaggatggc 300 ctgctggccc acgcttttgc ccctggaaca ggtgttggcg gcgactctca cttcgacgac 360 gatgagttgt ggaccctcgg cgaaggacag gtcgtcagag tgaagtacgg caacgccgat 420 ggcgagtact gcaagttccc cttcctgttc aacggcaaag agtacaactc ctgcaccgac 480 accggcagat ctgacggctt cctgtggtgc tccaccacct acaactttga gaaggacggc 540 aaatacggct tctgccctca cgaggccctg tttaccatgg gcggaaatgc tgagggccag 600 ccatgcaagt ttccattccg gttccaaggg acctcctacg acagctgtac caccgaggga 660 agaaccgatg gctatcgttg gtgcggcacc acagaggact acgacagaga caagaagtat 720 ggcttctgtc ccgagacagc catgtctacc gtcggcggca attctgaagg cgccccttgt 780 gtgttccctt tcaccttcct gggcaacaaa tacgagtcct gcacctccgc tggccgctct 840 gatggaaaaa tgtggtgcgc taccaccgcc aactacgacg acgacagaaa gtggggcttt 900 tgtcctgacc agggctactc cctgtttctg gtggccgctc acgagtttgg ccatgctatg 960 ggcctcgagc actctcaaga tcccggtgca ctgatggccc ctatctacac ctacaccaag 1020 aacttccggc tgtcccagga cgacatcaag ggcatccaag agctgtacgg cgcctctcct 1080 gatatcgatc tcggcaccgg acctactcct acactgggac ctgtgacacc cgagatctgc 1140 aagcaggaca tcgtgttcga cggaatcgcc cagatccggg gcgagatctt cttttttaag 1200 gaccggttca tctggcggac agtgacccct agagacaagc ctatgggacc tctgctggtg 1260 gctaccttct ggcctgagct gcctgagaag atcgacgccg tgtacgaggc ccctcaagag 1320 gaaaaggccg tctttttcgc cggcaacgag tactggatct actccgcttc taccctggaa 1380 cggggctacc ccaagcctct gacatctctg ggactgcctc cagacgtgca gagagtggac 1440 gccgccttca actggtccaa gaacaagaaa acctacatct tcgccgggga caagttctgg 1500 cggtacaacg aagtgaagaa aaagatggac cctggcttcc ccaagctgat cgccgatgcc 1560 tggaacgcta tccccgataa cctggacgct gtggtggatc tccaaggcgg cggacactcc 1620 tactttttca agggcgccta ctacctgaag ctggaaaacc agagcctgaa gtccgtgaag 1680 ttcggctcca tcaagtccga ctggctcgga tgtggtggcg gaggaagcgg aggcggagga 1740 tctggcggtg gcggatctga taagacccac acctgtccac cttgtcctgc tccagaactg 1800 ctcggcggac cttccgtgtt cctgtttcct ccaaagccta aggacaccct gatgatctct 1860 cggacccctg aagtgacctg cgtggtggtg gatgtgtccc acgaggaccc agaagtgaag 1920 ttcaattggt acgtggacgg cgtggaagtg cacaacgcca agaccaagcc tagagaggaa 1980 cagtacaaca gcacctacag agtggtgtcc gtgctgaccg tgctgcacca ggattggctg 2040 aatgggaaag agtataagtg caaggtgtcc aacaaggccc tgcctgctcc tatcgaaaag 2100 accatcagca aggccaaggg acagccccgg gaacctcaag tctgtaccct gcctcctagc 2160 cgggaagaga tgaccaagaa tcaggtgtcc ctgtcttgcg ccgtgaaggg cttttacccc 2220 tccgatatcg ccgtggaatg ggagtctaat ggccagcctg agaacaacta caagaccaca 2280 cctcctgtgc tggactccga cggctcattc ttcctggtgt ccaagctgac tgtggacaag 2340 tccagatggc agcagggcaa cgtgttctcc tgctccgtga tgcacgaggc tctgcacaac 2400 cactacacac agaagtctct gagcctgtct cctggcaagt gatga 2445 <210> SEQ ID NO 206 <211> LENGTH: 1872 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 206 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct agggaacccc aggtttacac cctgcctcca 1140 tgccgggaag agatgaccaa gaaccaggtg tccctgtggt gcctcgtgaa gggcttctac 1200 ccttccgata tcgccgtgga atgggagagc aatggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgt acagcaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca aaggtggcgg aggatctggc 1440 ggaggtggaa gcggcggagg cggatctgct cctacatcct ccagcaccaa gaaaacccag 1500 ctgcagttgg agcatctgct gctggacctg cagatgatcc tgaatggcat caacaattac 1560 aagaacccca agctgacccg gatgctgacc gccaagtttg ccatgcctaa gaaggccacc 1620 gagctgaaac atctgcagtg cctggaagag gaactgaagc ccctggaaga agtgctgaat 1680 ctggcccagt ccaagaactt ccacctgagg cctcgggacc tgatctccaa catcaacgtg 1740 atcgtgctcg agctgaaggg ctccgagaca accttcatgt gcgagtacgc cgacgagaca 1800 gctaccatcg tggaatttct gaaccggtgg atcaccttct gccagtccat catcagcacc 1860 ctgacctgat ga 1872 <210> SEQ ID NO 207 <211> LENGTH: 2715 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 207 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct cgggaacctc aagtctgtac cctgcctcct 1140 agccgggaag agatgaccaa gaaccaggtg tccctgagct gcgccgtgaa gggcttctac 1200 ccttctgata tcgccgtgga atgggagagc aacggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca aaggtggcgg aggatctggc 1440 ggaggtggaa gcggcggagg cggatctttt agaggacctc tgctgcccaa ccggcctttc 1500 accacagtgt ggaacgctaa cacccagtgg tgcctggaaa gacacggcgt tgacgtggac 1560 gtgtccgtgt tcgatgtggt ggctaatccc ggccagacct tcagaggccc tgacatgacc 1620 atcttctact ccagccagct gggcacctat ccttactaca cccctacagg cgagcccgtg 1680 tttggaggct tgcctcagaa tgccagcctg atcgctcacc tggccagaac ctttcaggac 1740 atcctggctg ctatccccgc tcctgacttt tccggactgg ccgtgatcga ttgggaagcc 1800 tggcgaccta gatgggcctt caactgggac accaaggaca tctaccggca gcggtctaga 1860 gcactggtgc aggctcaaca tcctgactgg cctgctccac aggttgaggc tgttgcccag 1920 gatcagtttc agggcgctgc cagagcttgg atggctggaa cattgcagct ggggagagcc 1980 ctgaggccta gaggactgtg gggcttttac ggcttccccg actgctacaa ctacgacttc 2040 ctgtctccta actacaccgg ccagtgtcct tccggcatca gagcccagaa tgatcagctc 2100 ggatggctct ggggacagtc cagggctctg tacccctcca tctacatgcc tgctgtcctg 2160 gaaggcaccg gcaagtccca gatgtacgtg cagcatagag tggccgaggc cttcagagtg 2220 gctgttgctg ctggcgatcc taacctgcct gtgctgcctt acgtgcagat cttctacgat 2280 accaccaacc actttctgcc cctggacgag ctggaacact ccctgggaga atctgctgct 2340 caaggtgctg caggcgtggt gttgtgggtg tcctgggaaa acacccggac caaagagtcc 2400 tgccaggcca tcaaagagta tatggacacc acactgggcc ccttcatcct gaacgtgaca 2460 tctggcgcac tgctgtgcag ccaggcactg tgttctggac acggaagatg cgtgcggaga 2520 acctctcatc ccaaggctct gctgctgctg aaccctgcca gcttctccat ccagttgaca 2580 ccaggcggag gccctctgtc tttgagaggt gcactgtccc tggaagatca ggcccagatg 2640 gctgtggaat tcaagtgcag atgctacccc ggctggcaag ctccttggtg cgagagaaag 2700 tccatgtggt agtga 2715 <210> SEQ ID NO 208 <211> LENGTH: 1416 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 208 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaggtgcagc tgttggaatc tggcggagga ttggttcagc ctggcggctc tctgagactg 120 tcttgtgccg cttccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 180 cctggcaaag gactggaatg ggtgtcctct atctacccct ctggcggcat caccttttac 240 gccgacaccg tgaagggcag attcaccatc tctcgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc cagaatcaag 360 ctgggcaccg tgaccaccgt ggattattgg ggacagggca ccctggtcac cgtgtcctct 420 gcttctacca agggacccag cgtgttccct ctggctcctt ccagcaagtc tacctccggt 480 ggaacagctg ctctgggctg cctggtcaag gactactttc ctgagcctgt gaccgtgtct 540 tggaactccg gcgctctgac atctggcgtg cacacatttc cagccgtgct gcagtcctcc 600 ggcctgtact ctctcagctc tgtcgtgacc gtgccttcca gctctctggg aacccagacc 660 tacatctgca atgtgaacca caagccttcc aacaccaagg tggacaagag agtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 780 ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatctc tcggacccct 840 gaagtgacct gcgtggtggt ggatgtgtct cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctaca gagtggtgtc cgtgctgaca gtgctgcacc aggattggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgaaaa gaccatctcc 1080 aaggccaagg gccagcctag ggaaccccag gtttacaccc tgcctccatg ccgggaagag 1140 atgaccaaga accaggtgtc cctgtggtgc ctggttaagg gcttctaccc ttccgatatc 1200 gccgtggaat gggagagcaa tggccagcct gagaacaact acaagacaac ccctcctgtg 1260 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtccagatgg 1320 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa tcactacacc 1380 cagaagtccc tgtctctgag ccccggcaag tgatga 1416 <210> SEQ ID NO 209 <211> LENGTH: 1860 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 209 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaggtgcagc tgttggaatc tggcggagga ttggttcagc ctggcggctc tctgagactg 120 tcttgtgccg cttccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 180 cctggcaaag gactggaatg ggtgtcctct atctacccct ctggcggcat caccttttac 240 gccgacaccg tgaagggcag attcaccatc tctcgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc cagaatcaag 360 ctgggcaccg tgaccaccgt ggattattgg ggacagggca ccctggtcac cgtgtcctct 420 gcttctacca agggacccag cgtgttccct ctggctcctt ccagcaagtc tacctccggt 480 ggaacagctg ctctgggctg cctggtcaag gactactttc ctgagcctgt gaccgtgtct 540 tggaactccg gcgctctgac atctggcgtg cacacatttc cagccgtgct gcagtcctcc 600 ggcctgtact ctctcagctc tgtcgtgacc gtgccttcca gctctctggg aacccagacc 660 tacatctgca atgtgaacca caagccttcc aacaccaagg tggacaagag agtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 780 ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatctc tcggacccct 840 gaagtgacct gcgtggtggt ggatgtgtct cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctaca gagtggtgtc cgtgctgaca gtgctgcacc aggattggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgaaaa gaccatctcc 1080 aaggccaagg gccagcctag ggaaccccag gtttacaccc tgcctccatg ccgggaagag 1140 atgaccaaga accaggtgtc cctgtggtgc ctggttaagg gcttctaccc ttccgatatc 1200 gccgtggaat gggagagcaa tggccagcct gagaacaact acaagacaac ccctcctgtg 1260 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtccagatgg 1320 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa tcactacacc 1380 cagaagtccc tgtctctgtc tcccggaaaa ggcggaggtg gaagcggcgg aggcggatct 1440 ggtggcggtg gatctgctcc tacctcctcc agcaccaaga aaacccagct gcagttggag 1500 catctgctgc tggacctcca gatgatcctg aatggcatca acaattacaa gaaccccaag 1560 ctcacccgga tgctgaccgc caagtttgcc atgcctaaga aggccaccga gctgaaacat 1620 ctgcagtgcc tggaagagga actgaagccc ctggaagaag tgctgaatct ggcccagtcc 1680 aagaacttcc acctgaggcc tcgggacctg atctccaaca tcaacgtgat cgtgctcgag 1740 ctgaagggct ccgagacaac cttcatgtgc gagtacgccg acgagacagc taccatcgtg 1800 gaatttctga accggtggat caccttctgt cagtccatca tcagcaccct gacctgatga 1860 <210> SEQ ID NO 210 <211> LENGTH: 2703 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 210 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcagcagtc tggccctgaa cttgtgaagc ctggcgcctc cgtgaagatg 120 tcctgcaagg cttctggcta caccttcacc gactacgtga tcaactgggg caagcagaga 180 tctggccagg gcctcgagtg gatcggcgag atctatcctg gctccggcac caactactac 240 aacgagaagt tcaaggccaa ggctaccctg accgccgaca agtcctccaa tatcgcctac 300 atgcagctgt ccagcctgac ctctgaggac tccgccgtgt acttctgcgc cagaagaggc 360 agatacggcc tgtacgccat ggactattgg ggccagggca cctctgtgac cgtgtcctct 420 gcttctacca agggacccag cgtgttccct ctggctcctt ccagcaagtc tacctctggc 480 ggaacagctg ctctgggctg cctggtcaag gactactttc ctgagcctgt gacagtgtct 540 tggaactctg gcgccctgac atccggcgtg cacacatttc cagctgtgct gcagtcctct 600 ggcctgtact ctctgtcctc cgtcgtgacc gtgccttcta gctctctggg cacccagacc 660 tacatctgca atgtgaacca caagccttcc aacaccaagg tggacaagag agtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 780 ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatctc tcggacccct 840 gaagtgacct gcgtggtggt ggatgtgtct cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctaca gagtggtgtc cgtgctgacc gtgctgcacc aggattggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgaaaa gaccatctcc 1080 aaggctaagg gccagcctcg cgaaccccaa gtctgtacac tgcctcctag ccgggaagag 1140 atgaccaaga accaggtgtc cctgtcctgc gccgtgaagg gcttctaccc ttctgatatc 1200 gccgtggaat gggagtccaa cggccagcct gagaacaact acaagacaac ccctcctgtg 1260 ctggactccg acggctcatt cttcctggtg tccaagctga cagtggacaa gtcccgatgg 1320 cagcagggca acgtgttctc ctgctctgtg atgcacgagg ctctgcacaa ccactacacc 1380 cagaagtccc tgtctctgtc ccctggaaaa ggcggcggag gatctggcgg aggtggaagc 1440 ggaggcggtg gatcttttag aggacctctg ctgcccaacc ggcctttcac cacagtgtgg 1500 aacgctaaca cccagtggtg cctggaaaga catggcgtcg acgtggacgt gtccgtgttc 1560 gatgtggtgg ctaatcccgg ccagaccttc agaggccccg acatgaccat cttctactcc 1620 agccagctgg gcacctatcc ttactacacc cctacaggcg agcccgtgtt tggtggcttg 1680 cctcagaatg cctctctgat cgcccacctg gctagaacct tccaggatat tctggctgct 1740 atccccgctc ctgacttttc tggcctggcc gtgatcgatt gggaagcttg gaggcctaga 1800 tgggccttca actgggacac caaggacatc taccggcagc ggtctagagc actggtgcag 1860 gctcaacatc ctgactggcc tgctccacag gttgaggctg ttgcccagga tcagtttcag 1920 ggcgctgcca gagcttggat ggctggaaca ttgcagctgg ggagagccct gaggccaaga 1980 ggattgtggg gcttttacgg cttccccgac tgctacaact acgacttcct gtctcctaac 2040 tacaccggcc agtgtccttc cggcatcaga gcccagaatg atcagctcgg atggctctgg 2100 ggacagtcca gggctctgta cccctccatc tacatgcctg ctgtgctcga aggcaccggc 2160 aagtcccaga tgtacgtgca gcatagagtg gccgaggcct tcagagtggc tgttgctgct 2220 ggcgatccta acctgcctgt gctgccttac gtgcagatct tctacgatac caccaaccac 2280 tttctgcccc tggacgagct ggaacactcc ctgggagaat ctgctgctca aggtgctgca 2340 ggcgtggtgt tgtgggtgtc ctgggaaaac acccggacca aagagtcctg ccaggccatc 2400 aaagagtata tggacaccac actgggcccc ttcatcctga acgtgacatc tggcgctctg 2460 ctgtgcagcc aggctctgtg ttctggccat ggtagatgcg tgcggagaac ctctcatccc 2520 aaggctctgc tgctgctgaa ccctgccagc ttctccatcc agttgacacc aggcggaggc 2580 cctctgtctt tgagaggtgc actgtccctg gaagatcagg cccagatggc tgtggaattc 2640 aagtgcagat gctaccccgg ctggcaagct ccttggtgcg agagaaagtc catgtggtag 2700 tga 2703 <210> SEQ ID NO 211 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 211 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 gacatccaga tgacccagac cacctctagc ctgtctgcct ctctgggcga cagagtgacc 120 atctcctgta gagccagcca ggacatctcc aactacctga actggtatca gcagaaaccc 180 gacggcaccg tgaagctgct gatctactac acctctcggc tgcactctgg cgtgccctct 240 agattttctg gctccggctc tggcaccgac tactccctga ccatcaacaa cctggaacaa 300 gaggatatcg ctacctactt ctgccagcaa ggcaacaccc ggccttggac atttggcggc 360 ggaacaaagc tggaaatcaa gcggacagtg gccgctcctt ccgtgttcat cttcccacct 420 tccgacgagc agctgaagtc cggcacagct tctgtcgtgt gcctgctgaa caacttctac 480 cctcgggaag ccaaggtgca gtggaaggtg gacaatgccc tgcagtccgg caactcccaa 540 gagtctgtga ccgagcagga ctccaaggac agcacctaca gcctgtcctc cacactgacc 600 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccatcagggc 660 ctgtctagcc ctgtgaccaa gtctttcaac cggggcgagt gctgatga 708 <210> SEQ ID NO 212 <211> LENGTH: 2037 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 212 atggctgctc atctgctgcc tatctgcgcc ctgttcctga ccctgctgga tatggcccag 60 ggcttcagag gccctctgct gcccaacaga cccttcacca ccgtgtggaa cgccaacacc 120 cagtggtgcc tggaaagaca cggcgtggac gtggacgtgt ccgtgttcga tgtggtggcc 180 aaccccggcc agaccttcag gggccctgac atgaccatct tctactccag ccagctgggc 240 acctacccct actacacccc tacaggcgag cctgtgtttg gcggcctgcc tcagaacgcc 300 tctctgatcg ctcacctggc ccggaccttc caggacatcc tggctgctat ccctgccccc 360 gacttttctg gcctggccgt gatcgattgg gaggcctggc gacctagatg ggccttcaac 420 tgggacacca aggacatcta ccggcagcgg tccagagccc tggtgcaggc tcagcatcct 480 gattggcctg cccctcaggt ggaagccgtg gcccaggatc agtttcaggg cgctgccaga 540 gcttggatgg ctggcacact gcagctggga agggccctga ggcctagagg actgtggggc 600 ttctacggct tccccgactg ctacaactac gacttcctgt cccccaacta caccggccag 660 tgcccctctg gaatccgggc ccagaatgat cagctgggct ggctgtgggg ccagtctaga 720 gccctgtacc cctccatcta catgcccgcc gtgctggaag gcaccggcaa gtcccagatg 780 tacgtgcagc acagagtggc cgaggccttc agggtggcag tggctgctgg cgatcctaac 840 ctgcccgtgc tgccctacgt gcagatcttc tacgatacca ccaaccactt tctgcccctg 900 gacgagctgg aacactccct gggagagtct gctgctcagg gtgctgcagg cgtggtgctg 960 tgggtgtcct gggagaacac ccggaccaaa gagtcctgcc aggccatcaa agagtacatg 1020 gacaccaccc tgggcccctt catcctgaac gtgacctctg gcgccctgct gtgtagccag 1080 gctctgtgtt ctggccacgg cagatgcgtg cggagaacct ctcaccctaa ggctctgctg 1140 ctgctgaacc ccgcctcctt cagcatccag ctgacacctg gcggcggacc cctgtctctg 1200 agaggtgctc tgtccctgga agatcaggcc cagatggccg tggaattcaa gtgccggtgc 1260 taccctggct ggcaggcccc ttggtgcgag cggaaatcta tgtggggcgg aggcggatca 1320 ggcggcggag gatctggggg tggtggctct gataagaccc acacctgtcc tccctgccct 1380 gcccctgaac tgctgggagg cccttccgtg ttcctgttcc ccccaaagcc caaggacacc 1440 ctgatgatct cccggacccc cgaagtgacc tgcgtggtgg tggatgtgtc ccacgaggac 1500 cctgaagtga agttcaattg gtacgtggac ggggtggaag tgcacaacgc caagaccaag 1560 cccagagagg aacagtacaa ctccacctac agagtggtgt ccgtgctgac cgtgctgcat 1620 caggactggc tgaacggcaa agagtataag tgcaaggtgt ccaacaaggc cctgcccgct 1680 cccatcgaaa agaccatctc caaggccaag ggccagcccc gggaacctca agtgtgcacc 1740 ctgcctccat cccgggaaga gatgaccaag aaccaggtgt ccctgtcctg cgccgtgaag 1800 ggcttttacc cctccgatat cgctgtggaa tgggagtcca acggccagcc tgagaacaac 1860 tacaagacca ccccccctgt gctggactcc gacggctcat tcttcctggt gtccaagctg 1920 acagtggaca agtcccggtg gcagcagggc aacgtgttct cctgctccgt gatgcacgag 1980 gccctgcaca accactacac ccagaagtcc ctgagcctgt cccctggcaa gtgatga 2037 <210> SEQ ID NO 213 <211> LENGTH: 2385 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 213 atgaagacct gggtcaagat cgtgtttggc gtggccacct ctgctgtgct ggctctgctg 60 gtcatgtgca tcgtgctgcg gccttccaga gtgcacaact ccgaagagaa caccatgcgg 120 gctctgaccc tgaaggacat cctgaacggc accttcagct acaagacctt ctttcccaac 180 tggatctccg gccaagagta cctgcaccag tccgccgaca acaatatcgt gctgtacaac 240 atcgagacag gccagtccta caccatcctg tccaaccgga ccatgaagtc cgtgaacgcc 300 tccaactacg gactgtctcc tgaccggcag ttcgtgtacc tggaatccga ctactccaag 360 ctgtggcggt actcctacac cgccacctac tacatctacg acctgagcaa cggcgagttc 420 gtgcggggaa atgagctgcc cagacctatc cagtacctgt gctggtcccc tgtgggctct 480 aagctggctt acgtgtacca gaacaacatc tacctgaagc agcggcctgg cgaccctcca 540 ttccagatca ccttcaacgg cagagagaac aagatcttta acggcatccc cgactgggtg 600 tacgaggaag agatgctgcc cactaagtac gccctctggt ggtcccctaa cggcaagttt 660 ctggcctacg ccgagttcaa cgacaaggat atccccgtga tcgcctactc ctactacggc 720 gacgagcagt accctcggac catcaacatc ccttatccta aggctggcgc caagaatccc 780 gtcgtgcgga tcttcatcat cgacaccacc tatcctgcct acgtgggccc tcaagaggtg 840 ccagtgcctg ctatgatcgc ctccagcgac tactacttct cctggctgac atgggtcacc 900 gacgagcgag tttgtctgca gtggctgaag cgggtgcaga acgtgtccgt gctgtccatc 960 tgcgacttca gagaggactg gcagacctgg gactgcccca agacacaaga gcacatcgag 1020 gaatctcgga ccggatgggc tggcggcttc ttcgtgtcta gacccgtgtt ctcctacgac 1080 gccatcagct actataagat cttctccgac aaggacggct acaagcacat ccactacatc 1140 aaggacaccg tcgagaacgc catccagatt acctccggca agtgggaagc catcaatatc 1200 ttcagagtga cccaggactc cctgttctac tcctccaacg agttcgagga ataccccggc 1260 agacggaaca tctacagaat ctccatcggc agctaccctc catccaagaa atgcgtgacc 1320 tgccacctga gaaaagagcg gtgccagtac tataccgcca gcttctctga ctacgccaag 1380 tactacgccc tcgtgtgtta cggccctggc atccctatct ctaccctgca cgatggcaga 1440 accgaccaag agatcaagat cctggaagaa aacaaagagc tggaaaacgc cctgaagaac 1500 attcagctgc ccaaagagga aatcaagaag ctggaagtcg acgagatcac cctgtggtac 1560 aagatgatcc tgcctcctca gttcgaccgg tccaagaagt accctctgct gatccaggtg 1620 tacggcggac cttgctctca gtccgtcaga tctgtgttcg ccgtgaattg gatctcctac 1680 ctggcctcca aagaaggcat ggttatcgcc ctggtggacg gcagaggcac agcttttcaa 1740 ggcgacaagc tgctgtacgc cgtgtacaga aagctgggcg tgtacgaagt ggaagatcag 1800 atcaccgccg tgcggaagtt catcgagatg ggcttcatcg acgagaagcg gatcgctatc 1860 tggggctggt cttacggcgg ctacgtttcc tctctggccc tggcttctgg caccggcctg 1920 ttcaagtgtg gaatcgctgt tgcccctgtg tcctcctggg agtactatgc ctctgtgtac 1980 accgagcggt tcatgggcct gcctaccaag gacgacaacc tggaacacta caagaacagc 2040 accgtgatgg ccagagccga gtacttccgg aacgtggact acctgctgat tcacggcacc 2100 gccgacgaca acgtgcactt ccaaaacagc gcccagatcg ccaaggctct ggtcaatgcc 2160 caggtggact ttcaggccat gtggtactcc gaccagaacc acggcctgtc tggcctgagc 2220 accaatcacc tgtacaccca catgacccac tttctgaagc agtgcttctc cctgtctgat 2280 ggcggcggag gctctggact gaacgatatc ttcgaggccc agaaaatcga gtggcacgaa 2340 ggcggaggcg gctcccacca tcatcatcac caccatcact gatga 2385 <210> SEQ ID NO 214 <211> LENGTH: 454 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 214 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> SEQ ID NO 215 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 215 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 216 <211> LENGTH: 1020 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 216 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Tyr Asn Phe Phe Pro Arg Lys Pro Lys Trp Asp 465 470 475 480 Lys Asn Gln Ile Thr Tyr Arg Ile Ile Gly Tyr Thr Pro Asp Leu Asp 485 490 495 Pro Glu Thr Val Asp Asp Ala Phe Ala Arg Ala Phe Gln Val Trp Ser 500 505 510 Asp Val Thr Pro Leu Arg Phe Ser Arg Ile His Asp Gly Glu Ala Asp 515 520 525 Ile Met Ile Asn Phe Gly Arg Trp Glu His Gly Asp Gly Tyr Pro Phe 530 535 540 Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe Ala Pro Gly Thr Gly 545 550 555 560 Val Gly Gly Asp Ser His Phe Asp Asp Asp Glu Leu Trp Thr Leu Gly 565 570 575 Glu Gly Gln Val Val Arg Val Lys Tyr Gly Asn Ala Asp Gly Glu Tyr 580 585 590 Cys Lys Phe Pro Phe Leu Phe Asn Gly Lys Glu Tyr Asn Ser Cys Thr 595 600 605 Asp Thr Gly Arg Ser Asp Gly Phe Leu Trp Cys Ser Thr Thr Tyr Asn 610 615 620 Phe Glu Lys Asp Gly Lys Tyr Gly Phe Cys Pro His Glu Ala Leu Phe 625 630 635 640 Thr Met Gly Gly Asn Ala Glu Gly Gln Pro Cys Lys Phe Pro Phe Arg 645 650 655 Phe Gln Gly Thr Ser Tyr Asp Ser Cys Thr Thr Glu Gly Arg Thr Asp 660 665 670 Gly Tyr Arg Trp Cys Gly Thr Thr Glu Asp Tyr Asp Arg Asp Lys Lys 675 680 685 Tyr Gly Phe Cys Pro Glu Thr Ala Met Ser Thr Val Gly Gly Asn Ser 690 695 700 Glu Gly Ala Pro Cys Val Phe Pro Phe Thr Phe Leu Gly Asn Lys Tyr 705 710 715 720 Glu Ser Cys Thr Ser Ala Gly Arg Ser Asp Gly Lys Met Trp Cys Ala 725 730 735 Thr Thr Ala Asn Tyr Asp Asp Asp Arg Lys Trp Gly Phe Cys Pro Asp 740 745 750 Gln Gly Tyr Ser Leu Phe Leu Val Ala Ala His Glu Phe Gly His Ala 755 760 765 Met Gly Leu Glu His Ser Gln Asp Pro Gly Ala Leu Met Ala Pro Ile 770 775 780 Tyr Thr Tyr Thr Lys Asn Phe Arg Leu Ser Gln Asp Asp Ile Lys Gly 785 790 795 800 Ile Gln Glu Leu Tyr Gly Ala Ser Pro Asp Ile Asp Leu Gly Thr Gly 805 810 815 Pro Thr Pro Thr Leu Gly Pro Val Thr Pro Glu Ile Cys Lys Gln Asp 820 825 830 Ile Val Phe Asp Gly Ile Ala Gln Ile Arg Gly Glu Ile Phe Phe Phe 835 840 845 Lys Asp Arg Phe Ile Trp Arg Thr Val Thr Pro Arg Asp Lys Pro Met 850 855 860 Gly Pro Leu Leu Val Ala Thr Phe Trp Pro Glu Leu Pro Glu Lys Ile 865 870 875 880 Asp Ala Val Tyr Glu Ala Pro Gln Glu Glu Lys Ala Val Phe Phe Ala 885 890 895 Gly Asn Glu Tyr Trp Ile Tyr Ser Ala Ser Thr Leu Glu Arg Gly Tyr 900 905 910 Pro Lys Pro Leu Thr Ser Leu Gly Leu Pro Pro Asp Val Gln Arg Val 915 920 925 Asp Ala Ala Phe Asn Trp Ser Lys Asn Lys Lys Thr Tyr Ile Phe Ala 930 935 940 Gly Asp Lys Phe Trp Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro 945 950 955 960 Gly Phe Pro Lys Leu Ile Ala Asp Ala Trp Asn Ala Ile Pro Asp Asn 965 970 975 Leu Asp Ala Val Val Asp Leu Gln Gly Gly Gly His Ser Tyr Phe Phe 980 985 990 Lys Gly Ala Tyr Tyr Leu Lys Leu Glu Asn Gln Ser Leu Lys Ser Val 995 1000 1005 Lys Phe Gly Ser Ile Lys Ser Asp Trp Leu Gly Cys 1010 1015 1020 <210> SEQ ID NO 217 <211> LENGTH: 793 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 217 Tyr Asn Phe Phe Pro Arg Lys Pro Lys Trp Asp Lys Asn Gln Ile Thr 1 5 10 15 Tyr Arg Ile Ile Gly Tyr Thr Pro Asp Leu Asp Pro Glu Thr Val Asp 20 25 30 Asp Ala Phe Ala Arg Ala Phe Gln Val Trp Ser Asp Val Thr Pro Leu 35 40 45 Arg Phe Ser Arg Ile His Asp Gly Glu Ala Asp Ile Met Ile Asn Phe 50 55 60 Gly Arg Trp Glu His Gly Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly 65 70 75 80 Leu Leu Ala His Ala Phe Ala Pro Gly Thr Gly Val Gly Gly Asp Ser 85 90 95 His Phe Asp Asp Asp Glu Leu Trp Thr Leu Gly Glu Gly Gln Val Val 100 105 110 Arg Val Lys Tyr Gly Asn Ala Asp Gly Glu Tyr Cys Lys Phe Pro Phe 115 120 125 Leu Phe Asn Gly Lys Glu Tyr Asn Ser Cys Thr Asp Thr Gly Arg Ser 130 135 140 Asp Gly Phe Leu Trp Cys Ser Thr Thr Tyr Asn Phe Glu Lys Asp Gly 145 150 155 160 Lys Tyr Gly Phe Cys Pro His Glu Ala Leu Phe Thr Met Gly Gly Asn 165 170 175 Ala Glu Gly Gln Pro Cys Lys Phe Pro Phe Arg Phe Gln Gly Thr Ser 180 185 190 Tyr Asp Ser Cys Thr Thr Glu Gly Arg Thr Asp Gly Tyr Arg Trp Cys 195 200 205 Gly Thr Thr Glu Asp Tyr Asp Arg Asp Lys Lys Tyr Gly Phe Cys Pro 210 215 220 Glu Thr Ala Met Ser Thr Val Gly Gly Asn Ser Glu Gly Ala Pro Cys 225 230 235 240 Val Phe Pro Phe Thr Phe Leu Gly Asn Lys Tyr Glu Ser Cys Thr Ser 245 250 255 Ala Gly Arg Ser Asp Gly Lys Met Trp Cys Ala Thr Thr Ala Asn Tyr 260 265 270 Asp Asp Asp Arg Lys Trp Gly Phe Cys Pro Asp Gln Gly Tyr Ser Leu 275 280 285 Phe Leu Val Ala Ala His Glu Phe Gly His Ala Met Gly Leu Glu His 290 295 300 Ser Gln Asp Pro Gly Ala Leu Met Ala Pro Ile Tyr Thr Tyr Thr Lys 305 310 315 320 Asn Phe Arg Leu Ser Gln Asp Asp Ile Lys Gly Ile Gln Glu Leu Tyr 325 330 335 Gly Ala Ser Pro Asp Ile Asp Leu Gly Thr Gly Pro Thr Pro Thr Leu 340 345 350 Gly Pro Val Thr Pro Glu Ile Cys Lys Gln Asp Ile Val Phe Asp Gly 355 360 365 Ile Ala Gln Ile Arg Gly Glu Ile Phe Phe Phe Lys Asp Arg Phe Ile 370 375 380 Trp Arg Thr Val Thr Pro Arg Asp Lys Pro Met Gly Pro Leu Leu Val 385 390 395 400 Ala Thr Phe Trp Pro Glu Leu Pro Glu Lys Ile Asp Ala Val Tyr Glu 405 410 415 Ala Pro Gln Glu Glu Lys Ala Val Phe Phe Ala Gly Asn Glu Tyr Trp 420 425 430 Ile Tyr Ser Ala Ser Thr Leu Glu Arg Gly Tyr Pro Lys Pro Leu Thr 435 440 445 Ser Leu Gly Leu Pro Pro Asp Val Gln Arg Val Asp Ala Ala Phe Asn 450 455 460 Trp Ser Lys Asn Lys Lys Thr Tyr Ile Phe Ala Gly Asp Lys Phe Trp 465 470 475 480 Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro Gly Phe Pro Lys Leu 485 490 495 Ile Ala Asp Ala Trp Asn Ala Ile Pro Asp Asn Leu Asp Ala Val Val 500 505 510 Asp Leu Gln Gly Gly Gly His Ser Tyr Phe Phe Lys Gly Ala Tyr Tyr 515 520 525 Leu Lys Leu Glu Asn Gln Ser Leu Lys Ser Val Lys Phe Gly Ser Ile 530 535 540 Lys Ser Asp Trp Leu Gly Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly 545 550 555 560 Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 565 570 575 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 580 585 590 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 595 600 605 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 610 615 620 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 625 630 635 640 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 645 650 655 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 660 665 670 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 675 680 685 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 690 695 700 Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro 705 710 715 720 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 725 730 735 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 740 745 750 Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 755 760 765 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 770 775 780 Lys Ser Leu Ser Leu Ser Pro Gly Lys 785 790 <210> SEQ ID NO 218 <211> LENGTH: 602 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 218 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln 465 470 475 480 Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly 485 490 495 Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys 500 505 510 Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu 515 520 525 Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser 530 535 540 Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val 545 550 555 560 Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr 565 570 575 Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr 580 585 590 Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr 595 600 <210> SEQ ID NO 219 <211> LENGTH: 883 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 219 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe 465 470 475 480 Thr Thr Val Trp Asn Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly 485 490 495 Val Asp Val Asp Val Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln 500 505 510 Thr Phe Arg Gly Pro Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly 515 520 525 Thr Tyr Pro Tyr Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu 530 535 540 Pro Gln Asn Ala Ser Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp 545 550 555 560 Ile Leu Ala Ala Ile Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile 565 570 575 Asp Trp Glu Ala Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys 580 585 590 Asp Ile Tyr Arg Gln Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro 595 600 605 Asp Trp Pro Ala Pro Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln 610 615 620 Gly Ala Ala Arg Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala 625 630 635 640 Leu Arg Pro Arg Gly Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr 645 650 655 Asn Tyr Asp Phe Leu Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly 660 665 670 Ile Arg Ala Gln Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg 675 680 685 Ala Leu Tyr Pro Ser Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly 690 695 700 Lys Ser Gln Met Tyr Val Gln His Arg Val Ala Glu Ala Phe Arg Val 705 710 715 720 Ala Val Ala Ala Gly Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln 725 730 735 Ile Phe Tyr Asp Thr Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu 740 745 750 His Ser Leu Gly Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu 755 760 765 Trp Val Ser Trp Glu Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile 770 775 780 Lys Glu Tyr Met Asp Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr 785 790 795 800 Ser Gly Ala Leu Leu Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg 805 810 815 Cys Val Arg Arg Thr Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro 820 825 830 Ala Ser Phe Ser Ile Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu 835 840 845 Arg Gly Ala Leu Ser Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe 850 855 860 Lys Cys Arg Cys Tyr Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys 865 870 875 880 Ser Met Trp <210> SEQ ID NO 220 <211> LENGTH: 450 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 220 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> SEQ ID NO 221 <211> LENGTH: 598 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 221 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu 465 470 475 480 His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr 485 490 495 Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro 500 505 510 Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu 515 520 525 Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His 530 535 540 Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu 545 550 555 560 Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr 565 570 575 Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser 580 585 590 Ile Ile Ser Thr Leu Thr 595 <210> SEQ ID NO 222 <211> LENGTH: 879 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 222 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 50 55 60 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp 465 470 475 480 Asn Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp 485 490 495 Val Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly 500 505 510 Pro Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr 515 520 525 Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala 530 535 540 Ser Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala 545 550 555 560 Ile Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala 565 570 575 Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg 580 585 590 Gln Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala 595 600 605 Pro Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg 610 615 620 Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg 625 630 635 640 Gly Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe 645 650 655 Leu Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln 660 665 670 Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro 675 680 685 Ser Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met 690 695 700 Tyr Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala 705 710 715 720 Gly Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp 725 730 735 Thr Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly 740 745 750 Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp 755 760 765 Glu Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met 770 775 780 Asp Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu 785 790 795 800 Leu Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg 805 810 815 Thr Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser 820 825 830 Ile Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu 835 840 845 Ser Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys 850 855 860 Tyr Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp 865 870 875 <210> SEQ ID NO 223 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 223 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 224 <211> LENGTH: 656 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 224 Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp Asn 1 5 10 15 Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp Val 20 25 30 Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly Pro 35 40 45 Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr Tyr 50 55 60 Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala Ser 65 70 75 80 Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala Ile 85 90 95 Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala Trp 100 105 110 Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg Gln 115 120 125 Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala Pro 130 135 140 Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg Ala 145 150 155 160 Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg Gly 165 170 175 Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe Leu 180 185 190 Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln Asn 195 200 205 Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro Ser 210 215 220 Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met Tyr 225 230 235 240 Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala Gly 245 250 255 Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp Thr 260 265 270 Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly Glu 275 280 285 Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp Glu 290 295 300 Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met Asp 305 310 315 320 Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu Leu 325 330 335 Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg Thr 340 345 350 Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser Ile 355 360 365 Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu Ser 370 375 380 Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys Tyr 385 390 395 400 Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp Gly Gly 405 410 415 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr 420 425 430 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 435 440 445 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 450 455 460 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 465 470 475 480 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 485 490 495 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 500 505 510 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 515 520 525 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 530 535 540 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 545 550 555 560 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys 565 570 575 Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 580 585 590 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 595 600 605 Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 610 615 620 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 625 630 635 640 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 645 650 655 <210> SEQ ID NO 225 <211> LENGTH: 775 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 225 Leu Leu Val Met Cys Ile Val Leu Arg Pro Ser Arg Val His Asn Ser 1 5 10 15 Glu Glu Asn Thr Met Arg Ala Leu Thr Leu Lys Asp Ile Leu Asn Gly 20 25 30 Thr Phe Ser Tyr Lys Thr Phe Phe Pro Asn Trp Ile Ser Gly Gln Glu 35 40 45 Tyr Leu His Gln Ser Ala Asp Asn Asn Ile Val Leu Tyr Asn Ile Glu 50 55 60 Thr Gly Gln Ser Tyr Thr Ile Leu Ser Asn Arg Thr Met Lys Ser Val 65 70 75 80 Asn Ala Ser Asn Tyr Gly Leu Ser Pro Asp Arg Gln Phe Val Tyr Leu 85 90 95 Glu Ser Asp Tyr Ser Lys Leu Trp Arg Tyr Ser Tyr Thr Ala Thr Tyr 100 105 110 Tyr Ile Tyr Asp Leu Ser Asn Gly Glu Phe Val Arg Gly Asn Glu Leu 115 120 125 Pro Arg Pro Ile Gln Tyr Leu Cys Trp Ser Pro Val Gly Ser Lys Leu 130 135 140 Ala Tyr Val Tyr Gln Asn Asn Ile Tyr Leu Lys Gln Arg Pro Gly Asp 145 150 155 160 Pro Pro Phe Gln Ile Thr Phe Asn Gly Arg Glu Asn Lys Ile Phe Asn 165 170 175 Gly Ile Pro Asp Trp Val Tyr Glu Glu Glu Met Leu Pro Thr Lys Tyr 180 185 190 Ala Leu Trp Trp Ser Pro Asn Gly Lys Phe Leu Ala Tyr Ala Glu Phe 195 200 205 Asn Asp Lys Asp Ile Pro Val Ile Ala Tyr Ser Tyr Tyr Gly Asp Glu 210 215 220 Gln Tyr Pro Arg Thr Ile Asn Ile Pro Tyr Pro Lys Ala Gly Ala Lys 225 230 235 240 Asn Pro Val Val Arg Ile Phe Ile Ile Asp Thr Thr Tyr Pro Ala Tyr 245 250 255 Val Gly Pro Gln Glu Val Pro Val Pro Ala Met Ile Ala Ser Ser Asp 260 265 270 Tyr Tyr Phe Ser Trp Leu Thr Trp Val Thr Asp Glu Arg Val Cys Leu 275 280 285 Gln Trp Leu Lys Arg Val Gln Asn Val Ser Val Leu Ser Ile Cys Asp 290 295 300 Phe Arg Glu Asp Trp Gln Thr Trp Asp Cys Pro Lys Thr Gln Glu His 305 310 315 320 Ile Glu Glu Ser Arg Thr Gly Trp Ala Gly Gly Phe Phe Val Ser Arg 325 330 335 Pro Val Phe Ser Tyr Asp Ala Ile Ser Tyr Tyr Lys Ile Phe Ser Asp 340 345 350 Lys Asp Gly Tyr Lys His Ile His Tyr Ile Lys Asp Thr Val Glu Asn 355 360 365 Ala Ile Gln Ile Thr Ser Gly Lys Trp Glu Ala Ile Asn Ile Phe Arg 370 375 380 Val Thr Gln Asp Ser Leu Phe Tyr Ser Ser Asn Glu Phe Glu Glu Tyr 385 390 395 400 Pro Gly Arg Arg Asn Ile Tyr Arg Ile Ser Ile Gly Ser Tyr Pro Pro 405 410 415 Ser Lys Lys Cys Val Thr Cys His Leu Arg Lys Glu Arg Cys Gln Tyr 420 425 430 Tyr Thr Ala Ser Phe Ser Asp Tyr Ala Lys Tyr Tyr Ala Leu Val Cys 435 440 445 Tyr Gly Pro Gly Ile Pro Ile Ser Thr Leu His Asp Gly Arg Thr Asp 450 455 460 Gln Glu Ile Lys Ile Leu Glu Glu Asn Lys Glu Leu Glu Asn Ala Leu 465 470 475 480 Lys Asn Ile Gln Leu Pro Lys Glu Glu Ile Lys Lys Leu Glu Val Asp 485 490 495 Glu Ile Thr Leu Trp Tyr Lys Met Ile Leu Pro Pro Gln Phe Asp Arg 500 505 510 Ser Lys Lys Tyr Pro Leu Leu Ile Gln Val Tyr Gly Gly Pro Cys Ser 515 520 525 Gln Ser Val Arg Ser Val Phe Ala Val Asn Trp Ile Ser Tyr Leu Ala 530 535 540 Ser Lys Glu Gly Met Val Ile Ala Leu Val Asp Gly Arg Gly Thr Ala 545 550 555 560 Phe Gln Gly Asp Lys Leu Leu Tyr Ala Val Tyr Arg Lys Leu Gly Val 565 570 575 Tyr Glu Val Glu Asp Gln Ile Thr Ala Val Arg Lys Phe Ile Glu Met 580 585 590 Gly Phe Ile Asp Glu Lys Arg Ile Ala Ile Trp Gly Trp Ser Tyr Gly 595 600 605 Gly Tyr Val Ser Ser Leu Ala Leu Ala Ser Gly Thr Gly Leu Phe Lys 610 615 620 Cys Gly Ile Ala Val Ala Pro Val Ser Ser Trp Glu Tyr Tyr Ala Ser 625 630 635 640 Val Tyr Thr Glu Arg Phe Met Gly Leu Pro Thr Lys Asp Asp Asn Leu 645 650 655 Glu His Tyr Lys Asn Ser Thr Val Met Ala Arg Ala Glu Tyr Phe Arg 660 665 670 Asn Val Asp Tyr Leu Leu Ile His Gly Thr Ala Asp Asp Asn Val His 675 680 685 Phe Gln Asn Ser Ala Gln Ile Ala Lys Ala Leu Val Asn Ala Gln Val 690 695 700 Asp Phe Gln Ala Met Trp Tyr Ser Asp Gln Asn His Gly Leu Ser Gly 705 710 715 720 Leu Ser Thr Asn His Leu Tyr Thr His Met Thr His Phe Leu Lys Gln 725 730 735 Cys Phe Ser Leu Ser Asp Gly Gly Gly Gly Ser Gly Leu Asn Asp Ile 740 745 750 Phe Glu Ala Gln Lys Ile Glu Trp His Glu Gly Gly Gly Gly Ser His 755 760 765 His His His His His His His 770 775 <210> SEQ ID NO 226 <211> LENGTH: 327 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 226 Met Lys Asp Asn Thr Val Pro Leu Lys Leu Ile Ala Leu Leu Ala Asn 1 5 10 15 Gly Glu Phe His Ser Gly Glu Gln Leu Gly Glu Thr Leu Gly Met Ser 20 25 30 Arg Ala Ala Ile Asn Lys His Ile Gln Thr Leu Arg Asp Trp Gly Val 35 40 45 Asp Val Phe Thr Val Pro Gly Lys Gly Tyr Ser Leu Pro Glu Pro Ile 50 55 60 Gln Leu Leu Asn Ala Lys Gln Ile Leu Gly Gln Leu Asp Gly Gly Ser 65 70 75 80 Val Ala Val Leu Pro Val Ile Asp Ser Thr Asn Gln Tyr Leu Leu Asp 85 90 95 Arg Ile Gly Glu Leu Lys Ser Gly Asp Ala Cys Ile Ala Glu Tyr Gln 100 105 110 Gln Ala Gly Arg Gly Arg Arg Gly Arg Lys Trp Phe Ser Pro Phe Gly 115 120 125 Ala Asn Leu Tyr Leu Ser Met Phe Trp Arg Leu Glu Gln Gly Pro Ala 130 135 140 Ala Ala Ile Gly Leu Ser Leu Val Ile Gly Ile Val Met Ala Glu Val 145 150 155 160 Leu Arg Lys Leu Gly Ala Asp Lys Val Arg Val Lys Trp Pro Asn Asp 165 170 175 Leu Tyr Leu Gln Asp Arg Lys Leu Ala Gly Ile Leu Val Glu Leu Thr 180 185 190 Gly Lys Thr Gly Asp Ala Ala Gln Ile Val Ile Gly Ala Gly Ile Asn 195 200 205 Met Ala Met Arg Arg Val Glu Glu Ser Val Val Asn Gln Gly Trp Ile 210 215 220 Thr Leu Gln Glu Ala Gly Ile Asn Leu Asp Arg Asn Thr Leu Ala Ala 225 230 235 240 Met Leu Ile Arg Glu Leu Arg Ala Ala Leu Glu Leu Phe Glu Gln Glu 245 250 255 Gly Leu Ala Pro Tyr Leu Ser Arg Trp Glu Lys Leu Asp Asn Phe Ile 260 265 270 Asn Arg Pro Val Lys Leu Ile Ile Gly Asp Lys Glu Ile Phe Gly Ile 275 280 285 Ser Arg Gly Ile Asp Lys Gln Gly Ala Leu Leu Leu Glu Gln Asp Gly 290 295 300 Ile Ile Lys Pro Trp Met Gly Gly Glu Ile Ser Leu Arg Ser Ala Glu 305 310 315 320 Lys Ser Gly Lys Asp Glu Leu 325 <210> SEQ ID NO 227 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 227 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 228 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 228 Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 229 <211> LENGTH: 518 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 229 Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser 515 <210> SEQ ID NO 230 <211> LENGTH: 340 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 230 Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro 1 5 10 15 Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg 20 25 30 Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu 35 40 45 Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala 50 55 60 Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala 65 70 75 80 Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu 85 90 95 Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu 100 105 110 Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe 115 120 125 Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp 130 135 140 Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn 145 150 155 160 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 165 170 175 Gly Gly Gly Ser Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys 180 185 190 Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp 195 200 205 Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp 210 215 220 Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu 225 230 235 240 Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val 245 250 255 Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn 260 265 270 Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys 275 280 285 His Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val 290 295 300 Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met 305 310 315 320 Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met 325 330 335 Lys Ile Arg Asn 340 <210> SEQ ID NO 231 <211> LENGTH: 166 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 231 Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro 1 5 10 15 Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg 20 25 30 Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu 35 40 45 Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala 50 55 60 Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala 65 70 75 80 Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu 85 90 95 Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu 100 105 110 Pro Cys Glu Asn Gly Gly Gly Ser Gly Gly Lys Ser Lys Ala Val Glu 115 120 125 Gln Val Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys 130 135 140 Ala Met Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met 145 150 155 160 Thr Met Lys Ile Arg Asn 165 <210> SEQ ID NO 232 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 232 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Ala Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Ala Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 233 <211> LENGTH: 365 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 233 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 20 25 30 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 35 40 45 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 50 55 60 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 65 70 75 80 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 85 90 95 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 100 105 110 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 115 120 125 Phe Ile Asn Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 130 135 140 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 145 150 155 160 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 165 170 175 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 180 185 190 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 195 200 205 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 210 215 220 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 225 230 235 240 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 245 250 255 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys 260 265 270 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys 275 280 285 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 290 295 300 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 305 310 315 320 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 325 330 335 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 340 345 350 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 355 360 365 <210> SEQ ID NO 234 <211> LENGTH: 375 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 234 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu 50 55 60 Glu Trp Ile Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn 65 70 75 80 Gln Lys Phe Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Phe Cys Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys 260 265 270 Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr 275 280 285 Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe 290 295 300 Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile 305 310 315 320 His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser 325 330 335 Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu 340 345 350 Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val 355 360 365 Gln Met Phe Ile Asn Thr Ser 370 375 <210> SEQ ID NO 235 <211> LENGTH: 401 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 235 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile 20 25 30 Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser 35 40 45 Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser 50 55 60 Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro 65 70 75 80 Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile 85 90 95 Ser Ser Val Glu Ala Glu Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp 100 105 110 Ser Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 115 120 125 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 130 135 140 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 165 170 175 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 180 185 190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 195 200 205 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 210 215 220 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Val Pro Ser Gly 225 230 235 240 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Lys Gly 245 250 255 Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser Glu Ala Ser Ser 260 265 270 Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met 275 280 285 Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln Leu Thr Val Lys 290 295 300 Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn 305 310 315 320 Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys 325 330 335 Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala Ala Asn Thr His 340 345 350 Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His Leu Gly Gly Val 355 360 365 Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn Val Thr Asp Pro 370 375 380 Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys 385 390 395 400 Leu <210> SEQ ID NO 236 <211> LENGTH: 414 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 236 Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp Asn 1 5 10 15 Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp Val 20 25 30 Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly Pro 35 40 45 Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr Tyr 50 55 60 Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala Ser 65 70 75 80 Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala Ile 85 90 95 Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala Trp 100 105 110 Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg Gln 115 120 125 Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala Pro 130 135 140 Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg Ala 145 150 155 160 Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg Gly 165 170 175 Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe Leu 180 185 190 Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln Asn 195 200 205 Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro Ser 210 215 220 Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met Tyr 225 230 235 240 Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala Gly 245 250 255 Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp Thr 260 265 270 Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly Glu 275 280 285 Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp Glu 290 295 300 Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met Asp 305 310 315 320 Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu Leu 325 330 335 Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg Thr 340 345 350 Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser Ile 355 360 365 Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu Ser 370 375 380 Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys Tyr 385 390 395 400 Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp 405 410 <210> SEQ ID NO 237 <211> LENGTH: 507 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 237 Gln Gln Gln Thr Leu Pro Lys Pro Phe Ile Trp Ala Glu Pro His Phe 1 5 10 15 Met Val Pro Lys Glu Lys Gln Val Thr Ile Cys Cys Gln Gly Asn Tyr 20 25 30 Gly Ala Val Glu Tyr Gln Leu His Phe Glu Gly Ser Leu Phe Ala Val 35 40 45 Asp Arg Pro Lys Pro Pro Glu Arg Ile Asn Lys Val Lys Phe Tyr Ile 50 55 60 Pro Asp Met Asn Ser Arg Met Ala Gly Gln Tyr Ser Cys Ile Tyr Arg 65 70 75 80 Val Gly Glu Leu Trp Ser Glu Pro Ser Asn Leu Leu Asp Leu Val Val 85 90 95 Thr Glu Met Tyr Asp Thr Pro Thr Leu Ser Val His Pro Gly Pro Glu 100 105 110 Val Ile Ser Gly Glu Lys Val Thr Phe Tyr Cys Arg Leu Asp Thr Ala 115 120 125 Thr Ser Met Phe Leu Leu Leu Lys Glu Gly Arg Ser Ser His Val Gln 130 135 140 Arg Gly Tyr Gly Lys Val Gln Ala Glu Phe Pro Leu Gly Pro Val Thr 145 150 155 160 Thr Ala His Arg Gly Thr Tyr Arg Cys Phe Gly Ser Tyr Asn Asn His 165 170 175 Ala Trp Ser Phe Pro Ser Glu Pro Val Lys Leu Leu Val Thr Gly Asp 180 185 190 Ile Glu Asn Thr Ser Leu Ala Pro Glu Asp Pro Thr Phe Pro Asp Thr 195 200 205 Trp Gly Thr Tyr Leu Leu Thr Thr Glu Thr Gly Leu Gln Lys Asp His 210 215 220 Ala Leu Trp Asp His Thr Ala Gln Asn Gly Gly Gly Gly Ser Gly Gly 225 230 235 240 Gly Gly Ser Glu Pro Arg Thr Asp Thr Asp Thr Cys Pro Asn Pro Pro 245 250 255 Asp Pro Cys Pro Thr Cys Pro Thr Pro Asp Leu Leu Gly Gly Pro Ser 260 265 270 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Met Ile Ser Leu 275 280 285 Thr Pro Lys Ile Thr Cys Val Val Val Asp Val Ser Glu Glu Glu Pro 290 295 300 Asp Val Gln Phe Asn Trp Tyr Val Asn Asn Val Glu Asp Lys Thr Ala 305 310 315 320 Gln Thr Glu Thr Arg Gln Arg Gln Tyr Asn Ser Thr Tyr Arg Val Val 325 330 335 Ser Val Leu Pro Ile Lys His Gln Asp Trp Met Ser Gly Lys Val Phe 340 345 350 Lys Cys Lys Val Asn Asn Asn Ala Leu Pro Ser Pro Ile Glu Lys Thr 355 360 365 Ile Ser Lys Pro Arg Gly Gln Val Arg Val Pro Gln Ile Tyr Thr Phe 370 375 380 Pro Pro Pro Ile Glu Gln Thr Val Lys Lys Asp Val Ser Val Thr Cys 385 390 395 400 Leu Val Thr Gly Phe Leu Pro Gln Asp Ile His Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Gln Pro Glu Gln Asn Tyr Lys Asn Thr Gln Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val Pro 435 440 445 Lys Ser Arg Trp Asp Gln Gly Asp Ser Phe Thr Cys Ser Val Ile His 450 455 460 Glu Ala Leu His Asn His His Met Thr Lys Thr Ile Ser Arg Ser Leu 465 470 475 480 Gly Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Leu Asn Asp 485 490 495 Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu 500 505 <210> SEQ ID NO 238 <211> LENGTH: 375 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 238 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Gln Gln Ser Gly Arg Glu Leu Glu Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu 50 55 60 Glu Trp Ile Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn 65 70 75 80 Gln Lys Phe Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Phe Cys Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys 260 265 270 Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr 275 280 285 Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Ala 290 295 300 Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile 305 310 315 320 His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser 325 330 335 Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu 340 345 350 Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val 355 360 365 Gln Met Phe Ile Asn Thr Ser 370 375 <210> SEQ ID NO 239 <211> LENGTH: 242 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 239 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala Asp Ile Val Met Thr Gln Ser Pro Asp Ser 20 25 30 Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser 35 40 45 Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr 50 55 60 Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser 65 70 75 80 Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly 85 90 95 Thr Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala 100 105 110 Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln 115 120 125 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe 130 135 140 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 145 150 155 160 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 165 170 175 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 180 185 190 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 195 200 205 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 210 215 220 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 225 230 235 240 Glu Cys <210> SEQ ID NO 240 <211> LENGTH: 716 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 240 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 35 40 45 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 50 55 60 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 65 70 75 80 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 115 120 125 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 145 150 155 160 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 165 170 175 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 210 215 220 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 225 230 235 240 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 465 470 475 480 Asp Leu Lys Val Glu Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu 485 490 495 Asn Asp Asn Val Thr Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu 500 505 510 Asn Ile Thr Ser Met Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe 515 520 525 Asp Lys Glu Val Lys Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala 530 535 540 Phe Arg Pro Gly Ala Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp 545 550 555 560 Ala Ser Leu Arg Leu Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr 565 570 575 Arg Cys Glu Val Val Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln 580 585 590 Leu Glu Trp Ala Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val Gly 595 600 605 Met Lys Glu Asn Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe Tyr 610 615 620 Pro Glu Ala Ile Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe Pro 625 630 635 640 His Pro Ile Glu Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile Lys 645 650 655 Asn Met Asp Gly Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn Ser 660 665 670 Ser Gln Glu Asp Pro Gly Thr Val Tyr Gln Cys Trp Arg His Ala Ser 675 680 685 Leu His Thr Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala Arg His 690 695 700 Ser Leu Ser Glu Thr Glu Lys Thr Asp Asn Phe Ser 705 710 715 <210> SEQ ID NO 241 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 241 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> SEQ ID NO 242 <211> LENGTH: 215 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 242 His Arg Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp 1 5 10 15 Phe Val Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser 20 25 30 Leu Ser Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe 35 40 45 Val Lys Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser 50 55 60 Phe Glu Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val 65 70 75 80 Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu 85 90 95 Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly 100 105 110 Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln 115 120 125 Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile 130 135 140 Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu 145 150 155 160 Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser 165 170 175 Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe 180 185 190 Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr 195 200 205 Ser Phe Gly Leu Leu Lys Leu 210 215

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 242 <210> SEQ ID NO 1 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 1 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> SEQ ID NO 2 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 2 Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn 1 5 10 <210> SEQ ID NO 3 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 3 Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe Arg 1 5 10 15 Gly <210> SEQ ID NO 4 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 4 Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr 1 5 10 <210> SEQ ID NO 5 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 5 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 100 105 <210> SEQ ID NO 6 <211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 6 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys <210> SEQ ID NO 7 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 7 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 8 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 8 Ser Ala Ser Ser Ser Val Ser Tyr Met His 1 5 10 <210> SEQ ID NO 9 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 9 Asp Thr Ser Lys Leu Ala Ser 1 5 <210> SEQ ID NO 10 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 10 Gln Gln Trp Ser Gly Tyr Pro Leu Thr 1 5 <210> SEQ ID NO 11 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 11 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105

<210> SEQ ID NO 12 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 12 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala 20 <210> SEQ ID NO 13 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 13 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 14 <211> LENGTH: 103 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 14 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys Ser Cys 100 <210> SEQ ID NO 15 <211> LENGTH: 21 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 15 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val 20 <210> SEQ ID NO 16 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 16 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly 20 <210> SEQ ID NO 17 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 18 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu 65 70 75 <210> SEQ ID NO 19 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 19 Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly 1 5 10 15 Gly Ser Leu Gln 20 <210> SEQ ID NO 20 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 21 <211> LENGTH: 157 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn 1 5 10 15 Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp 20 25 30 Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile 35 40 45 Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile 50 55 60 Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile 65 70 75 80

Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys 85 90 95 Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys 100 105 110 Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu 115 120 125 Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu 130 135 140 Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 145 150 155 <210> SEQ ID NO 22 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 Gln Gly Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile 1 5 10 15 Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu 20 25 30 Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser 35 40 45 Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu 50 55 60 Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser 65 70 75 80 Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys 85 90 95 Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys 100 105 110 Ser Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His 115 120 125 Gly Ser Glu Asp Ser 130 <210> SEQ ID NO 23 <211> LENGTH: 138 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Gln Asp Pro Tyr Val Lys Glu Ala Glu Asn Leu Lys Lys Tyr Phe Asn 1 5 10 15 Ala Gly His Ser Asp Val Ala Asp Asn Gly Thr Leu Phe Leu Gly Ile 20 25 30 Leu Lys Asn Trp Lys Glu Glu Ser Asp Arg Lys Ile Met Gln Ser Gln 35 40 45 Ile Val Ser Phe Tyr Phe Lys Leu Phe Lys Asn Phe Lys Asp Asp Gln 50 55 60 Ser Ile Gln Lys Ser Val Glu Thr Ile Lys Glu Asp Met Asn Val Lys 65 70 75 80 Phe Phe Asn Ser Asn Lys Lys Lys Arg Asp Asp Phe Glu Lys Leu Thr 85 90 95 Asn Tyr Ser Val Thr Asp Leu Asn Val Gln Arg Lys Ala Ile His Glu 100 105 110 Leu Ile Gln Val Met Ala Glu Leu Ser Pro Ala Ala Lys Thr Gly Lys 115 120 125 Arg Lys Arg Ser Gln Met Leu Phe Arg Gly 130 135 <210> SEQ ID NO 24 <211> LENGTH: 238 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 24 Asp Leu Lys Val Glu Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu 1 5 10 15 Asn Asp Asn Val Thr Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu 20 25 30 Asn Ile Thr Ser Met Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe 35 40 45 Asp Lys Glu Val Lys Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala 50 55 60 Phe Arg Pro Gly Ala Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp 65 70 75 80 Ala Ser Leu Arg Leu Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr 85 90 95 Arg Cys Glu Val Val Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln 100 105 110 Leu Glu Val Val Ala Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val 115 120 125 Gly Met Lys Glu Asn Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe 130 135 140 Tyr Pro Glu Ala Ile Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe 145 150 155 160 Pro His Pro Ile Glu Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile 165 170 175 Lys Asn Met Asp Gly Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn 180 185 190 Ser Ser Gln Glu Asp Pro Gly Thr Val Tyr Gln Cys Val Val Arg His 195 200 205 Ala Ser Leu His Thr Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala 210 215 220 Arg His Ser Leu Ser Glu Thr Glu Lys Thr Asp Asn Phe Ser 225 230 235 <210> SEQ ID NO 25 <211> LENGTH: 284 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 25 Glu Pro His Ser Leu Arg Tyr Asn Leu Thr Val Leu Ser Trp Asp Gly 1 5 10 15 Ser Val Gln Ser Gly Phe Leu Thr Glu Val His Leu Asp Gly Gln Pro 20 25 30 Phe Leu Arg Cys Asp Arg Gln Lys Cys Arg Ala Lys Pro Gln Gly Gln 35 40 45 Trp Ala Glu Asp Val Leu Gly Asn Lys Thr Trp Asp Arg Glu Thr Arg 50 55 60 Asp Leu Thr Gly Asn Gly Lys Asp Leu Arg Met Thr Leu Ala His Ile 65 70 75 80 Lys Asp Gln Lys Glu Gly Leu His Ser Leu Gln Glu Ile Arg Val Cys 85 90 95 Glu Ile His Glu Asp Asn Ser Thr Arg Ser Ser Gln His Phe Tyr Tyr 100 105 110 Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Lys Glu Trp Thr 115 120 125 Met Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Arg Asn 130 135 140 Phe Leu Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr His Ala Met 145 150 155 160 His Ala Asp Cys Leu Gln Glu Leu Arg Arg Tyr Leu Lys Ser Gly Val 165 170 175 Val Leu Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Arg Ser Glu 180 185 190 Ala Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Gly Phe Tyr 195 200 205 Pro Trp Asn Ile Thr Leu Ser Trp Arg Gln Asp Gly Val Ser Leu Ser 210 215 220 His Asp Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly Thr 225 230 235 240 Tyr Gln Thr Trp Val Ala Thr Arg Ile Cys Gln Gly Glu Glu Gln Arg 245 250 255 Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Ser Thr His Pro Val 260 265 270 Pro Ser Gly Lys Val Leu Val Leu Gln Ser His Trp 275 280 <210> SEQ ID NO 26 <211> LENGTH: 287 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 26 Ala Glu Pro His Ser Leu Arg Tyr Asn Leu Met Val Leu Ser Gln Asp 1 5 10 15 Glu Ser Val Gln Ser Gly Phe Leu Ala Glu Gly His Leu Asp Gly Gln 20 25 30 Pro Phe Leu Arg Tyr Asp Arg Gln Lys Arg Arg Ala Lys Pro Gln Gly 35 40 45 Gln Trp Ala Glu Asp Val Leu Gly Ala Lys Thr Trp Asp Thr Glu Thr 50 55 60 Glu Asp Leu Thr Glu Asn Gly Gln Asp Leu Arg Arg Thr Leu Thr His 65 70 75 80 Ile Lys Asp Gln Lys Gly Gly Leu His Ser Leu Gln Glu Ile Arg Val 85 90 95 Cys Glu Ile His Glu Asp Ser Ser Thr Arg Gly Ser Arg His Phe Tyr 100 105 110 Tyr Asp Gly Glu Leu Phe Leu Ser Gln Asn Leu Glu Thr Gln Glu Ser 115 120 125 Thr Val Pro Gln Ser Ser Arg Ala Gln Thr Leu Ala Met Asn Val Thr 130 135 140 Asn Phe Trp Lys Glu Asp Ala Met Lys Thr Lys Thr His Tyr Arg Ala 145 150 155 160

Met Gln Ala Asp Cys Leu Gln Lys Leu Gln Arg Tyr Leu Lys Ser Gly 165 170 175 Val Ala Ile Arg Arg Thr Val Pro Pro Met Val Asn Val Thr Cys Ser 180 185 190 Glu Val Ser Glu Gly Asn Ile Thr Val Thr Cys Arg Ala Ser Ser Phe 195 200 205 Tyr Pro Arg Asn Ile Thr Leu Thr Trp Arg Gln Asp Gly Val Ser Leu 210 215 220 Ser His Asn Thr Gln Gln Trp Gly Asp Val Leu Pro Asp Gly Asn Gly 225 230 235 240 Thr Tyr Gln Thr Trp Val Ala Thr Arg Ile Arg Gln Gly Glu Glu Gln 245 250 255 Arg Phe Thr Cys Tyr Met Glu His Ser Gly Asn His Gly Thr His Pro 260 265 270 Val Pro Ser Gly Lys Val Leu Val Leu Gln Ser Gln Arg Thr Asp 275 280 285 <210> SEQ ID NO 27 <211> LENGTH: 191 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 27 Gly Trp Val Asp Thr His Cys Leu Cys Tyr Asp Phe Ile Ile Thr Pro 1 5 10 15 Lys Ser Arg Pro Glu Pro Gln Trp Cys Glu Val Gln Gly Leu Val Asp 20 25 30 Glu Arg Pro Phe Leu His Tyr Asp Cys Val Asn His Lys Ala Lys Ala 35 40 45 Phe Ala Ser Leu Gly Lys Lys Val Asn Val Thr Lys Thr Trp Glu Glu 50 55 60 Gln Thr Glu Thr Leu Arg Asp Val Val Asp Phe Leu Lys Gly Gln Leu 65 70 75 80 Leu Asp Ile Gln Val Glu Asn Leu Ile Pro Ile Glu Pro Leu Thr Leu 85 90 95 Gln Ala Arg Met Ser Cys Glu His Glu Ala His Gly His Gly Arg Gly 100 105 110 Ser Trp Gln Phe Leu Phe Asn Gly Gln Lys Phe Leu Leu Phe Asp Ser 115 120 125 Asn Asn Arg Lys Trp Thr Ala Leu His Pro Gly Ala Lys Lys Met Thr 130 135 140 Glu Lys Trp Glu Lys Asn Arg Asp Val Thr Met Phe Phe Gln Lys Ile 145 150 155 160 Ser Leu Gly Asp Cys Lys Met Trp Leu Glu Glu Phe Leu Met Tyr Trp 165 170 175 Glu Gln Met Leu Asp Pro Thr Lys Pro Pro Ser Leu Ala Pro Gly 180 185 190 <210> SEQ ID NO 28 <211> LENGTH: 329 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 28 Gln Asp Val Arg Val Gln Val Leu Pro Glu Val Arg Gly Gln Leu Gly 1 5 10 15 Gly Thr Val Glu Leu Pro Cys His Leu Leu Pro Pro Val Pro Gly Leu 20 25 30 Tyr Ile Ser Leu Val Thr Trp Gln Arg Pro Asp Ala Pro Ala Asn His 35 40 45 Gln Asn Val Ala Ala Phe His Pro Lys Met Gly Pro Ser Phe Pro Ser 50 55 60 Pro Lys Pro Gly Ser Glu Arg Leu Ser Phe Val Ser Ala Lys Gln Ser 65 70 75 80 Thr Gly Gln Asp Thr Glu Ala Glu Leu Gln Asp Ala Thr Leu Ala Leu 85 90 95 His Gly Leu Thr Val Glu Asp Glu Gly Asn Tyr Thr Cys Glu Phe Ala 100 105 110 Thr Phe Pro Lys Gly Ser Val Arg Gly Met Thr Trp Leu Arg Val Ile 115 120 125 Ala Lys Pro Lys Asn Gln Ala Glu Ala Gln Lys Val Thr Phe Ser Gln 130 135 140 Asp Pro Thr Thr Val Ala Leu Cys Ile Ser Lys Glu Gly Arg Pro Pro 145 150 155 160 Ala Arg Ile Ser Trp Leu Ser Ser Leu Asp Trp Glu Ala Lys Glu Thr 165 170 175 Gln Val Ser Gly Thr Leu Ala Gly Thr Val Thr Val Thr Ser Arg Phe 180 185 190 Thr Leu Val Pro Ser Gly Arg Ala Asp Gly Val Thr Val Thr Cys Lys 195 200 205 Val Glu His Glu Ser Phe Glu Glu Pro Ala Leu Ile Pro Val Thr Leu 210 215 220 Ser Val Arg Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asp Asn 225 230 235 240 Trp Tyr Leu Gly Arg Thr Asp Ala Thr Leu Ser Cys Asp Val Arg Ser 245 250 255 Asn Pro Glu Pro Thr Gly Tyr Asp Trp Ser Thr Thr Ser Gly Thr Phe 260 265 270 Pro Thr Ser Ala Val Ala Gln Gly Ser Gln Leu Val Ile His Ala Val 275 280 285 Asp Ser Leu Phe Asn Thr Thr Phe Val Cys Thr Val Thr Asn Ala Val 290 295 300 Gly Met Gly Arg Ala Glu Gln Val Ile Phe Val Arg Glu Thr Pro Asn 305 310 315 320 Thr Ala Gly Ala Gly Ala Thr Gly Gly 325 <210> SEQ ID NO 29 <211> LENGTH: 323 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 29 Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln Ala Pro Thr Gln 1 5 10 15 Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro Cys Tyr Leu Gln 20 25 30 Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu Thr Trp Ala Arg 35 40 45 His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln Thr Gln Gly Pro 50 55 60 Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala Ala Arg Leu Gly 65 70 75 80 Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly Leu Arg Val Glu 85 90 95 Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe Pro Gln Gly Ser 100 105 110 Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys Pro Gln Asn Thr 115 120 125 Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro Val Pro Met Ala 130 135 140 Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln Ile Thr Trp His 145 150 155 160 Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val Pro Gly Phe Leu 165 170 175 Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu Val Pro Ser Ser 180 185 190 Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu His Glu Ser Phe 195 200 205 Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val Tyr Tyr Pro Pro 210 215 220 Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr Leu Gly Gln Asn 225 230 235 240 Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro Glu Pro Thr Gly 245 250 255 Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro Phe Ala Val Ala 260 265 270 Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys Pro Ile Asn Thr 275 280 285 Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala Arg Gln Ala Glu 290 295 300 Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu His Ser Gly Ile 305 310 315 320 Ser Arg Asn <210> SEQ ID NO 30 <211> LENGTH: 330 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 30 Gln Asn Leu Phe Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala 1 5 10 15 Thr Ile Ser Cys Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu 20 25 30 Leu Asn Pro Asn Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu 35 40 45 Lys Asp Ser Arg Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys 50 55 60 Val Ser Leu Thr Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys 65 70 75 80 Gln Leu Tyr Thr Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val 85 90 95

Leu Val Pro Pro Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala 100 105 110 Val Glu Gly Glu Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys 115 120 125 Pro Ala Thr Thr Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly 130 135 140 Lys Ser Glu Val Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln 145 150 155 160 Leu Met Leu Lys Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys 165 170 175 Gln Val Glu His Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr 180 185 190 Leu Glu Val Gln Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro 195 200 205 Leu Gln Gly Leu Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu 210 215 220 Ala Ile Gly Lys Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp 225 230 235 240 Asp Glu Met Pro Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile 245 250 255 Asn Asn Leu Asn Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser 260 265 270 Asn Ile Val Gly Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp 275 280 285 Pro Pro Thr Thr Ile Pro Pro Pro Thr Thr Thr Thr Thr Thr Thr Thr 290 295 300 Thr Thr Thr Thr Thr Ile Leu Thr Ile Ile Thr Asp Ser Arg Ala Gly 305 310 315 320 Glu Glu Gly Ser Ile Arg Ala Val Asp His 325 330 <210> SEQ ID NO 31 <211> LENGTH: 155 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 31 Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu Pro Leu Glu Ser Leu Gly 1 5 10 15 Trp Asp Val Ala Glu Leu Gln Leu Asn His Thr Gly Pro Gln Gln Asp 20 25 30 Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala Leu Gly Arg Ser Phe Leu 35 40 45 His Gly Pro Glu Leu Asp Lys Gly Gln Leu Arg Ile His Arg Asp Gly 50 55 60 Ile Tyr Met Val His Ile Gln Val Thr Leu Ala Ile Cys Ser Ser Thr 65 70 75 80 Thr Ala Ser Arg His His Pro Thr Thr Leu Ala Val Gly Ile Cys Ser 85 90 95 Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg Leu Ser Phe His Gln Gly 100 105 110 Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro Leu Ala Arg Gly Asp Thr 115 120 125 Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu Pro Ser Arg Asn Thr Asp 130 135 140 Glu Thr Phe Phe Gly Val Gln Trp Val Arg Pro 145 150 155 <210> SEQ ID NO 32 <211> LENGTH: 294 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 32 Trp Thr Tyr His Tyr Ser Glu Lys Pro Met Asn Trp Gln Arg Ala Arg 1 5 10 15 Arg Phe Cys Arg Asp Asn Tyr Thr Asp Leu Val Ala Ile Gln Asn Lys 20 25 30 Ala Glu Ile Glu Tyr Leu Glu Lys Thr Leu Pro Phe Ser Arg Ser Tyr 35 40 45 Tyr Trp Ile Gly Ile Arg Lys Ile Gly Gly Ile Trp Thr Trp Val Gly 50 55 60 Thr Asn Lys Ser Leu Thr Glu Glu Ala Glu Asn Trp Gly Asp Gly Glu 65 70 75 80 Pro Asn Asn Lys Lys Asn Lys Glu Asp Cys Val Glu Ile Tyr Ile Lys 85 90 95 Arg Asn Lys Asp Ala Gly Lys Trp Asn Asp Asp Ala Cys His Lys Leu 100 105 110 Lys Ala Ala Leu Cys Tyr Thr Ala Ser Cys Gln Pro Trp Ser Cys Ser 115 120 125 Gly His Gly Glu Cys Val Glu Ile Ile Asn Asn Tyr Thr Cys Asn Cys 130 135 140 Asp Val Gly Tyr Tyr Gly Pro Gln Cys Gln Phe Val Ile Gln Cys Glu 145 150 155 160 Pro Leu Glu Ala Pro Glu Leu Gly Thr Met Asp Cys Thr His Pro Leu 165 170 175 Gly Asn Phe Ser Phe Ser Ser Gln Cys Ala Phe Ser Cys Ser Glu Gly 180 185 190 Thr Asn Leu Thr Gly Ile Glu Glu Thr Thr Cys Gly Pro Phe Gly Asn 195 200 205 Trp Ser Ser Pro Glu Pro Thr Cys Gln Val Ile Gln Cys Glu Pro Leu 210 215 220 Ser Ala Pro Asp Leu Gly Ile Met Asn Cys Ser His Pro Leu Ala Ser 225 230 235 240 Phe Ser Phe Thr Ser Ala Cys Thr Phe Ile Cys Ser Glu Gly Thr Glu 245 250 255 Leu Ile Gly Lys Lys Lys Thr Ile Cys Glu Ser Ser Gly Ile Trp Ser 260 265 270 Asn Pro Ser Pro Ile Cys Gln Lys Leu Asp Lys Ser Phe Ser Met Ile 275 280 285 Lys Glu Gly Asp Tyr Asn 290 <210> SEQ ID NO 33 <211> LENGTH: 243 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 33 Arg Tyr Leu Gln Val Ser Gln Gln Leu Gln Gln Thr Asn Arg Val Leu 1 5 10 15 Glu Val Thr Asn Ser Ser Leu Arg Gln Gln Leu Arg Leu Lys Ile Thr 20 25 30 Gln Leu Gly Gln Ser Ala Glu Asp Leu Gln Gly Ser Arg Arg Glu Leu 35 40 45 Ala Gln Ser Gln Glu Ala Leu Gln Val Glu Gln Arg Ala His Gln Ala 50 55 60 Ala Glu Gly Gln Leu Gln Ala Cys Gln Ala Asp Arg Gln Lys Thr Lys 65 70 75 80 Glu Thr Leu Gln Ser Glu Glu Gln Gln Arg Arg Ala Leu Glu Gln Lys 85 90 95 Leu Ser Asn Met Glu Asn Arg Leu Lys Pro Phe Phe Thr Cys Gly Ser 100 105 110 Ala Asp Thr Cys Cys Pro Ser Gly Trp Ile Met His Gln Lys Ser Cys 115 120 125 Phe Tyr Ile Ser Leu Thr Ser Lys Asn Trp Gln Glu Ser Gln Lys Gln 130 135 140 Cys Glu Thr Leu Ser Ser Lys Leu Ala Thr Phe Ser Glu Ile Tyr Pro 145 150 155 160 Gln Ser His Ser Tyr Tyr Phe Leu Asn Ser Leu Leu Pro Asn Gly Gly 165 170 175 Ser Gly Asn Ser Tyr Trp Thr Gly Leu Ser Ser Asn Lys Asp Trp Lys 180 185 190 Leu Thr Asp Asp Thr Gln Arg Thr Arg Thr Tyr Ala Gln Ser Ser Lys 195 200 205 Cys Asn Lys Val His Lys Thr Trp Ser Trp Trp Thr Leu Glu Ser Glu 210 215 220 Ser Cys Arg Ser Ser Leu Pro Tyr Ile Cys Glu Met Thr Ala Phe Arg 225 230 235 240 Phe Pro Asp <210> SEQ ID NO 34 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 34 Lys Leu Thr Arg Asp Ser Gln Ser Leu Cys Pro Tyr Asp Trp Ile Gly 1 5 10 15 Phe Gln Asn Lys Cys Tyr Tyr Phe Ser Lys Glu Glu Gly Asp Trp Asn 20 25 30 Ser Ser Lys Tyr Asn Cys Ser Thr Gln His Ala Asp Leu Thr Ile Ile 35 40 45 Asp Asn Ile Glu Glu Met Asn Phe Leu Arg Arg Tyr Lys Cys Ser Ser 50 55 60 Asp His Trp Ile Gly Leu Lys Met Ala Lys Asn Arg Thr Gly Gln Trp 65 70 75 80 Val Asp Gly Ala Thr Phe Thr Lys Ser Phe Gly Met Arg Gly Ser Glu 85 90 95 Gly Cys Ala Tyr Leu Ser Asp Asp Gly Ala Ala Thr Ala Arg Cys Tyr 100 105 110 Thr Glu Arg Lys Trp Ile Cys Arg Lys Arg Ile His 115 120

<210> SEQ ID NO 35 <211> LENGTH: 194 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 35 Gln Gly His Leu Val His Met Thr Val Val Ser Gly Ser Asn Val Thr 1 5 10 15 Leu Asn Ile Ser Glu Ser Leu Pro Glu Asn Tyr Lys Gln Leu Thr Trp 20 25 30 Phe Tyr Thr Phe Asp Gln Lys Ile Val Glu Trp Asp Ser Arg Lys Ser 35 40 45 Lys Tyr Phe Glu Ser Lys Phe Lys Gly Arg Val Arg Leu Asp Pro Gln 50 55 60 Ser Gly Ala Leu Tyr Ile Ser Lys Val Gln Lys Glu Asp Asn Ser Thr 65 70 75 80 Tyr Ile Met Arg Val Leu Lys Lys Thr Gly Asn Glu Gln Glu Trp Lys 85 90 95 Ile Lys Leu Gln Val Leu Asp Pro Val Pro Lys Pro Val Ile Lys Ile 100 105 110 Glu Lys Ile Glu Asp Met Asp Asp Asn Cys Tyr Leu Lys Leu Ser Cys 115 120 125 Val Ile Pro Gly Glu Ser Val Asn Tyr Thr Trp Tyr Gly Asp Lys Arg 130 135 140 Pro Phe Pro Lys Glu Leu Gln Asn Ser Val Leu Glu Thr Thr Leu Met 145 150 155 160 Pro His Asn Tyr Ser Arg Cys Tyr Thr Cys Gln Val Ser Asn Ser Val 165 170 175 Ser Ser Lys Asn Gly Thr Val Cys Leu Ser Pro Pro Cys Thr Leu Ala 180 185 190 Arg Ser <210> SEQ ID NO 36 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 36 Gln Val Ser His Arg Tyr Pro Arg Ile Gln Ser Ile Lys Val Gln Phe 1 5 10 15 Thr Glu Tyr Lys Lys Glu Lys Gly Phe Ile Leu Thr Ser Gln Lys Glu 20 25 30 Asp Glu Ile Met Lys Val Gln Asn Asn Ser Val Ile Ile Asn Cys Asp 35 40 45 Gly Phe Tyr Leu Ile Ser Leu Lys Gly Tyr Phe Ser Gln Glu Val Asn 50 55 60 Ile Ser Leu His Tyr Gln Lys Asp Glu Glu Pro Leu Phe Gln Leu Lys 65 70 75 80 Lys Val Arg Ser Val Asn Ser Leu Met Val Ala Ser Leu Thr Tyr Lys 85 90 95 Asp Lys Val Tyr Leu Asn Val Thr Thr Asp Asn Thr Ser Leu Asp Asp 100 105 110 Phe His Val Asn Gly Gly Glu Leu Ile Leu Ile His Gln Asn Pro Gly 115 120 125 Glu Phe Cys Val Leu 130 <210> SEQ ID NO 37 <211> LENGTH: 149 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 37 Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 1 5 10 15 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 20 25 30 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 35 40 45 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 50 55 60 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 65 70 75 80 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 85 90 95 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 100 105 110 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 115 120 125 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 130 135 140 Gly Leu Leu Lys Leu 145 <210> SEQ ID NO 38 <211> LENGTH: 205 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 38 Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser Ala 1 5 10 15 Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp Pro 20 25 30 Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala 35 40 45 Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro 50 55 60 Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp 65 70 75 80 Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe 85 90 95 Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val 100 105 110 Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala 115 120 125 Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg 130 135 140 Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly 145 150 155 160 Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala 165 170 175 Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Thr 180 185 190 Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu 195 200 205 <210> SEQ ID NO 39 <211> LENGTH: 455 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 39 Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp 1 5 10 15 Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro 20 25 30 Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala 35 40 45 Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr 50 55 60 Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro 65 70 75 80 Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile 85 90 95 Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp 100 105 110 Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val 115 120 125 Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu 130 135 140 Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala 145 150 155 160 Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg 165 170 175 Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His 180 185 190 His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile 195 200 205 Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu 210 215 220 Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr 225 230 235 240 Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile 245 250 255 Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val 260 265 270 Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr 275 280 285 Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp 290 295 300

Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp 305 310 315 320 Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu 325 330 335 Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys 340 345 350 Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp 355 360 365 Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly 370 375 380 Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys 385 390 395 400 Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp 405 410 415 Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala 420 425 430 Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn 435 440 445 Ala Ser Pro Ser Thr Leu Ser 450 455 <210> SEQ ID NO 40 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu 65 70 75 <210> SEQ ID NO 41 <211> LENGTH: 157 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 41 Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn 1 5 10 15 Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp 20 25 30 Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile 35 40 45 Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile 50 55 60 Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile 65 70 75 80 Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys 85 90 95 Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys 100 105 110 Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu 115 120 125 Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu 130 135 140 Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 145 150 155 <210> SEQ ID NO 42 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 42 Gly Gly Gly Gly Ser 1 5 <210> SEQ ID NO 43 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 43 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> SEQ ID NO 44 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 44 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> SEQ ID NO 45 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 45 Asp Val Pro Ser Gly Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly 1 5 10 15 Ser <210> SEQ ID NO 46 <211> LENGTH: 356 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 46 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp 245 250 255 Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp 260 265 270 Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu 275 280 285 Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr 290 295 300 Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly 305 310 315 320 Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys 325 330 335 Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe 340 345 350 Ile Asn Thr Ser 355 <210> SEQ ID NO 47 <211> LENGTH: 379 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 47 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30

His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys Asp Val Pro Ser Gly Pro Gly Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile 225 230 235 240 Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu 245 250 255 Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr 260 265 270 Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr 275 280 285 Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln 290 295 300 Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu 305 310 315 320 Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys 325 330 335 Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly 340 345 350 Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly 355 360 365 Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu 370 375 <210> SEQ ID NO 48 <211> LENGTH: 454 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 48 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> SEQ ID NO 49 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 49 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 50 <211> LENGTH: 346 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 50 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110 Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 115 120 125 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 130 135 140 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 145 150 155 160 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 165 170 175 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 180 185 190 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 195 200 205 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 210 215 220 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 225 230 235 240 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu 245 250 255 Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 260 265 270 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 275 280 285 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 290 295 300 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 305 310 315 320 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 325 330 335 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> SEQ ID NO 51 <211> LENGTH: 500 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 51 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 115 120 125 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 130 135 140 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 145 150 155 160 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 165 170 175 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 180 185 190 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 195 200 205 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 210 215 220 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 225 230 235 240 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu 245 250 255 Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 260 265 270 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 275 280 285 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 290 295 300 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 305 310 315 320 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 325 330 335 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Met 340 345 350 Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser Glu 355 360 365 Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly Tyr 370 375 380 Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln Leu 385 390 395 400 Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr Phe 405 410 415 Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser Leu 420 425 430 Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala Ala 435 440 445 Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His Leu 450 455 460 Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn Val 465 470 475 480 Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe Gly 485 490 495 Leu Leu Lys Leu 500 <210> SEQ ID NO 52 <211> LENGTH: 697 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 52 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445

Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Asp Leu Lys Val Glu 450 455 460 Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu Asn Asp Asn Val Thr 465 470 475 480 Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu Asn Ile Thr Ser Met 485 490 495 Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe Asp Lys Glu Val Lys 500 505 510 Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala Phe Arg Pro Gly Ala 515 520 525 Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp Ala Ser Leu Arg Leu 530 535 540 Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr Arg Cys Glu Val Val 545 550 555 560 Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln Leu Glu Val Val Ala 565 570 575 Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val Gly Met Lys Glu Asn 580 585 590 Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe Tyr Pro Glu Ala Ile 595 600 605 Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe Pro His Pro Ile Glu 610 615 620 Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile Lys Asn Met Asp Gly 625 630 635 640 Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn Ser Ser Gln Glu Asp 645 650 655 Pro Gly Thr Val Tyr Gln Cys Val Val Arg His Ala Ser Leu His Thr 660 665 670 Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala Arg His Ser Leu Ser 675 680 685 Glu Thr Glu Lys Thr Asp Asn Phe Ser 690 695 <210> SEQ ID NO 53 <211> LENGTH: 459 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 53 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 450 455 <210> SEQ ID NO 54 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 54 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 55 <211> LENGTH: 475 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 55 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 35 40 45 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 50 55 60 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 65 70 75 80 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 115 120 125 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 145 150 155 160 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 165 170 175 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 210 215 220 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 225 230 235 240 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> SEQ ID NO 56 <211> LENGTH: 379 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 56 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys Asp Val Pro Ser Gly Pro Gly Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile 225 230 235 240 Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu 245 250 255 Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr 260 265 270 Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr 275 280 285 Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln 290 295 300 Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu 305 310 315 320 Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys 325 330 335 Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly 340 345 350 Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly 355 360 365 Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu 370 375 <210> SEQ ID NO 57 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 57 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 58 <211> LENGTH: 519 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 58 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 20 25 30 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 35 40 45 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 50 55 60 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 65 70 75 80 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 85 90 95 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 100 105 110 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 115 120 125 Phe Ile Asn Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 130 135 140 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 145 150 155 160 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 165 170 175 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 180 185 190 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 195 200 205 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 210 215 220 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 225 230 235 240 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 245 250 255 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys

260 265 270 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys 275 280 285 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 290 295 300 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 305 310 315 320 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 325 330 335 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 340 345 350 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly 355 360 365 Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val 370 375 380 Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu 385 390 395 400 Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly 405 410 415 Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln 420 425 430 Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile 435 440 445 Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu 450 455 460 Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser 465 470 475 480 Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe 485 490 495 Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr 500 505 510 Ser Phe Gly Leu Leu Lys Leu 515 <210> SEQ ID NO 59 <211> LENGTH: 718 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 59 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 35 40 45 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 50 55 60 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 65 70 75 80 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 115 120 125 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 145 150 155 160 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 165 170 175 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 210 215 220 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 225 230 235 240 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 465 470 475 480 Asp Leu Lys Val Glu Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu 485 490 495 Asn Asp Asn Val Thr Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu 500 505 510 Asn Ile Thr Ser Met Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe 515 520 525 Asp Lys Glu Val Lys Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala 530 535 540 Phe Arg Pro Gly Ala Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp 545 550 555 560 Ala Ser Leu Arg Leu Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr 565 570 575 Arg Cys Glu Val Val Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln 580 585 590 Leu Glu Val Val Ala Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val 595 600 605 Gly Met Lys Glu Asn Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe 610 615 620 Tyr Pro Glu Ala Ile Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe 625 630 635 640 Pro His Pro Ile Glu Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile 645 650 655 Lys Asn Met Asp Gly Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn 660 665 670 Ser Ser Gln Glu Asp Pro Gly Thr Val Tyr Gln Cys Val Val Arg His 675 680 685 Ala Ser Leu His Thr Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala 690 695 700 Arg His Ser Leu Ser Glu Thr Glu Lys Thr Asp Asn Phe Ser 705 710 715 <210> SEQ ID NO 60 <211> LENGTH: 242 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 60 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala Asp Ile Val Met Thr Gln Ser Pro Asp Ser 20 25 30 Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser 35 40 45 Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr 50 55 60 Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser 65 70 75 80 Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly 85 90 95 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala 100 105 110 Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln 115 120 125 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe 130 135 140 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 145 150 155 160 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 165 170 175 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 180 185 190 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 195 200 205 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 210 215 220

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 225 230 235 240 Glu Cys <210> SEQ ID NO 61 <211> LENGTH: 455 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 61 Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp 1 5 10 15 Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro 20 25 30 Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala 35 40 45 Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr 50 55 60 Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro 65 70 75 80 Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile 85 90 95 Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp 100 105 110 Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val 115 120 125 Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu 130 135 140 Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala 145 150 155 160 Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg 165 170 175 Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His 180 185 190 His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile 195 200 205 Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu 210 215 220 Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr 225 230 235 240 Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile 245 250 255 Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val 260 265 270 Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr 275 280 285 Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp 290 295 300 Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp 305 310 315 320 Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu 325 330 335 Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys 340 345 350 Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp 355 360 365 Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly 370 375 380 Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys 385 390 395 400 Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp 405 410 415 Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala 420 425 430 Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn 435 440 445 Ala Ser Pro Ser Thr Leu Ser 450 455 <210> SEQ ID NO 62 <211> LENGTH: 413 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 62 Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp Asn 1 5 10 15 Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp Val 20 25 30 Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly Pro 35 40 45 Asp Met Thr Ile Phe Tyr Ser Ser Gln Gly Thr Tyr Pro Tyr Tyr Thr 50 55 60 Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala Ser Leu 65 70 75 80 Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala Ile Pro 85 90 95 Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala Trp Arg 100 105 110 Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg Gln Arg 115 120 125 Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala Pro Gln 130 135 140 Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg Ala Trp 145 150 155 160 Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg Gly Leu 165 170 175 Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe Leu Ser 180 185 190 Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln Asn Asp 195 200 205 Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro Ser Ile 210 215 220 Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met Tyr Val 225 230 235 240 Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala Gly Asp 245 250 255 Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp Thr Thr 260 265 270 Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly Glu Ser 275 280 285 Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp Glu Asn 290 295 300 Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met Asp Thr 305 310 315 320 Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu Leu Cys 325 330 335 Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg Thr Ser 340 345 350 His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser Ile Gln 355 360 365 Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu Ser Leu 370 375 380 Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys Tyr Pro 385 390 395 400 Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp 405 410 <210> SEQ ID NO 63 <211> LENGTH: 551 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 63 Tyr Asn Phe Phe Pro Arg Lys Pro Lys Trp Asp Lys Asn Gln Ile Thr 1 5 10 15 Tyr Arg Ile Ile Gly Tyr Thr Pro Asp Leu Asp Pro Glu Thr Val Asp 20 25 30 Asp Ala Phe Ala Arg Ala Phe Gln Val Trp Ser Asp Val Thr Pro Leu 35 40 45 Arg Phe Ser Arg Ile His Asp Gly Glu Ala Asp Ile Met Ile Asn Phe 50 55 60 Gly Arg Trp Glu His Gly Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly 65 70 75 80 Leu Leu Ala His Ala Phe Ala Pro Gly Thr Gly Val Gly Gly Asp Ser 85 90 95 His Phe Asp Asp Asp Glu Leu Trp Thr Leu Gly Glu Gly Gln Val Val 100 105 110 Arg Val Lys Tyr Gly Asn Ala Asp Gly Glu Tyr Cys Lys Phe Pro Phe 115 120 125 Leu Phe Asn Gly Lys Glu Tyr Asn Ser Cys Thr Asp Thr Gly Arg Ser 130 135 140 Asp Gly Phe Leu Trp Cys Ser Thr Thr Tyr Asn Phe Glu Lys Asp Gly 145 150 155 160 Lys Tyr Gly Phe Cys Pro His Glu Ala Leu Phe Thr Met Gly Gly Asn 165 170 175 Ala Glu Gly Gln Pro Cys Lys Phe Pro Phe Arg Phe Gln Gly Thr Ser 180 185 190 Tyr Asp Ser Cys Thr Thr Glu Gly Arg Thr Asp Gly Tyr Arg Trp Cys 195 200 205 Gly Thr Thr Glu Asp Tyr Asp Arg Asp Lys Lys Tyr Gly Phe Cys Pro 210 215 220 Glu Thr Ala Met Ser Thr Val Gly Gly Asn Ser Glu Gly Ala Pro Cys 225 230 235 240

Val Phe Pro Phe Thr Phe Leu Gly Asn Lys Tyr Glu Ser Cys Thr Ser 245 250 255 Ala Gly Arg Ser Asp Gly Lys Met Trp Cys Ala Thr Thr Ala Asn Tyr 260 265 270 Asp Asp Asp Arg Lys Trp Gly Phe Cys Pro Asp Gln Gly Tyr Ser Leu 275 280 285 Phe Leu Val Ala Ala His Glu Phe Gly His Ala Met Gly Leu Glu His 290 295 300 Ser Gln Asp Pro Gly Ala Leu Met Ala Pro Ile Tyr Thr Tyr Thr Lys 305 310 315 320 Asn Phe Arg Leu Ser Gln Asp Asp Ile Lys Gly Ile Gln Glu Leu Tyr 325 330 335 Gly Ala Ser Pro Asp Ile Asp Leu Gly Thr Gly Pro Thr Pro Thr Leu 340 345 350 Gly Pro Val Thr Pro Glu Ile Cys Lys Gln Asp Ile Val Phe Asp Gly 355 360 365 Ile Ala Gln Ile Arg Gly Glu Ile Phe Phe Phe Lys Asp Arg Phe Ile 370 375 380 Trp Arg Thr Val Thr Pro Arg Asp Lys Pro Met Gly Pro Leu Leu Val 385 390 395 400 Ala Thr Phe Trp Pro Glu Leu Pro Glu Lys Ile Asp Ala Val Tyr Glu 405 410 415 Ala Pro Gln Glu Glu Lys Ala Val Phe Phe Ala Gly Asn Glu Tyr Trp 420 425 430 Ile Tyr Ser Ala Ser Thr Leu Glu Arg Gly Tyr Pro Lys Pro Leu Thr 435 440 445 Ser Leu Gly Leu Pro Pro Asp Val Gln Arg Val Asp Ala Ala Phe Asn 450 455 460 Trp Ser Lys Asn Lys Lys Thr Tyr Ile Phe Ala Gly Asp Lys Phe Trp 465 470 475 480 Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro Gly Phe Pro Lys Leu 485 490 495 Ile Ala Asp Ala Trp Asn Ala Ile Pro Asp Asn Leu Asp Ala Val Val 500 505 510 Asp Leu Gln Gly Gly Gly His Ser Tyr Phe Phe Lys Gly Ala Tyr Tyr 515 520 525 Leu Lys Leu Glu Asn Gln Ser Leu Lys Ser Val Lys Phe Gly Ser Ile 530 535 540 Lys Ser Asp Trp Leu Gly Cys 545 550 <210> SEQ ID NO 64 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 64 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly 20 <210> SEQ ID NO 65 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 65 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 66 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 66 Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His 1 5 10 <210> SEQ ID NO 67 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 67 Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> SEQ ID NO 68 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 68 Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr 1 5 10 15 <210> SEQ ID NO 69 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 69 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys <210> SEQ ID NO 70 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 70 Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <210> SEQ ID NO 71 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 71 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> SEQ ID NO 72 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 72 Gln Gln Tyr Phe Ser Tyr Pro Leu Thr 1 5 <210> SEQ ID NO 73 <211> LENGTH: 77 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic

polypeptide <400> SEQUENCE: 73 Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr 20 25 30 Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser 35 40 45 Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys 50 55 60 Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu 65 70 75 <210> SEQ ID NO 74 <211> LENGTH: 157 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 74 Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn 1 5 10 15 Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp 20 25 30 Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile 35 40 45 Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile 50 55 60 Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile 65 70 75 80 Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys 85 90 95 Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys 100 105 110 Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu 115 120 125 Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu 130 135 140 Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp 145 150 155 <210> SEQ ID NO 75 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 75 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala Ala 1 5 10 <210> SEQ ID NO 76 <211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 76 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Ala Ala Ala <210> SEQ ID NO 77 <211> LENGTH: 24 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 77 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Glu Ala Ala Ala Lys Ala Ala Ala 20 <210> SEQ ID NO 78 <211> LENGTH: 29 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 78 Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys 1 5 10 15 Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala Ala 20 25 <210> SEQ ID NO 79 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 79 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr 225 <210> SEQ ID NO 80 <211> LENGTH: 213 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 80 Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 81 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 81

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys 225 <210> SEQ ID NO 82 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 83 <211> LENGTH: 227 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 83 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> SEQ ID NO 84 <211> LENGTH: 60 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 84 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 <210> SEQ ID NO 85 <211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 85 caggtccagc tgcaggaaag cggccctgga ctggtcaagc ctagccagac cctgagcctg 60 acctgtaccg tgtccggcgg cagcatcaac aacaacaatt actactggac atggatccgg 120 cagcaccccg gcaagggcct ggaatggatc ggctacatct actacagcgg ctccaccttc 180 tacaacccca gcctgaagtc cagagtgacc atcagcgtgg acaccagcaa gacccagttc 240 tccctgaagc tgagcagcgt gacagccgcc gacacagccg tgtactactg cgccagagaa 300 gataccatga ccggcctgga tgtgtggggc cagggcacca cagtgacagt gtctagc 357 <210> SEQ ID NO 86 <211> LENGTH: 318 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 86 gatatccaga tgacacagag ccctagcagc ctgagcgcca gcgtgggcga tagagtgacc 60 atcacctgtc gggccagcca gagcatcaac aactacctga actggtatca gcagaagccc 120 ggcaaggccc ctaccctgct gatctatgcc gcttctagcc tgcagagcgg cgtgcccagc 180 agattttctg gcagcagatc cggcaccgac ttcaccctga caatcagcag cctgcagccc 240 gaggacttcg ccgcctactt ctgccagcag acctacagca atcccacctt cggccagggc 300 accaaggtgg aagtgaag 318 <210> SEQ ID NO 87 <211> LENGTH: 399 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 87 gcccctacca gcagcagcac caagaaaacc cagctccagc tcgagcacct cctgctggac 60 ctgcagatga tcctgaacgg catcaacaac tacaagaacc ccaagctgac ccggatgctg 120 accttcaagt tctacatgcc caagaaggcc accgagctga agcacctcca gtgcctggaa 180 gaggaactga agcccctgga agaagtgctg aacctggccc agagcaagaa cttccacctg 240 aggcccaggg acctgatcag caacatcaac gtgatcgtgc tggaactgaa aggcagcgag 300 acaaccttca tgtgcgagta cgccgacgag acagccacca tcgtggaatt tctgaaccgg 360 tggatcacct tctgccagag catcatcagc accctgaca 399 <210> SEQ ID NO 88 <211> LENGTH: 30 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 88 ggcggcggag gatctggcgg aggcggcagc 30

<210> SEQ ID NO 89 <211> LENGTH: 687 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 89 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 60 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 360 ggccagcccc gcgaacctca ggtgtacaca ctgcctccct gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtggtg cctggtcaag ggcttctacc cctccgatat cgccgtggaa 480 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 540 gacggcagct tcttcctgta ctccaaactg accgtggaca agagccggtg gcagcagggc 600 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctgagcctga gccccggcaa gtaatga 687 <210> SEQ ID NO 90 <211> LENGTH: 687 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 60 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 120 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 180 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 240 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 300 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 360 ggccagccta gagagcctca ggtctgcacc ctgcctccca gccgggaaga gatgaccaag 420 aaccaggtgt ccctgtcctg cgccgtgaag ggcttctacc cctccgatat cgccgtggaa 480 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 540 gacggcagct tcttcctggt gtccaaactg accgtggaca agagccggtg gcagcagggc 600 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 660 ctgagcctga gccccggcaa gtaatga 687 <210> SEQ ID NO 91 <211> LENGTH: 309 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 91 gccagcacca agggccctag cgtgttccct ctggccccta gctctaagag cacatctggc 60 ggaacagccg ccctgggctg cctggtcaag gattactttc ctgagcccgt gaccgtgtcc 120 tggaactctg gtgctctgac cagcggcgtg cacacctttc cagctgtgct gcagagcagc 180 ggcctgtaca gcctgtctag cgtggtcaca gtgcctagca gcagcctggg cacacagacc 240 tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagcg ggtggaaccc 300 aagagctgc 309 <210> SEQ ID NO 92 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 92 agaacagtgg ccgctcccag cgtgttcatc ttcccaccca gcgacgagca gctgaagtct 60 ggcacagcca gcgtcgtgtg cctgctgaac aacttctacc ccagagaagc caaggtgcag 120 tggaaggtgg acaacgccct gcagtccggc aacagccagg aaagcgtcac cgagcaggac 180 agcaaggact ccacctacag cctgtccagc accctgaccc tgagcaaggc cgactacgag 240 aagcacaaag tgtacgcctg cgaagtgacc caccagggcc tgagcagccc cgtgaccaag 300 agcttcaata gaggcgagtg ctaatga 327 <210> SEQ ID NO 93 <211> LENGTH: 324 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 93 ggccagccca aggccaaccc caccgtgacc ctgttccctc catcctccga ggaactgcag 60 gctaacaagg ccaccctcgt gtgcctgatc tccgacttct accctggcgc cgtgaccgtg 120 gcttggaagg ctgatggctc tcctgtgaag gccggcgtgg aaaccaccaa gccctccaag 180 cagtccaaca acaaatacgc cgcctccagc tacctgtccc tgacccctga gcagtggaag 240 tcccaccggt cctacagctg ccaggtcaca catgagggct ccaccgtgga aaagaccgtg 300 gcccctaccg agtgctccta atga 324 <210> SEQ ID NO 94 <211> LENGTH: 360 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 94 gaggtgcagc tgctggaatc tggcggagga ctggtgcagc ctggcggctc tctgagactg 60 tcttgtgccg cctccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 120 cctggcaagg gcctggaatg ggtgtcctct atctacccct ccggcggcat caccttttac 180 gccgacaccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc tagaatcaag 300 ctgggcaccg tgaccaccgt ggactattgg ggccagggca ccctggtcac cgtgtcctct 360 <210> SEQ ID NO 95 <211> LENGTH: 330 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 95 cagtctgctc tgacccagcc tgcctctgtg tctggctccc ctggccagtc catcaccatc 60 agctgtaccg gcacctcctc cgacgtgggc ggctacaact acgtgtcctg gtatcagcag 120 catcccggca aggcccctaa gctgatgatc tacgacgtgt ccaaccggcc ctccggcgtg 180 tccaatcggt tctctggctc caagtccggc aacaccgcct ccctgacaat cagcggactg 240 caggccgagg acgaggccga ctactactgc tcctcctaca cctccagctc tacccgggtg 300 ttcggcaccg gcaccaaagt gacagtgctg 330 <210> SEQ ID NO 96 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 96 ggcggcggag gatctggcgg aggtggaagc ggaggcggtg gatct 45 <210> SEQ ID NO 97 <211> LENGTH: 360 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 97 caggttcagt tgcagcagtc cggacctgag ctggttaagc ctggcgcttc cgtgaagatg 60 tcctgcaagg cttccggcta caccttcacc gactacgtga tcaactgggg caagcagaga 120 tctggccagg gactcgagtg gatcggcgag atctatcctg gctccggcac caattactac 180 aacgagaagt tcaaggctaa ggctaccctg accgccgaca agtcctccaa tatcgcctac 240 atgcagctgt ccagcctgac ctctgaggac tccgctgtgt acttctgcgc tcggagaggc 300 agatacggcc tgtatgccat ggattactgg ggacagggaa ccagtgtgac agtgtcaagt 360 <210> SEQ ID NO 98 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 98 gatattcaga tgacccagac cacctccagc ctgtccgctt ctctgggcga cagagtgaca 60 atcagctgca gagccagcca ggacatcagc aactacctga actggtatca acagaaaccc 120 gacggcaccg tgaagctgct gatctactac acctctcggc tgcactctgg cgtgccctct 180 agattttctg gcagcggaag cggcaccgac tattccctga ccatcaacaa cctggaacaa 240 gaggatatcg ctacctactt ctgccagcaa ggcaacaccc ggccttggac atttggcggc 300 ggaacaaagc tggaaatcaa gtgatga 327 <210> SEQ ID NO 99 <211> LENGTH: 60 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 99 ggtggcggag gaagcggcgg aggcggctct ggtggtggtg gttctggtgg cggtggctcc 60 <210> SEQ ID NO 100 <211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 100 caggtccagc tgcaggaatc tggccctggc ctggtcaagc cctccgagac actgtctctg 60 acctgcaccg tgtccggcgg ctctgtgtcc tccggctcct actactggtc ctggatccgg 120 cagcctccag gcaagggact ggaatggatc ggctacatct actactccgg cagcaccaac 180 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 240 tccctgaagc tgtcctccgt gaccgccgct gacaccgccg tgtactactg tgccagagag 300 ggcaagaacg gcgccttcga tatctggggc cagggcacca tggtcaccgt gtctagc 357 <210> SEQ ID NO 101 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 101 gacatccaga tgacccagag cccttccagc ctgtccgcct ctgtgggcga cagagtgacc 60 atcacctgtc gggcctccca gtccatctcc tcctacctga actggtatca gcagaagccc 120 ggcaaggccc ctaagctgct gatctacgcc gcctccagtc tgcagtctgg cgtgccatct 180 ggcttctccg gctctggctc tggcaccgac ttcaccctga ccatctccag cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag tcctactcca cccctctgac cttcggcgga 300 ggcaccaagg tggaaatcaa g 321 <210> SEQ ID NO 102 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic oligonucleotide <400> SEQUENCE: 102 ggcggcggag gctcc 15 <210> SEQ ID NO 103 <400> SEQUENCE: 103 000 <210> SEQ ID NO 104 <211> LENGTH: 456 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104 gactgtgaca tcgaaggcaa ggacggcaag cagtacgaga gcgtgctgat ggtgtccatc 60 gaccagctgc tggacagcat gaaggaaatc ggctccaact gcctgaacaa cgagttcaac 120 ttcttcaagc ggcacatctg cgacgccaac aaagaaggca tgttcctgtt cagagccgcc 180 agaaagctgc ggcagttcct gaagatgaac tccaccggcg acttcgacct gcatctgctg 240 aaagtgtctg agggcaccac catcctgctg aactgtaccg gccaagtgaa gggcagaaag 300 cctgctgctc tgggcgaagc ccagcctacc aagtctctgg aagagaacaa gagcctgaaa 360 gagcagaaga agctgaacga cctctgcttc ctgaagcggc tgctgcaaga gatcaagacc 420 tgctggaaca agattctgat ggggaccaaa gagcac 456 <210> SEQ ID NO 105 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 105 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 60 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 120 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 180 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 300 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 360 tcctct 366 <210> SEQ ID NO 106 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 106 gacatccaga tgacccagtc tccatcctct ctgtctgcca gcctgggcga cagagtgacc 60 atcacctgta gagcctctca gggcatctcc tcctacctgg cctggtatca gcagaagcct 120 ggcaaggctc ccaagctgct gatctacgcc aagagcacac tgcagtctgg cgtgccctct 180 agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 240 gaggactccg ccacctacta ctgtcagcag tactggacct ttccactgac cttcggcgga 300 ggcaccaagg tggaaatcaa g 321 <210> SEQ ID NO 107 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 107 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 60 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 120 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 180 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 240 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 300 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 360 tctagt 366 <210> SEQ ID NO 108 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 108 tcttacgagc tgacccagga tccagccgtg tctgttgctc tgggccagac agtgcggatt 60 acctgccagg gcgactccct gagatcctac tacgcctcct ggtatcagca gaagccaggc 120 caggctcctg tgctggtcat ctacggcaag aacaaccggc ctagcggcat ccctgacaga 180 ttctccggct ctacctccgg caactctgcc agcctgacaa ttactggcgc ccaggctgag 240 gacgaggccg actactactg caactccaga gacagccctg gcaatcagtg ggttttcggc 300 ggaggcacca aagtgacagt tcttggt 327 <210> SEQ ID NO 109 <211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 109 caagttcagt tggttcaaag cggtggcggc gtggtgcagc ctggaagatc tctcagactg 60 tcctgcaagg cctccggcta caccttcacc agatacacca tgcattgggt tcgacaagca 120 ccaggcaagg gcctcgagtg gatcggctac atcaaccctt ccagaggcta caccaactac 180 aaccagaaag tgaaggaccg gttcaccatc agcagagaca acagcaagaa taccgccttt 240 ctgcagatgg actccctgcg gcctgaagat accggcgtgt acttttgcgc ccggtactac 300 gacgaccact actccctgga ttactgggga cagggaacac ccgtgacagt gtctagc 357 <210> SEQ ID NO 110 <211> LENGTH: 324 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 110 gatattcaga tgacccagtc tccttccagc ctgtccgctt ctgtgggcga cagagtgact 60 attacctgct ccgcctcttc ctccgtgtcc tacatgaact ggtatcaaca aacacccggc 120 aaggccccta agagatggat ctacgacacc agcaagctgg cctctggcgt gccctctaga 180 ttttctggct ctggctccgg caccgactat acctttacaa tctccagcct gcagcctgag 240 gatatcgcca cctactactg tcagcagtgg tctagcaacc ccttcacctt tggacagggc 300 accaagctgc agatcacctg atga 324 <210> SEQ ID NO 111

<211> LENGTH: 399 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 111 gctcctacct cctccagcac caagaaaacc cagctgcagt tggagcatct gctgctggac 60 ctccagatga tcctgaatgg catcaacaat tacaagaacc ccaagctcac ccggatgctg 120 accgccaagt ttgccatgcc taagaaggcc accgagctga aacatctgca gtgcctggaa 180 gaggaactga agcccctgga agaagtgctg aatctggccc agtccaagaa cttccacctg 240 aggcctcggg acctgatctc caacatcaac gtgatcgtgc tcgagctgaa gggctccgag 300 acaaccttca tgtgcgagta cgccgacgag acagctacca tcgtggaatt tctgaaccgg 360 tggatcacct tctgtcagtc catcatcagc accctgacc 399 <210> SEQ ID NO 112 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 112 gaagtgcagc tccaagaatc tggacccggg ctcgtgaagc ccagccagtc tctgagtctg 60 acctgtacag tgaccggcta ctccatcacc tccgactacg cttggaactg gatccggcag 120 ttccccggca acaagttgga gtggatgggc tatatcacct acagcggcag cacctcttac 180 aacccttctc tggaatcccg gatcagcatc acccgggaca cctctaccaa tcagttcttt 240 ctgcagctga acagcgtgac caccgaggac accgccacct actattgtgc tagaggcggc 300 tactacggct cctcctgggg agtgtttgct tactggggac agggaaccct cgtgactgtt 360 tctgct 366 <210> SEQ ID NO 113 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 113 gacatccaga tgacccagtc tccagccagc ctgtctgctt ctgtgggcga gacagtgacc 60 attacctgcc gggtgtccga gaacatctac tcctacctgg cctggtatca acagaaacag 120 ggcaagtccc ctcagctgct ggtgtacaat gctaagaccc tggctgaggg cgtgccctct 180 agattttctg gctctggcag cggcacccag tttagcctga agatcaactc cctgcagcct 240 gaggacttcg gcagctacta ctgccagcac cactatggca ccccttggac atttggcgga 300 ggcaccaagc tggaaatcaa g 321 <210> SEQ ID NO 114 <211> LENGTH: 351 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 114 caggttcagt tgcagcagtc tgccgtggaa ctggctagac ctggcgcttc cgtgaagatg 60 tcctgcaagg cctccggcta caccttcacc agcttcacca tgcactgggt caagcagagg 120 cctggacaag gcttggagtg gattggatat atcaacccta gctctggcta caccgagtac 180 aaccagaagt tcaaggacaa gaccactctg accgccgaca agtcctccag caccgcttac 240 atgcagctcg actccctgac ctctgacgac tctgctgtgt actattgcgt gcggggctcc 300 tccagaggct tcgattattg gggacaaggc acactcgtga cagtgtcagc t 351 <210> SEQ ID NO 115 <211> LENGTH: 321 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 115 gatatccaga tgatccagtc tcctgccagc ctgtccgtgt ctgtgggaga gactgtgacc 60 atcacctgtc gggcctccga gaacatctac tccaacctgg cctggttcca gcagaagcag 120 ggaaagtctc ctcagctgct ggtgtacgcc gccaccaatt tggctgatgg cgtgccctct 180 cggttctccg gatctggatc tggcacacag tattccctga agatcaactc cctgcagtcc 240 gaggacttcg gcatctacta ttgccagcac ttctggggca cccctagaac ctttggcggc 300 ggaacaaagc tggaaatcaa g 321 <210> SEQ ID NO 116 <211> LENGTH: 1176 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 116 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 gcccctacca gcagcagcac caagaaaacc cagctccagc tcgagcacct cctgctggac 120 ctgcagatga tcctgaacgg catcaacaac tacaagaacc ccaagctgac ccggatgctg 180 accttcaagt tctacatgcc caagaaggcc accgagctga agcacctcca gtgcctggaa 240 gaggaactga agcccctgga agaagtgctg aacctggccc agagcaagaa cttccacctg 300 aggcccaggg acctgatcag caacatcaac gtgatcgtgc tggaactgaa aggcagcgag 360 acaaccttca tgtgcgagta cgccgacgag acagccacca tcgtggaatt tctgaaccgg 420 tggatcacct tctgccagag catcatcagc accctgacag gcggcggagg atctggcgga 480 ggcggcagcg ataagaccca cacctgtcct ccatgtcccg cccctgaact gctgggcgga 540 cctagcgtgt tcctgttccc tccaaagccc aaggacaccc tgatgatcag ccggacccct 600 gaagtgacct gcgtggtggt ggatgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 660 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 720 agcacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaatggcaaa 780 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ctatcgagaa aaccatcagc 840 aaggccaagg gccagcctag agagcctcag gtctgcaccc tgcctcccag ccgggaagag 900 atgaccaaga accaggtgtc cctgagctgc gccgtgaagg gcttctaccc ctccgatatc 960 gccgtggaat gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcccgtg 1020 ctggacagcg acggcagctt cttcctggtg tccaaactga ccgtggacaa gagccggtgg 1080 cagcagggca atgtgttcag ctgtagcgtg atgcacgagg ccctgcacaa ccactacacc 1140 cagaagtctc tgagcctgag ccccggcaag taatga 1176 <210> SEQ ID NO 117 <211> LENGTH: 1452 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 117 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 caggtccagc tgcaggaaag cggccctgga ctggtcaagc ctagccagac cctgagcctg 120 acctgtaccg tgtccggcgg cagcatcaac aacaacaatt actactggac atggatccgg 180 cagcaccccg gcaagggcct ggaatggatc ggctacatct actacagcgg ctccaccttc 240 tacaacccca gcctgaagtc cagagtgacc atcagcgtgg acaccagcaa gacccagttc 300 tccctgaagc tgagcagcgt gacagccgcc gacacagccg tgtactactg cgccagagaa 360 gataccatga ccggcctgga tgtgtggggc cagggcacca cagtgacagt gtctagcgcc 420 agcaccaagg gccctagcgt gttccctctg gcccctagct ctaagagcac atctggcgga 480 acagccgccc tgggctgcct ggtcaaggat tactttcctg agcccgtgac cgtgtcctgg 540 aactctggtg ctctgaccag cggcgtgcac acctttccag ctgtgctgca gagcagcggc 600 ctgtacagcc tgtctagcgt ggtcacagtg cctagcagca gcctgggcac acagacctac 660 atctgcaacg tgaaccacaa gcccagcaac accaaggtgg acaagcgggt ggaacccaag 720 agctgcgaca agacccacac ctgtcctccc tgtcctgccc ctgaactgct gggcggacct 780 tccgtgttcc tgttccctcc aaagcccaag gacaccctga tgatcagccg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtcccac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gtacaacagc 960 acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg ccagccccta tcgagaaaac catcagcaag 1080 gccaagggcc agccccgcga acctcaggtg tacacactgc ctccctgccg ggaagagatg 1140 accaagaacc aggtgtccct gtggtgtctc gtgaagggct tctacccctc cgatatcgcc 1200 gtggaatggg agagcaacgg ccagcccgag aacaactaca agaccacccc tcccgtgctg 1260 gacagcgacg gcagcttctt cctgtactcc aaactgaccg tggacaagag ccggtggcag 1320 cagggcaatg tgttcagctg tagcgtgatg cacgaggccc tgcacaacca ctacacccag 1380 aagtccctgt ccctgagccc tggaaaaggt ggcggaggaa gcggaggcgg aggttctggc 1440 ggcggaggat ct 1452 <210> SEQ ID NO 118 <211> LENGTH: 705 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 118 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg cagcaccggc 60 gatatccaga tgacacagag ccctagcagc ctgagcgcca gcgtgggcga tagagtgacc 120

atcacctgtc gggccagcca gagcatcaac aactacctga actggtatca gcagaagccc 180 ggcaaggccc ctaccctgct gatctatgcc gcttctagcc tgcagagcgg cgtgcccagc 240 agattttctg gcagcagatc cggcaccgac ttcaccctga caatcagcag cctgcagccc 300 gaggacttcg ccgcctactt ctgccagcag acctacagca atcccacctt cggccagggc 360 accaaggtgg aagtgaagag aacagtggcc gctcccagcg tgttcatctt cccacccagc 420 gacgagcagc tgaagtctgg cacagccagc gtcgtgtgcc tgctgaacaa cttctacccc 480 agagaagcca aggtgcagtg gaaggtggac aacgccctgc agtccggcaa cagccaggaa 540 agcgtcaccg agcaggacag caaggactcc acctacagcc tgtccagcac cctgaccctg 600 agcaaggccg actacgagaa gcacaaagtg tacgcctgcg aagtgaccca ccagggcctg 660 agcagccccg tgaccaagag cttcaataga ggcgagtgct aatga 705 <210> SEQ ID NO 119 <211> LENGTH: 1176 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 119 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 gcccctacca gcagcagcac caagaaaacc cagctccagc tcgagcacct cctgctggac 120 ctgcagatga tcctgaacgg catcaacaac tacaagaacc ccaagctgac ccggatgctg 180 accttcaagt tctacatgcc caagaaggcc accgagctga agcacctcca gtgcctggaa 240 gaggaactga agcccctgga agaagtgctg aacctggccc agagcaagaa cttccacctg 300 aggcccaggg acctgatcag caacatcaac gtgatcgtgc tggaactgaa aggcagcgag 360 acaaccttca tgtgcgagta cgccgacgag acagccacca tcgtggaatt tctgaaccgg 420 tggatcacct tctgccagag catcatcagc accctgacag gcggcggagg atctggcgga 480 ggcggcagcg ataagaccca cacctgtcct ccatgtcccg cccctgaact gctgggcgga 540 cctagcgtgt tcctgttccc tccaaagccc aaggacaccc tgatgatcag ccggacccct 600 gaagtgacct gcgtggtggt ggatgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 660 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ccagagagga acagtacaac 720 agcacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggactggct gaatggcaaa 780 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ctatcgagaa aaccatcagc 840 aaggccaagg gccagcctag agagcctcag gtctgcaccc tgcctcccag ccgggaagag 900 atgaccaaga accaggtgtc cctgagctgc gccgtgaagg gcttctaccc ctccgatatc 960 gccgtggaat gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcccgtg 1020 ctggacagcg acggcagctt cttcctggtg tccaaactga ccgtggacaa gagccggtgg 1080 cagcagggca atgtgttcag ctgtagcgtg atgcacgagg ccctgcacaa ccactacacc 1140 cagaagtctc tgagcctgag ccccggcaag taatga 1176 <210> SEQ ID NO 120 <400> SEQUENCE: 120 000 <210> SEQ ID NO 121 <211> LENGTH: 714 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 121 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg ctctaccggc 60 cagtctgctc tgacccagcc tgcctctgtg tctggctccc ctggccagtc catcaccatc 120 agctgtaccg gcacctcctc cgacgtgggc ggctacaact acgtgtcctg gtatcagcag 180 catcccggca aggcccctaa gctgatgatc tacgacgtgt ccaaccggcc ctccggcgtg 240 tccaatcggt tctctggctc caagtccggc aacaccgcct ccctgacaat cagcggactg 300 caggccgagg acgaggccga ctactactgc tcctcctaca cctccagctc tacccgggtg 360 ttcggcaccg gcaccaaagt gacagtgctg ggccagccca aggccaaccc caccgtgacc 420 ctgttccctc catcctccga ggaactgcag gctaacaagg ccaccctcgt gtgcctgatc 480 tccgacttct accctggcgc cgtgaccgtg gcttggaagg ctgatggctc tcctgtgaag 540 gccggcgtgg aaaccaccaa gccctccaag cagtccaaca acaaatacgc cgcctccagc 600 tacctgtccc tgacccctga gcagtggaag tcccaccggt cctacagctg ccaggtcaca 660 catgagggct ccaccgtgga aaagaccgtg gcccctaccg agtgctccta atga 714 <210> SEQ ID NO 122 <211> LENGTH: 1413 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 122 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg ctctacagga 60 caggtccagc tgcaggaatc tggccctggc ctggtcaagc cctccgagac actgtctctg 120 acctgcaccg tgtccggcgg ctctgtgtcc tccggctcct actactggtc ctggatccgg 180 cagcctccag gcaagggact ggaatggatc ggctacatct actactccgg cagcaccaac 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 300 tccctgaagc tgtcctccgt gaccgccgct gacaccgccg tgtactactg tgccagagag 360 ggcaagaacg gcgccttcga tatctggggc cagggcacca tggtcaccgt gtctagcgct 420 tccaccaagg gcccctccgt gttccctctg gccccttcca gcaagtccac ctctggcgga 480 accgctgctc tgggctgcct cgtgaaggac tacttccccg agcctgtgac cgtgtcctgg 540 aactctggcg ccctgacatc cggcgtgcac acctttccag ccgtgctgca gtccagcggc 600 ctgtactctc tgtccagcgt cgtgaccgtg ccttccagct ctctgggcac acagacctac 660 atctgcaacg tgaaccacaa gccttccaac accaaggtgg acaagcgggt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctccc tgtcctgccc ctgaactgct gggcggaccc 780 agcgtgttcc tgttccctcc aaagcccaag gacaccctga tgatctcccg gacccctgaa 840 gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctaccggg tggtgtccgt gctgacagtg ctgcaccagg actggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg ccagccccta tcgaaaagac catcagcaag 1080 gctaagggcc agccccgcga gccccaggtt tacacactgc ctccctgccg ggaagagatg 1140 accaagaatc aggtgtccct gtggtgtctg gtcaagggct tctacccctc cgatatcgcc 1200 gtggaatggg agtccaacgg ccagcccgag aacaactaca agaccacccc tcccgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgaccg tggacaagtc ccggtggcag 1320 cagggcaacg tgttctcctg ctctgtgatg cacgaggccc tgcacaacca ctacacccag 1380 aagtccctgt ccctgagccc cggcaagtaa tga 1413 <210> SEQ ID NO 123 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 123 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg ctctaccggc 60 gacatccaga tgacccagag cccttccagc ctgtccgcct ctgtgggcga cagagtgacc 120 atcacctgtc gggcctccca gtccatctcc tcctacctga actggtatca gcagaagccc 180 ggcaaggccc ctaagctgct gatctacgcc gcctccagtc tgcagtctgg cgtgccatct 240 ggcttctccg gctctggctc tggcaccgac ttcaccctga ccatctccag cctgcagccc 300 gaggacttcg ccacctacta ctgccagcag tcctactcca cccctctgac cttcggcgga 360 ggcaccaagg tggaaatcaa gcggaccgtg gccgctccct ccgtgttcat cttcccacct 420 tccgacgagc agctgaagtc cggcaccgct tctgtcgtgt gcctgctgaa caacttctac 480 cctcgggaag ccaaggtgca gtggaaggtg gacaatgccc tgcagtccgg caactcccag 540 gaatccgtca ccgagcagga ctccaaggac agcacctact ccctgtcctc taccctgacc 600 ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 660 ctgagcagcc ccgtgaccaa gtccttcaac agaggcgagt gctaatga 708 <210> SEQ ID NO 124 <211> LENGTH: 747 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 124 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg cagcaccggc 60 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 120 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 180 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 240 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 300 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 360 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 420 ggccagcccc gcgaacctca ggtgtacaca ctgcctccct gccgggaaga gatgaccaag 480 aaccaggtgt ccctgtggtg cctggtcaag ggcttctacc cctccgatat cgccgtggaa 540 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 600 gacggcagct tcttcctgta ctccaaactg accgtggaca agagccggtg gcagcagggc 660 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 720 ctgagcctga gccccggcaa gtaatga 747

<210> SEQ ID NO 125 <211> LENGTH: 747 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 125 atggaaaccg atacactgct gctgtgggtg ctgctcctct gggtgccagg cagcaccggc 60 gataagaccc acacctgtcc tccatgtcct gcccctgagc tgctgggcgg acctagcgtg 120 ttcctgttcc ctccaaagcc caaggacacc ctgatgatca gccggacccc tgaagtgacc 180 tgcgtggtgg tggatgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 240 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa cagcacctac 300 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 360 tgcaaggtgt ccaacaaggc cctgcctgcc cctatcgaga aaaccatcag caaggccaag 420 ggccagccta gagagcctca ggtctgcacc ctgcctccca gccgggaaga gatgaccaag 480 aaccaggtgt ccctgtcctg cgccgtgaag ggcttctacc cctccgatat cgccgtggaa 540 tgggagagca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggacagc 600 gacggcagct tcttcctggt gtccaaactg accgtggaca agagccggtg gcagcagggc 660 aatgtgttca gctgtagcgt gatgcacgag gccctgcaca accactacac ccagaagtct 720 ctgagcctga gccccggcaa gtaatga 747 <210> SEQ ID NO 126 <211> LENGTH: 1422 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 126 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 120 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 180 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 240 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 360 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 420 tcctctgctt ctaccaaggg acccagcgtg ttccctctgg ctccttccag caagtctacc 480 tctggcggaa cagctgctct gggctgcctg gtcaaggact actttcctga gcctgtgaca 540 gtgtcctgga actctggcgc tctgacatcc ggcgtgcaca cctttccagc tgtgctgcaa 600 tccagcggcc tgtactctct gtcctccgtc gtgacagtgc cttccagctc tctgggaacc 660 cagacctaca tctgcaatgt gaaccacaag ccttccaaca ccaaggtgga caagagagtg 720 gaacccaagt cctgcgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 780 ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatctctcgg 840 acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggatcccga agtgaagttc 900 aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 960 tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 1020 ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 1080 atctccaagg ccaagggcca gcctcgggaa cctcaagtct gtaccctgcc tcctagccgg 1140 gaagagatga ccaagaacca ggtgtccctg tcctgtgccg tgaagggctt ctacccttcc 1200 gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1260 cctgtgctgg actccgacgg ctcattcttc ctggtgtcca agctgacagt ggacaagtcc 1320 agatggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaatcac 1380 tacacccaga agtccctgtc tctgagcccc ggcaagtgat ga 1422 <210> SEQ ID NO 127 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 127 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 gacatccaga tgacccagtc tccatcctct ctgtctgcca gcctgggcga cagagtgacc 120 atcacctgta gagcctctca gggcatctcc tcctacctgg cctggtatca gcagaagcct 180 ggcaaggctc ccaagctgct gatctacgcc aagagcacac tgcagtctgg cgtgccctct 240 agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 300 gaggactccg ccacctacta ctgtcagcag tactggacct ttccactgac cttcggcgga 360 ggcaccaagg tggaaatcaa gagaaccgtg gccgctcctt ccgtgttcat cttcccacct 420 tccgacgagc agctgaagtc cggcacagct tctgtcgtgt gcctgctgaa caacttctac 480 cctcgggaag ccaaagtgca gtggaaggtg gacaacgctc tgcagtccgg caactcccaa 540 gagtctgtga ccgagcagga ctccaaggac agcacctaca gcctgtcctc cacactgacc 600 ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccatcagggc 660 ctgtctagcc ctgtgaccaa gtctttcaac cggggcgagt gctgatga 708 <210> SEQ ID NO 128 <211> LENGTH: 1866 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 128 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 120 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 180 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 240 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 360 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 420 tcctctgctt ctaccaaggg acccagcgtg ttccctctgg ctccttccag caagtctacc 480 tctggcggaa cagctgctct gggctgcctg gtcaaggact actttcctga gcctgtgaca 540 gtgtcctgga actctggcgc tctgacatcc ggcgtgcaca cctttccagc tgtgctgcaa 600 tccagcggcc tgtactctct gtcctccgtc gtgacagtgc cttccagctc tctgggaacc 660 cagacctaca tctgcaatgt gaaccacaag ccttccaaca ccaaggtgga caagagagtg 720 gaacccaagt cctgcgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 780 ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatctctcgg 840 acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggatcccga agtgaagttc 900 aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 960 tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 1020 ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 1080 atctccaagg ccaagggcca gcctcgggaa cctcaagtct gtaccctgcc tcctagccgg 1140 gaagagatga ccaagaacca ggtgtccctg tcctgtgccg tgaagggctt ctacccttcc 1200 gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1260 cctgtgctgg actccgacgg ctcattcttc ctggtgtcca agctgacagt ggacaagtcc 1320 agatggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaatcac 1380 tacacccaga agtccctgtc tctgagccct ggcaaaggcg gaggcggatc tggtggtggc 1440 ggttctggcg gcggtggatc tgctcctaca tcctccagca ccaagaaaac ccagctgcag 1500 ttggagcatc tgctgctgga cctccagatg atcctgaatg gcatcaacaa ttacaagaac 1560 cccaagctca cccggatgct gaccttcaag ttctacatgc ccaagaaggc caccgagctg 1620 aaacatctgc agtgcctgga agaggaactg aagcctctgg aagaagtgct gaatctggcc 1680 cagtccaaga acttccacct gaggcctcgg gacctgatct ccaacatcaa cgtgatcgtg 1740 ctcgagctga agggctccga gactaccttc atgtgcgagt acgccgacga gacagctacc 1800 atcgtggaat ttctgaaccg gtggatcacc ttctgccagt ccatcatcag caccctgacc 1860 tgatga 1866 <210> SEQ ID NO 129 <211> LENGTH: 1923 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 129 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaagtgcagc tgttgcagtc tggcggagga ttggttcagc ctggcggatc cctgagactg 120 tcttgtgccg cctctggctt catgttcagc agatacccca tgcactgggt ccgacaggcc 180 cctggaaaag gactggaatg ggtcggatcc atctccggaa gtggcggcgc taccccttac 240 gccgattctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacttc 360 taccagatcc tgaccggcaa cgccttcgac tattggggcc agggcacaac cgtgaccgtg 420 tcctctgctt ctaccaaggg acccagcgtg ttccctctgg ctccttccag caagtctacc 480 tctggcggaa cagctgctct gggctgcctg gtcaaggact actttcctga gcctgtgaca 540 gtgtcctgga actctggcgc tctgacatcc ggcgtgcaca cctttccagc tgtgctgcaa 600 tccagcggcc tgtactctct gtcctccgtc gtgacagtgc cttccagctc tctgggaacc 660 cagacctaca tctgcaatgt gaaccacaag ccttccaaca ccaaggtgga caagagagtg 720 gaacccaagt cctgcgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 780 ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatctctcgg 840 acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggatcccga agtgaagttc 900

aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 960 tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 1020 ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 1080 atctccaagg ccaagggcca gcctcgggaa cctcaagtct gtaccctgcc tcctagccgg 1140 gaagagatga ccaagaacca ggtgtccctg tcctgtgccg tgaagggctt ctacccttcc 1200 gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1260 cctgtgctgg actccgacgg ctcattcttc ctggtgtcca agctgacagt ggacaagtcc 1320 agatggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaatcac 1380 tacacccaga agtccctgtc tctgagccct ggcaaaggcg gaggcggatc tggtggtggc 1440 ggttctggcg gcggtggatc tgactgtgat atcgaaggca aggacggcaa gcagtacgag 1500 tccgtcctga tggtgtccat cgaccagctg ctggacagca tgaaggaaat cggctccaac 1560 tgcctgaaca acgagttcaa cttcttcaag cggcacatct gcgacgccaa caaagaaggc 1620 atgtttctgt tccgggctgc cagaaagctg cggcagttcc tgaagatgaa cagcaccggc 1680 gacttcgacc tgcacctgtt gaaagtgtct gagggcacca ccatcctgct gaactgtacc 1740 ggccaagtga agggaagaaa gcctgccgct ctgggcgaag cccagcctac aaagtctctg 1800 gaagagaaca agtccctgaa agagcagaag aagctgaacg acctctgttt cctgaagcgg 1860 ctgctgcaag agatcaagac ctgctggaac aagatcctga tgggcaccaa agagcactga 1920 tag 1923 <210> SEQ ID NO 130 <211> LENGTH: 1539 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 130 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 120 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 180 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 240 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 300 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 360 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 420 tctagtgctt ctactggtgg tggcggatct ggcggcggag gaagcggagg cggaggtagt 480 ggtggcggtg gatcttctta cgagctgacc caggatccag ccgtgtctgt tgctctgggc 540 cagacagtgc ggattacctg ccagggcgac tccctgagat cctactacgc ctcctggtat 600 cagcagaagc caggccaggc tcctgtgctg gtcatctacg gcaagaacaa ccggcctagc 660 ggcatccctg acagattctc cggctctacc tccggcaact ctgccagcct gacaattact 720 ggcgcccagg ctgaggacga ggccgactac tactgcaact ccagagacag ccctggcaat 780 cagtgggttt tcggcggagg caccaaagtg acagttcttg gtggcggagg tggaagtggc 840 ggaggcggtt ctgataagac ccacacctgt ccaccttgtc ctgctccaga actgctcggc 900 ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat ctctcggacc 960 cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg atcccgaagt gaagttcaat 1020 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcctagaga ggaacagtac 1080 aactccacct atagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 1140 aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga aaagaccatc 1200 tccaaggcca agggccagcc tagggaaccc caggtttaca ccctgcctcc atgccgggaa 1260 gagatgacca agaaccaggt gtccctgtgg tgcctggtca agggcttcta cccttccgat 1320 atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac cacacctcca 1380 gtgctggact ccgacggctc attcttcctg tactccaagc tgacagtgga caagtccaga 1440 tggcagcagg gcaacgtgtt ctcctgctcc gtgatgcacg aggccctgca caatcactac 1500 acccagaagt ccctgtctct gagccccggc aagtgatga 1539 <210> SEQ ID NO 131 <211> LENGTH: 2325 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 131 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 120 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 180 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 240 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 300 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 360 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 420 tctagtgctt ctactggtgg tggcggatct ggcggcggag gaagcggagg cggaggtagt 480 ggtggcggtg gatcttctta cgagctgacc caggatccag ccgtgtctgt tgctctgggc 540 cagacagtgc ggattacctg ccagggcgac tccctgagat cctactacgc ctcctggtat 600 cagcagaagc caggccaggc tcctgtgctg gtcatctacg gcaagaacaa ccggcctagc 660 ggcatccctg acagattctc cggctctacc tccggcaact ctgccagcct gacaattact 720 ggcgcccagg ctgaggacga ggccgactac tactgcaact ccagagacag ccctggcaat 780 cagtgggttt tcggcggagg caccaaagtg acagttcttg gtggcggagg tggaagtggc 840 ggaggcggtt ctgataagac ccacacctgt ccaccttgtc ctgctccaga actgctcggc 900 ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat ctctcggacc 960 cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg atcccgaagt gaagttcaat 1020 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcctagaga ggaacagtac 1080 aactccacct atagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 1140 aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga aaagaccatc 1200 tccaaggcca agggccagcc tagggaaccc caggtttaca ccctgcctcc atgccgggaa 1260 gagatgacca agaaccaggt gtccctgtgg tgcctggtca agggcttcta cccttccgat 1320 atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac cacacctcca 1380 gtgctggact ccgacggctc attcttcctg tactccaagc tgacagtgga caagtccaga 1440 tggcagcagg gcaacgtgtt ctcctgctcc gtgatgcacg aggccctgca caatcactac 1500 acccagaagt ccctgtctct gtctcccgga aaaggcggtg gtggatcagg tggcggaggc 1560 tcaggcggag gcggatctca agttcagttg cagcagagcg gacccgagct ggtcaaacct 1620 ggcgcttccg tgaagatgtc ctgcaaggcc tccggctaca ccttcaccga ttacgtgatc 1680 aactggggca agcagcgctc tggccaaggc ctggaatgga tcggcgagat ctatcctggc 1740 tccggcacca actactacaa cgagaagttc aaggctaagg ctaccctgac cgccgacaag 1800 tcctccaata tcgcctacat gcagctgtct agcctgacct ccgaggactc tgccgtgtac 1860 ttctgcgcca gaagaggcag atacggcctg tacgccatgg actactgggg acagggaacc 1920 tccgtgacag ttagtagcgg tggcggcggt agcggcggtg gtggttctgg cggtggtggt 1980 agtggcggcg gaggatctga tatccagatg acccagacca ccagcagcct gtctgcttcc 2040 ctgggcgata gagtgaccat ctcttgcaga gccagccagg acatcagcaa ctacctgaac 2100 tggtatcaac aaaaacccga cggcaccgtg aagctgctga tctactacac ctctcggctg 2160 cactctggcg tgccctctag attttctggc agcggctctg gaaccgacta ctccctgacc 2220 atcaacaacc tggaacaaga ggatatcgct acctacttct gccagcaagg caacacccgg 2280 ccttggacat ttggaggcgg caccaagctg gaaatcaagt gatga 2325 <210> SEQ ID NO 132 <211> LENGTH: 2319 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 132 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcggagga ttggttcagc caggcggatc cctgagactg 120 tcttgtgccg cttctggctt caccttcgac gactacgcta tgcactgggt ccgacaggcc 180 cctggcaaag gattggaatg ggtggccggc atctcttggg actctggctc taccggctac 240 gccgactctg tgaagggcag attcaccatc tctcgggaca acgccaagaa ctccctgtac 300 ctgcagatga acagcctgag agccgaggac accgctctgt actactgcgc tagagatctg 360 ggcgcctacc agtgggtgga aggctttgat tattggggcc agggcaccct ggtcaccgtg 420 tctagtgctt ctactggtgg tggcggatct ggcggcggag gaagcggagg cggaggtagt 480 ggtggcggtg gatcttctta cgagctgacc caggatccag ccgtgtctgt tgctctgggc 540 cagacagtgc ggattacctg ccagggcgac tccctgagat cctactacgc ctcctggtat 600 cagcagaagc caggccaggc tcctgtgctg gtcatctacg gcaagaacaa ccggcctagc 660 ggcatccctg acagattctc cggctctacc tccggcaact ctgccagcct gacaattact 720 ggcgcccagg ctgaggacga ggccgactac tactgcaact ccagagacag ccctggcaat 780 cagtgggttt tcggcggagg caccaaagtg acagttcttg gtggcggagg tggaagtggc 840 ggaggcggtt ctgataagac ccacacctgt ccaccttgtc ctgctccaga actgctcggc 900 ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat ctctcggacc 960 cctgaagtga cctgcgtggt ggtggatgtg tctcacgagg atcccgaagt gaagttcaat 1020 tggtacgtgg acggcgtgga agtgcacaat gccaagacca agcctagaga ggaacagtac 1080 aactccacct atagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 1140 aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga aaagaccatc 1200 tccaaggcca agggccagcc tagggaaccc caggtttaca ccctgcctcc atgccgggaa 1260 gagatgacca agaaccaggt gtccctgtgg tgcctggtca agggcttcta cccttccgat 1320 atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac cacacctcca 1380 gtgctggact ccgacggctc attcttcctg tactccaagc tgacagtgga caagtccaga 1440 tggcagcagg gcaacgtgtt ctcctgctcc gtgatgcacg aggccctgca caatcactac 1500

acccagaagt ccctgtctct gtctcccgga aaaggcggtg gtggatcagg tggcggaggc 1560 tcaggcggag gcggatctca agttcagttg gttcaaagcg gtggcggcgt ggtgcagcct 1620 ggaagatctc tcagactgtc ctgcaaggcc tccggctaca ccttcaccag atacaccatg 1680 cattgggttc gacaagcacc aggcaagggc ctcgagtgga tcggctacat caacccttcc 1740 agaggctaca ccaactacaa ccagaaagtg aaggaccggt tcaccatcag cagagacaac 1800 agcaagaata ccgcctttct gcagatggac tccctgcggc ctgaagatac cggcgtgtac 1860 ttttgcgccc ggtactacga cgaccactac tccctggatt actggggaca gggaacaccc 1920 gtgacagtgt ctagcggtgg cggtggttca ggcggcggtg gtagtggcgg cggaggtagc 1980 ggcggtggcg gatctgatat tcagatgacc cagtctcctt ccagcctgtc cgcttctgtg 2040 ggcgacagag tgactattac ctgctccgcc tcttcctccg tgtcctacat gaactggtat 2100 caacaaacac ccggcaaggc ccctaagaga tggatctacg acaccagcaa gctggcctct 2160 ggcgtgccct ctagattttc tggctctggc tccggcaccg actatacctt tacaatctcc 2220 agcctgcagc ctgaggatat cgccacctac tactgtcagc agtggtctag caaccccttc 2280 acctttggac agggcaccaa gctgcagatc acctgatga 2319 <210> SEQ ID NO 133 <211> LENGTH: 2199 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 133 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcaagagtc tggccctgga ctggtcaagc cctctcagac cctgtctctg 120 acctgtaccg tgtccggcgg ctccatcaac aacaacaatt actactggac ctggatccgg 180 cagcaccctg gcaaaggact ggaatggatc ggctacatct actactccgg ctccaccttc 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acaccagcaa gacccagttc 300 tccctgaagc tgtcctctgt gaccgccgct gataccgccg tgtactactg cgccagagaa 360 gataccatga ccggcctgga tgtgtggggc cagggaacaa cagtgaccgt gtcctccgct 420 tccaccaagg gaccttccgt gtttcctctg gctccctcca gcaagtctac ctctggtgga 480 acagctgccc tgggctgcct ggtcaaggat tactttcctg agcctgtgac agtgtcctgg 540 aactctggcg ctctgacatc cggcgtgcac acctttccag ctgtgctgca atcctccggc 600 ctgtactctc tgtcctccgt cgtgaccgtg ccttctagct ctctgggcac ccagacctac 660 atctgcaatg tgaaccacaa gccttccaac accaaggtgg acaagagagt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctcca tgtcctgctc cagaactgct cggcggaccc 780 tctgtgttcc tgtttccacc taagcctaag gacaccctga tgatctctcg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtctcac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctacagag tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg cctgctccta tcgaaaagac catcagcaag 1080 gccaagggcc agcctaggga accccaggtt tacaccctgc ctccatgccg ggaagagatg 1140 accaagaacc aggtgtccct gtggtgcctc gtgaagggct tctacccttc cgatatcgcc 1200 gtggaatggg agagcaatgg ccagcctgag aacaactaca agacaacccc tcctgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc cagatggcag 1320 cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaatca ctacacccag 1380 aagagtctgt ctctgtctcc cggcaaaggc ggcggaggat ctggcggagg cggtagcggt 1440 ggtggcggat ctcaggttca gttgcagcag tccggacctg agctggttaa gcctggcgcc 1500 tccgtgaaga tgtcctgcaa ggcttctggc tacaccttca ccgactacgt gatcaactgg 1560 ggcaagcaga gatctggcca gggactcgag tggatcggag agatctatcc tggctccggc 1620 accaactact acaatgagaa gttcaaggct aaggctaccc tgaccgccga caagtcctcc 1680 aatatcgcct acatgcagct gtccagcctg acctctgagg actccgctgt gtacttctgt 1740 gctcggagag gcagatacgg cctgtatgcc atggattact ggggacaggg cacctccgtg 1800 actgtctcta gcggtggcgg aggtagcgga ggcggtggtt caggcggagg cggctctggt 1860 ggcggtggat ctgatattca gatgacccag accacctcca gcctgtccgc ttctctgggc 1920 gacagagtga caatcagctg cagagccagc caggacatca gcaactacct gaactggtat 1980 cagcagaaac ccgacggcac cgtgaagctg ctgatctact acacctctcg gctgcactct 2040 ggcgtgccct ctagattttc tggcagcgga agcggcaccg attactccct gacaatcaac 2100 aacctcgagc aagaggatat cgctacctac ttctgccagc aaggcaacac ccggccttgg 2160 acatttggcg gcggaacaaa gctggaaatc aagtgatga 2199 <210> SEQ ID NO 134 <211> LENGTH: 1158 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 134 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccgga 60 cagtctgctc tgacccagcc tgcttctgtg tctggctctc ccggccagtc catcaccatc 120 tcttgtaccg gcacctcctc tgacgtcggc ggctacaact acgtgtcctg gtatcagcag 180 catcccggca aggcccctaa gctgatgatc tacgacgtgt ccaaccggcc ttccggcgtg 240 tccaatagat tctccggctc caagtccggc aacaccgctt ctctgacaat cagcggactg 300 caggccgagg acgaggccga ctactactgt tcctcctaca cctcctccag caccagagtg 360 tttggcaccg gcaccaaagt gaccgtgctg ggacagccta aggccaatcc taccgtgaca 420 ctgttccctc catcctccga ggaactgcag gctaacaagg ctaccctcgt gtgcctgatc 480 tccgactttt accctggcgc tgtgaccgtg gcctggaagg ctgatggatc tcctgtgaag 540 gctggcgtgg aaaccaccaa gccttccaag cagtccaaca acaaatacgc cgcctcctcc 600 tacctgtctc tgacccctga acagtggaag tcccaccggt cctacagctg ccaagtgacc 660 catgagggct ccaccgtgga aaagaccgtg gctcctactg agtgttctgg cggcggagga 720 tctggcggag gtggaagcgg aggcggtgga tctgctccta cctccagctc caccaagaaa 780 acccagctgc agttggagca tctgctgctg gacctgcaga tgatcctgaa cggcatcaac 840 aactacaaga accccaagct gacccggatg ctgaccgcca agtttgccat gcctaagaag 900 gccaccgagc tgaaacatct gcagtgcctg gaagaggaac tgaagcccct ggaagaagtg 960 ctgaatctgg cccagtccaa gaacttccac ctgaggcctc gggacctgat cagcaacatc 1020 aacgtgatcg tgctcgagct gaagggctcc gagacaacct tcatgtgcga gtacgccgac 1080 gagacagcta ccatcgtgga atttctgaac cggtggatca ccttctgcca gagcatcatc 1140 agcaccctga cctgatga 1158 <210> SEQ ID NO 135 <211> LENGTH: 1416 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 135 atggaaaccg ataccctgct gctgtgggtg ctgctcctct gggtgccagg atctacaggc 60 gaggtgcagc tgctggaatc tggcggagga ctggtgcagc ctggcggctc tctgagactg 120 tcttgtgccg cctccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 180 cctggcaagg gcctggaatg ggtgtcctct atctacccct ccggcggcat caccttttac 240 gccgacaccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc tagaatcaag 360 ctgggcaccg tgaccaccgt ggactattgg ggccagggca ccctggtcac cgtgtcctct 420 gcttctacca agggcccctc cgtgttccct ctggcccctt ccagcaagtc cacctctggc 480 ggaaccgctg ctctgggctg cctggtcaag gactacttcc ccgagcccgt gaccgtgtct 540 tggaactctg gcgccctgac cagcggcgtg cacacatttc cagccgtgct gcagtccagc 600 ggcctgtact ctctgtcctc cgtcgtgaca gtgccctcca gctctctggg cacacagacc 660 tacatctgca acgtgaacca caagccctcc aacaccaagg tggacaagcg ggtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccctgtcctg cccctgaact gctgggcgga 780 cccagcgtgt tcctgttccc tccaaagcct aaggacaccc tgatgatctc ccggacccct 840 gaagtgacct gcgtggtggt ggacgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctacc gggtggtgtc cgtgctgaca gtgctgcatc aggactggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgccagccc ctatcgaaaa gaccatctcc 1080 aaggccaagg gccagccaag agagcctcaa gtctgcacac tgcctcccag ccgggaagag 1140 atgaccaaga accaggtgtc cctgagctgc gctgtgaagg gcttctaccc ttccgatatc 1200 gccgtggaat gggagagcaa cggccagccc gagaacaatt acaagaccac ccctcccgtg 1260 ctggactccg acggctcatt cttcctggtg tccaagctga ccgtggacaa gtcccggtgg 1320 cagcagggca acgtgttctc ctgctctgtg atgcacgagg ccctgcacaa ccactacacc 1380 cagaagtccc tgtccctgtc tcccggcaag taatga 1416 <210> SEQ ID NO 136 <400> SEQUENCE: 136 000 <210> SEQ ID NO 137 <211> LENGTH: 2205 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 137 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcaagagtc tggccctgga ctggtcaagc cttccgagac actgtctctg 120 acctgcaccg tgtctggcgg ctctgtgtcc tctggctcct actactggtc ctggatcaga 180

cagcctcctg gcaaaggcct ggaatggatc ggctacatct actactccgg ctccaccaac 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 300 tccctgaagc tgtcctccgt gaccgctgct gataccgccg tgtactactg tgccagagag 360 ggcaagaacg gcgccttcga tatttggggc cagggcacca tggtcaccgt gtccagtgct 420 tctaccaagg gacccagcgt gttcccactg gctcccagct ctaagtctac ctctggcgga 480 acagctgccc tgggctgtct ggtcaaggat tacttccctg agcctgtgac cgtgtcctgg 540 aattctggcg ctctgacatc cggcgtgcac acctttccag ctgtgctgca atcctccggc 600 ctgtactctc tgtccagcgt cgtgaccgtg ccttctagct ctctgggcac ccagacctac 660 atctgcaatg tgaaccacaa gcctagcaac accaaggtgg acaagagagt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctcca tgtcctgctc cagaactgct cggcggacct 780 tccgtgttcc tgtttcctcc aaagcctaag gacaccctga tgatctctcg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtctcac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctacagag tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg cctgctccta tcgaaaagac catcagcaag 1080 gccaagggcc agcctaggga accccaggtt tacaccctgc ctccatgccg ggaagagatg 1140 accaagaatc aggtgtccct gtggtgcctc gtgaagggct tctacccttc cgatatcgcc 1200 gtggaatggg agagcaatgg ccagcctgag aacaactaca agacaacccc tcctgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc cagatggcag 1320 cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaatca ctacacccag 1380 aagtccctgt ctctgtcccc tggaaaaggc ggcggaggat ctggcggagg tggaagcgga 1440 ggcggtggat ctgaagtgca gctccaagaa tctggacccg ggctcgtgaa gcccagccag 1500 tctctgagtc tgacctgtac agtgaccggc tactccatca cctccgacta cgcttggaac 1560 tggatccggc agttccccgg caacaagttg gagtggatgg gctatatcac ctacagcggc 1620 agcacctctt acaacccttc tctggaatcc cggatcagca tcacccggga cacctctacc 1680 aatcagttct ttctgcagct gaacagcgtg accaccgagg acaccgccac ctactattgt 1740 gctagaggcg gctactacgg ctcctcctgg ggagtgtttg cttactgggg acagggaacc 1800 ctcgtgactg tttctgctgg tggcggagga agcggcggag gcggctctgg tggtggtggt 1860 tctggtggcg gcggatctga catccagatg acccagtctc cagccagcct gtctgcttct 1920 gtgggcgaga cagtgaccat tacctgccgg gtgtccgaga acatctactc ctacctggcc 1980 tggtatcaac agaaacaggg caagtcccct cagctgctgg tgtacaatgc taagaccctg 2040 gctgagggcg tgccctctag attttctggc tctggcagcg gcacccagtt tagcctgaag 2100 atcaactccc tgcagcctga ggacttcggc agctactact gccagcacca ctatggcacc 2160 ccttggacat ttggcggagg caccaagctg gaaatcaagt gatga 2205 <210> SEQ ID NO 138 <211> LENGTH: 2190 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 138 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcaagagtc tggccctgga ctggtcaagc cttccgagac actgtctctg 120 acctgcaccg tgtctggcgg ctctgtgtcc tctggctcct actactggtc ctggatcaga 180 cagcctcctg gcaaaggcct ggaatggatc ggctacatct actactccgg ctccaccaac 240 tacaacccca gcctgaagtc cagagtgacc atctccgtgg acacctccaa gaaccagttc 300 tccctgaagc tgtcctccgt gaccgctgct gataccgccg tgtactactg tgccagagag 360 ggcaagaacg gcgccttcga tatttggggc cagggcacca tggtcaccgt gtccagtgct 420 tctaccaagg gacccagcgt gttcccactg gctcccagct ctaagtctac ctctggcgga 480 acagctgccc tgggctgtct ggtcaaggat tacttccctg agcctgtgac cgtgtcctgg 540 aattctggcg ctctgacatc cggcgtgcac acctttccag ctgtgctgca atcctccggc 600 ctgtactctc tgtccagcgt cgtgaccgtg ccttctagct ctctgggcac ccagacctac 660 atctgcaatg tgaaccacaa gcctagcaac accaaggtgg acaagagagt ggaacccaag 720 tcctgcgaca agacccacac ctgtcctcca tgtcctgctc cagaactgct cggcggacct 780 tccgtgttcc tgtttcctcc aaagcctaag gacaccctga tgatctctcg gacccctgaa 840 gtgacctgcg tggtggtgga tgtgtctcac gaggatcccg aagtgaagtt caattggtac 900 gtggacggcg tggaagtgca caacgccaag accaagccta gagaggaaca gtacaactcc 960 acctacagag tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 1020 tacaagtgca aggtgtccaa caaggccctg cctgctccta tcgaaaagac catcagcaag 1080 gccaagggcc agcctaggga accccaggtt tacaccctgc ctccatgccg ggaagagatg 1140 accaagaatc aggtgtccct gtggtgcctc gtgaagggct tctacccttc cgatatcgcc 1200 gtggaatggg agagcaatgg ccagcctgag aacaactaca agacaacccc tcctgtgctg 1260 gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc cagatggcag 1320 cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaatca ctacacccag 1380 aagtccctgt ctctgtcccc tggaaaaggc ggcggaggat ctggcggagg tggaagcgga 1440 ggcggtggat ctcaggttca gttgcagcag tctgccgtgg aactggctag acctggcgct 1500 tccgtgaaga tgtcctgcaa ggcctccggc tacaccttca ccagcttcac catgcactgg 1560 gtcaagcaga ggcctggaca aggcttggag tggattggat atatcaaccc tagctctggc 1620 tacaccgagt acaaccagaa gttcaaggac aagaccactc tgaccgccga caagtcctcc 1680 agcaccgctt acatgcagct cgactccctg acctctgacg actctgctgt gtactattgc 1740 gtgcggggct cctccagagg cttcgattat tggggacaag gcacactcgt gacagtgtca 1800 gctggtggtg gcggtagtgg cggtggcggt tcaggtggcg gaggaagcgg cggaggcgga 1860 tctgatatcc agatgatcca gtctcctgcc agcctgtccg tgtctgtggg agagactgtg 1920 accatcacct gtcgggcctc cgagaacatc tactccaacc tggcctggtt ccagcagaag 1980 cagggaaagt ctcctcagct gctggtgtac gccgccacca atttggctga tggcgtgccc 2040 tctcggttct ccggatctgg atctggcaca cagtattccc tgaagatcaa ctccctgcag 2100 tccgaggact tcggcatcta ctattgccag cacttctggg gcacccctag aacctttggc 2160 ggcggaacaa agctggaaat caagtgatga 2190 <210> SEQ ID NO 139 <211> LENGTH: 675 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 139 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gagctgtgcg acgatgaccc tcctgagatc cctcacgcca ccttcaaggc catggcttac 120 aaagagggca ccatgctgaa ctgcgagtgc aagcggggct tcagacggat caagtccggc 180 agcctgtaca tgctgtgcac cggcaactcc tctcactcct cctgggacaa ccagtgccag 240 tgcacctcct ctgccaccag aaacaccacc aagcaagtga cccctcagcc tgaggaacag 300 aaagagcgca agaccaccga gatgcagagc cccatgcagc ctgtggatca ggcttctctg 360 cctggccact gtagagagcc tccaccttgg gagaatgagg ccaccgagcg gatctaccac 420 tttgtcgtgg gccagatggt gtactaccag tgcgtgcagg gatacagagc cctgcataga 480 ggccctgctg agtccgtgtg caagatgacc catggcaaga ccagatggac ccagcctcag 540 ctgatctgta caggcggagg cggaggatct ggtggtggtg gatctggcct gaacgacatc 600 ttcgaggccc agaaaatcga gtggcacgaa ggcggtggcg gctcccacca tcatcatcac 660 caccatcact gatga 675 <210> SEQ ID NO 140 <211> LENGTH: 1734 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 140 atggaaaccg acaccctgct gctgtgggtg ctgctgctct gggtcccagg ctccaccggc 60 ggactgaacg acatcttcga ggcccagaaa atcgagtggc acgagggcgg aggcggctcc 120 gagcctagaa ccgacaccga cacctgtccc aacccccccg acccctgccc tacctgtcct 180 acccctgatc tgctgggcgg accctccgtg ttcatcttcc cacccaagcc taaggacgtg 240 ctgatgatct ccctgacccc caagatcacc tgtgtggtgg tggacgtgtc cgaagaggaa 300 cccgacgtgc agttcaattg gtacgtgaac aacgtggaag ataagaccgc ccagaccgag 360 acacggcagc ggcagtacaa ctccacctac cgggtggtgt ccgtgctgcc catcaagcac 420 caggactgga tgtccggcaa ggtgttcaag tgcaaagtga acaacaacgc cctgcccagc 480 cccatcgaaa agaccatctc caagcctcgg ggccaagtcc gagtgcccca gatctacacc 540 ttcccacccc ctatcgagca gaccgtgaag aaagacgtgt ccgtgacctg cctcgtgacc 600 ggattcctgc cacaagacat ccacgtggaa tgggagtcca acggccagcc ccagcccgag 660 cagaactaca agaacaccca gcccgtgctg gactccgacg gctcctactt cctgtactcc 720 aagctgaacg tgcccaagtc cagatgggac cagggcgact ccttcacctg ttccgtgatc 780 cacgaggccc tgcacaacca ccacatgacc aagaccatca gccggtccct gggcaatggc 840 ggcggaggct ccgaggtgga aaagaccgcc tgcccctccg gcaagaaggc cagagagatc 900 gacgagtccc tgatcttcta caagaagtgg gagctggaag cctgcgtgga cgccgccctg 960 ctggccaccc agatggacag agtgaacgcc atccccttca cctacgagca gctggatgtg 1020 ctgaagcaca agctggacga gctgtacccc cagggctacc ccgagagcgt gatccagcac 1080 ctgggctacc tgtttctgaa gatgtccccc gaggacatcc ggaagtggaa cgtgacctcc 1140 ctggaaaccc tgaaggccct gctggaagtg aacaagggcc acgagatgag cccccaggcc 1200 cccagacgac ctctgcctca ggtggcaacc ctgatcgata gattcgtgaa gggcagaggc 1260 cagctggaca aggacaccct ggacacactg accgccttct accccggcta cctgtgctcc 1320 ctgtcccctg aggaactgtc ctccgtgccc ccctcctcta tctgggccgt gcggcctcag 1380 gatctggaca cctgtgaccc tcggcagctg gatgtcctgt atcccaaggc ccggctggcc 1440

ttccagaaca tgaacggctc cgagtacttc gtgaagatcc agtccttcct gggcggagcc 1500 cccaccgagg acctgaaggc tctgtcccag cagaacgtgt ccatggacct ggccaccttc 1560 atgaagctgc ggaccgacgc cgtgctgcct ctgaccgtgg ctgaggtgca gaagctgctg 1620 ggcccccacg tggaaggcct gaaggccgag gaacggcaca gacccgtgcg ggactggatc 1680 ctgcggcaga gacaggacga cctggatacc ctgggcctgg gcctgcagta atga 1734 <210> SEQ ID NO 141 <211> LENGTH: 822 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 141 atgagaatct tcgccgtgtt catcttcatg acctactggc atctgctgaa cgccttcacc 60 gtgaccgtgc ccaaggacct gtacgtggtg gaatacggct ccaacatgac catcgagtgc 120 aagttccccg tggaaaagca gctggacctg gccgccctga tcgtgtactg ggagatggaa 180 gataagaaca tcatccagtt cgtgcacggg gaagaggacc tgaaggtgca gcactcctcc 240 taccggcaga gagccagact gctgaaggac cagctgtccc tgggcaatgc cgccctgcag 300 atcaccgacg tgaagctgca ggatgccggc gtgtaccggt gcatgatctc ttacggcgga 360 gccgactaca agcggatcac cgtgaaagtg aacgccccct acaacaagat caaccagcgg 420 atcctggtgg tggaccccgt gacctctgag cacgagctga cctgtcaggc cgagggctac 480 cctaaggccg aagtgatctg gacctcctcc gaccaccagg tgctgtccgg caagaccacc 540 accacaaact ccaagcggga agagaagctg ttcaacgtga cctccaccct gcggatcaac 600 acaaccacca acgagatctt ctactgtacc ttccggcggc tggaccccga ggaaaatcac 660 accgctgagc tcgtgatccc cgagctgcct ctggcccacc ctcctaatga gagaacaggc 720 ggcggaggct ccggcctgaa cgacatcttt gaggcccaga aaatcgagtg gcacgagggc 780 ggaggcggct cccaccatca tcaccaccac catcactgat ga 822 <210> SEQ ID NO 142 <211> LENGTH: 1182 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 142 atggcttgga tgctgctgct gatcctgatc atggtgcacc ccggctcttg cgccctgtgg 60 gtgtcccagc ctcctgagat cagaaccctg gaaggctcct ccgccttcct gccctgctcc 120 ttcaatgcct ctcagggcag actggccatc ggctccgtga cctggttcag ggatgaggtg 180 gtgcccggca aagaagtgcg gaacggcaca cctgagttca gaggcagact cgcccctctg 240 gcctcctcta gattcctgca cgatcaccag gccgagctgc acatcagaga tgtgcggggc 300 cacgacgcct ccatctacgt gtgcagagtg gaagtgctgg gcctgggcgt gggcaccggc 360 aatggaacac ggctggtggt ggaaaaagag ggcggaggcg gatctggcgg cggaggctct 420 gataagaccc acacctgtcc tccctgtcct gcccctgaac tgctgggcgg accttccgtg 480 ttcctgttcc ctccaaagcc caaggacacc ctgatgatct cccggacccc tgaagtgacc 540 tgcgtggtgg tggacgtgtc ccacgaggat cccgaagtga agttcaattg gtacgtggac 600 ggcgtggaag tgcacaacgc caagaccaag cccagagagg aacagtacaa ctccacctac 660 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 720 tgcaaggtgt ccaacaaggc cctgccagcc ccaatcgaaa agaccatctc caaggccaag 780 ggccagcccc gcgagcctca ggtgtacaca ctgcctccca gccgggaaga gatgaccaag 840 aaccaggtgt ccctgacctg tctggtcaag ggcttctacc cctccgatat cgccgtggaa 900 tgggagtcca acggccagcc cgagaacaac tacaagacca cccctcccgt gctggactcc 960 gacggctcat tcttcctgta ctccaagctg accgtggaca agtcccggtg gcagcagggc 1020 aacgtgttct cctgctctgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1080 ctgtccctga gccctggcaa aggtggtggt ggtagcggtg gcggaggcag cggcctgaac 1140 gatatcttcg aggcccagaa aatcgagtgg cacgagtaat ga 1182 <210> SEQ ID NO 143 <211> LENGTH: 1587 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 143 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 cagcagcaga cactgcccaa gccttttatc tgggccgagc ctcacttcat ggtgcccaaa 120 gaaaagcaag tgaccatctg ctgccagggc aactacggcg ctgtggaata ccagctgcac 180 ttcgagggct ccctgttcgc cgtggataga cctaagcctc ctgagcggat caacaaagtg 240 aagttctaca tccccgacat gaactcccgg atggctggcc agtactcctg catctataga 300 gtgggcgagc tttggagcga gccctccaat ctgctggatc tggtggtcac cgagatgtac 360 gacaccccta cactgagcgt gcaccccgga cctgaagtga tctctggcga gaaagtgacc 420 ttctactgca gactggatac cgccacctcc atgtttctgc tgctcaaaga gggcagatcc 480 tctcacgtgc agcgcggcta tggaaaggtg caggctgagt ttcctctggg ccctgtgacc 540 accgctcaca gaggcaccta cagatgcttc ggctcctaca acaaccacgc ctggtctttc 600 ccatccgagc ctgtgaagct gctggtcacc ggcgacatcg agaacacatc tctggcccct 660 gaggacccca cctttcctga tacctggggc acctatctgc tgaccaccga gacaggcctg 720 cagaaagatc acgccctgtg ggatcacacc gctcagaatg gtggcggagg atctggcgga 780 ggcggatctg aacctagaac cgacaccgac acctgtccta atcctccaga tccttgtcct 840 acctgtccaa cacctgacct gctcggcgga ccttccgtgt tcatcttccc acctaagcca 900 aaggacgtgc tgatgatctc tctgacccct aagatcacct gtgtggtggt ggacgtgtcc 960 gaagaggaac ccgacgtgca gttcaattgg tacgtgaaca acgtcgagga caagacagcc 1020 cagaccgaga cacggcagcg gcagtacaac tctacctaca gagtggtgtc cgtgctgccc 1080 atcaagcacc aggattggat gtccggcaag gtgttcaagt gcaaagtgaa caacaacgcc 1140 ctgccttctc caatcgaaaa gaccatctcc aagcctcggg gccaagtgcg agtgccccag 1200 atctatacct ttccacctcc tatcgagcag accgtgaaga aagatgtgtc cgtgacctgc 1260 ctcgtgaccg gcttcctgcc tcaagacatc catgtggaat gggagtccaa cggccagcct 1320 cagcctgagc agaactacaa gaacacccag cctgtgctgg actccgacgg cagctacttc 1380 ctgtactcca agctgaacgt gcccaagtcc agatgggacc agggcgactc cttcacctgt 1440 tccgtgatcc acgaggccct gcacaaccac cacatgacca agaccatcag cagatccctc 1500 ggcaatggcg gtggtggttc tggcggcgga ggttccggac tgaacgatat cttcgaggcc 1560 cagaaaatcg agtggcacga gtgatga 1587 <210> SEQ ID NO 144 <211> LENGTH: 1041 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 144 atggaaactg acaccctcct cctttgggtg ctgctgcttt gggtgcctgg atcgaccggg 60 atgaaggaca ataccgtgcc tctgaagctc attgccctgc tggccaacgg agaattccat 120 tccggcgaac agctggggga gactctcggg atgtcccggg ccgccatcaa caagcacatc 180 cagactttgc gcgactgggg agtcgacgtg ttcacggtgc cggggaaggg ctactcgctc 240 ccggaaccga tccagctgct gaacgccaag cagattctgg gacagctgga tggcggaagc 300 gtggcagtgc tgcccgtgat cgactcaacc aaccagtatc tgctggatag aatcggtgaa 360 ctgaaatccg gcgacgcttg cattgccgag taccaacagg ccggaagggg acggcgcggc 420 aggaagtggt tctctccatt cggcgcgaac ctctacctga gcatgttctg gagattggag 480 cagggtcccg ccgcggccat cggcctctcc ctggtcatcg gcattgtgat ggctgaagtg 540 ctgaggaagt tgggtgccga caaggtccgc gtgaagtggc cgaacgacct gtacctccaa 600 gaccggaaat tggcggggat tctcgtcgag cttaccggaa agactggcga tgccgcacaa 660 attgtgatcg gggcgggaat caacatggcg atgcgacggg tggaagagag cgtcgtgaac 720 cagggatgga tcaccctgca agaggccgga atcaacctgg atcgcaacac cctggctgcc 780 atgctcattc gcgaactgag agccgcactg gagctgtttg agcaggaggg tctggccccc 840 tacctgtcac gctgggaaaa gcttgataac ttcatcaatc ggcctgtgaa gctgatcatc 900 ggagacaagg agattttcgg catctcgaga ggcatcgaca aacaaggagc cctcctgctg 960 gaacaggacg gaatcattaa gccctggatg ggtggagaga tctccctgcg gtccgccgaa 1020 aagtccggga aggatgaact c 1041 <210> SEQ ID NO 145 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 145 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115

<210> SEQ ID NO 146 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 146 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Thr Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ala Tyr Phe Cys Gln Gln Thr Tyr Ser Asn Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Val Lys 100 105 <210> SEQ ID NO 147 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 147 Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> SEQ ID NO 148 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 148 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 149 <211> LENGTH: 110 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 149 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 <210> SEQ ID NO 150 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 150 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 50 55 60 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 151 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 151 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 152 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 152 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> SEQ ID NO 153 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 153 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> SEQ ID NO 154 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 154 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> SEQ ID NO 155 <400> SEQUENCE: 155 000 <210> SEQ ID NO 156 <211> LENGTH: 152 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 156 Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu 1 5 10 15 Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser 20 25 30 Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp 35 40 45 Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg 50 55 60 Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu 65 70 75 80 Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val 85 90 95 Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser 100 105 110 Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu 115 120 125 Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys 130 135 140 Ile Leu Met Gly Thr Lys Glu His 145 150 <210> SEQ ID NO 157 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 157 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 158 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 158 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Lys Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> SEQ ID NO 159 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 159 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 160 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 160 Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn Gln 85 90 95 Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 <210> SEQ ID NO 161 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 161 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val 50 55 60

Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> SEQ ID NO 162 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 162 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr 100 105 <210> SEQ ID NO 163 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 163 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 164 <211> LENGTH: 140 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 164 Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser Leu 1 5 10 15 Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr Ala 20 25 30 Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met Gly 35 40 45 Tyr Ile Thr Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Glu Ser 50 55 60 Arg Ile Ser Ile Thr Arg Asp Thr Ser Thr Asn Gln Phe Phe Leu Gln 65 70 75 80 Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 85 90 95 Gly Gly Tyr Tyr Gly Ser Ser Trp Gly Val Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 <210> SEQ ID NO 165 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 165 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Val Ser Glu Asn Ile Tyr Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 166 <211> LENGTH: 117 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 166 Gln Val Gln Leu Gln Gln Ser Ala Val Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Asp Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Ser Ser Arg Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <210> SEQ ID NO 167 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 167 Asp Ile Gln Met Ile Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn 20 25 30 Leu Ala Trp Phe Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Gly Ile Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> SEQ ID NO 168 <211> LENGTH: 449 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 168 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe

65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> SEQ ID NO 169 <211> LENGTH: 213 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 169 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Thr Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ala Tyr Phe Cys Gln Gln Thr Tyr Ser Asn Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Val Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 170 <211> LENGTH: 370 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 170 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 130 135 140 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 145 150 155 160 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 165 170 175 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 180 185 190 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 195 200 205 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 210 215 220 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 225 230 235 240 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 245 250 255 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 260 265 270 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 275 280 285 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 290 295 300 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 305 310 315 320 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 325 330 335 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 340 345 350 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 355 360 365 Gly Lys 370 <210> SEQ ID NO 171 <211> LENGTH: 216 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 171 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys

145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> SEQ ID NO 172 <211> LENGTH: 449 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 172 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> SEQ ID NO 173 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 173 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 174 <211> LENGTH: 464 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 174 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 <210> SEQ ID NO 175 <400> SEQUENCE: 175 000 <210> SEQ ID NO 176 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 176 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 177 <211> LENGTH: 598 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 177 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu 465 470 475 480 His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr 485 490 495 Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro 500 505 510 Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu 515 520 525 Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His 530 535 540 Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu 545 550 555 560 Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr 565 570 575 Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser 580 585 590 Ile Ile Ser Thr Leu Thr 595 <210> SEQ ID NO 178 <211> LENGTH: 254 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 178 Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser 1 5 10 15 Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu 20 25 30 Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln 35 40 45 Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg 50 55 60 Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala 65 70 75 80 Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys 85 90 95 Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val 100 105 110 Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro 115 120 125 Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys 130 135 140 Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys 145 150 155 160 Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr 165 170 175 Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr 180 185 190 Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile 195 200 205 Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr Gly Gly Gly 210 215 220 Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His 225 230 235 240 Glu Gly Gly Gly Gly Ser His His His His His His His His 245 250 <210> SEQ ID NO 179 <211> LENGTH: 411 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic

polypeptide <400> SEQUENCE: 179 Thr Glu Met Tyr Asp Thr Pro Thr Leu Ser Val His Pro Gly Pro Glu 1 5 10 15 Val Ile Ser Gly Glu Lys Val Thr Phe Tyr Cys Arg Leu Asp Thr Ala 20 25 30 Thr Ser Met Phe Leu Leu Leu Lys Glu Gly Arg Ser Ser His Val Gln 35 40 45 Arg Gly Tyr Gly Lys Val Gln Ala Glu Phe Pro Leu Gly Pro Val Thr 50 55 60 Thr Ala His Arg Gly Thr Tyr Arg Cys Phe Gly Ser Tyr Asn Asn His 65 70 75 80 Ala Trp Ser Phe Pro Ser Glu Pro Val Lys Leu Leu Val Thr Gly Asp 85 90 95 Ile Glu Asn Thr Ser Leu Ala Pro Glu Asp Pro Thr Phe Pro Asp Thr 100 105 110 Trp Gly Thr Tyr Leu Leu Thr Thr Glu Thr Gly Leu Gln Lys Asp His 115 120 125 Ala Leu Trp Asp His Thr Ala Gln Asn Gly Gly Gly Gly Ser Gly Gly 130 135 140 Gly Gly Ser Glu Pro Arg Thr Asp Thr Asp Thr Cys Pro Asn Pro Pro 145 150 155 160 Asp Pro Cys Pro Thr Cys Pro Thr Pro Asp Leu Leu Gly Gly Pro Ser 165 170 175 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Met Ile Ser Leu 180 185 190 Thr Pro Lys Ile Thr Cys Val Val Val Asp Val Ser Glu Glu Glu Pro 195 200 205 Asp Val Gln Phe Asn Trp Tyr Val Asn Asn Val Glu Asp Lys Thr Ala 210 215 220 Gln Thr Glu Thr Arg Gln Arg Gln Tyr Asn Ser Thr Tyr Arg Val Val 225 230 235 240 Ser Val Leu Pro Ile Lys His Gln Asp Trp Met Ser Gly Lys Val Phe 245 250 255 Lys Cys Lys Val Asn Asn Asn Ala Leu Pro Ser Pro Ile Glu Lys Thr 260 265 270 Ile Ser Lys Pro Arg Gly Gln Val Arg Val Pro Gln Ile Tyr Thr Phe 275 280 285 Pro Pro Pro Ile Glu Gln Thr Val Lys Lys Asp Val Ser Val Thr Cys 290 295 300 Leu Val Thr Gly Phe Leu Pro Gln Asp Ile His Val Glu Trp Glu Ser 305 310 315 320 Asn Gly Gln Pro Gln Pro Glu Gln Asn Tyr Lys Asn Thr Gln Pro Val 325 330 335 Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val Pro 340 345 350 Lys Ser Arg Trp Asp Gln Gly Asp Ser Phe Thr Cys Ser Val Ile His 355 360 365 Glu Ala Leu His Asn His His Met Thr Lys Thr Ile Ser Arg Ser Leu 370 375 380 Gly Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Leu Asn Asp 385 390 395 400 Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu 405 410 <210> SEQ ID NO 180 <211> LENGTH: 374 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 180 Leu Trp Val Ser Gln Pro Pro Glu Ile Arg Thr Leu Glu Gly Ser Ser 1 5 10 15 Ala Phe Leu Pro Cys Ser Phe Asn Ala Ser Gln Gly Arg Leu Ala Ile 20 25 30 Gly Ser Val Thr Trp Phe Arg Asp Glu Val Val Pro Gly Lys Glu Val 35 40 45 Arg Asn Gly Thr Pro Glu Phe Arg Gly Arg Leu Ala Pro Leu Ala Ser 50 55 60 Ser Arg Phe Leu His Asp His Gln Ala Glu Leu His Ile Arg Asp Val 65 70 75 80 Arg Gly His Asp Ala Ser Ile Tyr Val Cys Arg Val Glu Val Leu Gly 85 90 95 Leu Gly Val Gly Thr Gly Asn Gly Thr Arg Leu Val Val Glu Lys Glu 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 115 120 125 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 130 135 140 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 145 150 155 160 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 165 170 175 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 180 185 190 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 195 200 205 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 210 215 220 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 225 230 235 240 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 245 250 255 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 260 265 270 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 275 280 285 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 290 295 300 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 305 310 315 320 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 325 330 335 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly 340 345 350 Gly Ser Gly Gly Gly Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln 355 360 365 Lys Ile Glu Trp His Glu 370 <210> SEQ ID NO 181 <211> LENGTH: 556 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 181 Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu Gly 1 5 10 15 Gly Gly Gly Ser Glu Pro Arg Thr Asp Thr Asp Thr Cys Pro Asn Pro 20 25 30 Pro Asp Pro Cys Pro Thr Cys Pro Thr Pro Asp Leu Leu Gly Gly Pro 35 40 45 Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Met Ile Ser 50 55 60 Leu Thr Pro Lys Ile Thr Cys Val Val Val Asp Val Ser Glu Glu Glu 65 70 75 80 Pro Asp Val Gln Phe Asn Trp Tyr Val Asn Asn Val Glu Asp Lys Thr 85 90 95 Ala Gln Thr Glu Thr Arg Gln Arg Gln Tyr Asn Ser Thr Tyr Arg Val 100 105 110 Val Ser Val Leu Pro Ile Lys His Gln Asp Trp Met Ser Gly Lys Val 115 120 125 Phe Lys Cys Lys Val Asn Asn Asn Ala Leu Pro Ser Pro Ile Glu Lys 130 135 140 Thr Ile Ser Lys Pro Arg Gly Gln Val Arg Val Pro Gln Ile Tyr Thr 145 150 155 160 Phe Pro Pro Pro Ile Glu Gln Thr Val Lys Lys Asp Val Ser Val Thr 165 170 175 Cys Leu Val Thr Gly Phe Leu Pro Gln Asp Ile His Val Glu Trp Glu 180 185 190 Ser Asn Gly Gln Pro Gln Pro Glu Gln Asn Tyr Lys Asn Thr Gln Pro 195 200 205 Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val 210 215 220 Pro Lys Ser Arg Trp Asp Gln Gly Asp Ser Phe Thr Cys Ser Val Ile 225 230 235 240 His Glu Ala Leu His Asn His His Met Thr Lys Thr Ile Ser Arg Ser 245 250 255 Leu Gly Asn Gly Gly Gly Gly Ser Glu Val Glu Lys Thr Ala Cys Pro 260 265 270 Ser Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys 275 280 285 Lys Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln 290 295 300 Met Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val 305 310 315 320 Leu Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser 325 330 335 Val Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp 340 345 350 Ile Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu 355 360 365 Glu Val Asn Lys Gly His Glu Met Ser Pro Gln Ala Pro Arg Arg Pro 370 375 380 Leu Pro Gln Val Ala Thr Leu Ile Asp Arg Phe Val Lys Gly Arg Gly

385 390 395 400 Gln Leu Asp Lys Asp Thr Leu Asp Thr Leu Thr Ala Phe Tyr Pro Gly 405 410 415 Tyr Leu Cys Ser Leu Ser Pro Glu Glu Leu Ser Ser Val Pro Pro Ser 420 425 430 Ser Ile Trp Ala Val Arg Pro Gln Asp Leu Asp Thr Cys Asp Pro Arg 435 440 445 Gln Leu Asp Val Leu Tyr Pro Lys Ala Arg Leu Ala Phe Gln Asn Met 450 455 460 Asn Gly Ser Glu Tyr Phe Val Lys Ile Gln Ser Phe Leu Gly Gly Ala 465 470 475 480 Pro Thr Glu Asp Leu Lys Ala Leu Ser Gln Gln Asn Val Ser Met Asp 485 490 495 Leu Ala Thr Phe Met Lys Leu Arg Thr Asp Ala Val Leu Pro Leu Thr 500 505 510 Val Ala Glu Val Gln Lys Leu Leu Gly Pro His Val Glu Gly Leu Lys 515 520 525 Ala Glu Glu Arg His Arg Pro Val Arg Asp Trp Ile Leu Arg Gln Arg 530 535 540 Gln Asp Asp Leu Asp Thr Leu Gly Leu Gly Leu Gln 545 550 555 <210> SEQ ID NO 182 <211> LENGTH: 203 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 182 Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro His Ala Thr Phe Lys 1 5 10 15 Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn Cys Glu Cys Lys Arg 20 25 30 Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr Met Leu Cys Thr Gly 35 40 45 Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys Gln Cys Thr Ser Ser 50 55 60 Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro Gln Pro Glu Glu Gln 65 70 75 80 Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro Met Gln Pro Val Asp 85 90 95 Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro Pro Pro Trp Glu Asn 100 105 110 Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val Gly Gln Met Val Tyr 115 120 125 Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His Arg Gly Pro Ala Glu 130 135 140 Ser Val Cys Lys Met Thr His Gly Lys Thr Arg Trp Thr Gln Pro Gln 145 150 155 160 Leu Ile Cys Thr Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 165 170 175 Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu Gly Gly 180 185 190 Gly Gly Ser His His His His His His His His 195 200 <210> SEQ ID NO 183 <211> LENGTH: 452 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 183 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys 450 <210> SEQ ID NO 184 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 184 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Lys Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 185 <211> LENGTH: 600 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 185 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln 465 470 475 480 Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn 485 490 495 Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr 500 505 510 Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu 515 520 525 Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn 530 535 540 Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val 545 550 555 560 Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp 565 570 575 Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys 580 585 590 Gln Ser Ile Ile Ser Thr Leu Thr 595 600 <210> SEQ ID NO 186 <211> LENGTH: 619 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 186 Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Arg Tyr 20 25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ser Ile Ser Gly Ser Gly Gly Ala Thr Pro Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Tyr Gln Ile Leu Thr Gly Asn Ala Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 450 455 460 Gly Gly Ser Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu 465 470 475 480 Ser Val Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu 485 490 495 Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His 500 505 510 Ile Cys Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg 515 520 525 Lys Leu Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu 530 535 540 His Leu Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr 545 550 555 560 Gly Gln Val Lys Gly Arg Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro 565 570 575 Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu 580 585 590 Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys 595 600 605 Trp Asn Lys Ile Leu Met Gly Thr Lys Glu His 610 615 <210> SEQ ID NO 187 <211> LENGTH: 491 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 187

Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly 145 150 155 160 Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr 165 170 175 Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile 180 185 190 Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 195 200 205 Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala 210 215 220 Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn 225 230 235 240 Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 260 265 270 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 275 280 285 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 290 295 300 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 305 310 315 320 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 325 330 335 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 340 345 350 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 355 360 365 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 370 375 380 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu 385 390 395 400 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 405 410 415 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 420 425 430 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 435 440 445 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 450 455 460 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 465 470 475 480 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 <210> SEQ ID NO 188 <211> LENGTH: 753 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 188 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly 145 150 155 160 Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr 165 170 175 Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile 180 185 190 Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 195 200 205 Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala 210 215 220 Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn 225 230 235 240 Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 260 265 270 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 275 280 285 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 290 295 300 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 305 310 315 320 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 325 330 335 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 340 345 350 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 355 360 365 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 370 375 380 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu 385 390 395 400 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 405 410 415 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 420 425 430 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 435 440 445 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 450 455 460 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 465 470 475 480 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 485 490 495 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln 500 505 510 Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys 515 520 525 Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Val Ile Asn Trp Gly Lys 530 535 540 Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Gly 545 550 555 560 Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe Lys Ala Lys Ala Thr Leu 565 570 575 Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr Met Gln Leu Ser Ser Leu 580 585 590 Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Arg Gly Arg Tyr 595 600 605 Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val 610 615 620 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 625 630 635 640 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser 645 650 655 Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser 660 665 670 Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly 675 680 685 Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val 690 695 700 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr 705 710 715 720 Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln 725 730 735 Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 740 745 750 Lys <210> SEQ ID NO 189

<211> LENGTH: 751 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 189 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Gly Ile Ser Trp Asp Ser Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Ala Tyr Gln Trp Val Glu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly 145 150 155 160 Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr 165 170 175 Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile 180 185 190 Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 195 200 205 Ser Thr Ser Gly Asn Ser Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala 210 215 220 Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Pro Gly Asn 225 230 235 240 Gln Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly Gly Gly 245 250 255 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 260 265 270 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 275 280 285 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 290 295 300 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 305 310 315 320 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 325 330 335 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 340 345 350 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 355 360 365 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 370 375 380 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu 385 390 395 400 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 405 410 415 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 420 425 430 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 435 440 445 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 450 455 460 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 465 470 475 480 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 485 490 495 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln 500 505 510 Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys 515 520 525 Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg 530 535 540 Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser 545 550 555 560 Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys Asp Arg Phe Thr Ile 565 570 575 Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu 580 585 590 Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp 595 600 605 His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser 610 615 620 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 625 630 635 640 Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 645 650 655 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser 660 665 670 Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro 675 680 685 Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser 690 695 700 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser 705 710 715 720 Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser 725 730 735 Ser Asn Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr 740 745 750 <210> SEQ ID NO 190 <211> LENGTH: 711 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 190 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Asn 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Phe Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Thr Met Thr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

465 470 475 480 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 485 490 495 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 500 505 510 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 515 520 525 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 530 535 540 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 545 550 555 560 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 565 570 575 Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 595 600 605 Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr 610 615 620 Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr 625 630 635 640 Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser 645 650 655 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 660 665 670 Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala 675 680 685 Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly 690 695 700 Gly Thr Lys Leu Glu Ile Lys 705 710 <210> SEQ ID NO 191 <211> LENGTH: 364 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 191 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys 225 230 235 240 Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu 245 250 255 Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 260 265 270 Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 275 280 285 Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala 290 295 300 Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile 305 310 315 320 Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 325 330 335 Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 340 345 350 Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr 355 360 <210> SEQ ID NO 192 <211> LENGTH: 450 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 192 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> SEQ ID NO 193 <211> LENGTH: 711 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 193 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 465 470 475 480 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 485 490 495 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 500 505 510 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 515 520 525 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 530 535 540 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 545 550 555 560 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 565 570 575 Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met 595 600 605 Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr 610 615 620 Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr 625 630 635 640 Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser 645 650 655 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 660 665 670 Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala 675 680 685 Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly 690 695 700 Gly Thr Lys Leu Glu Ile Lys 705 710 <210> SEQ ID NO 194 <211> LENGTH: 713 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 194 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 465 470 475 480 Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp 485 490 495 Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp 500 505 510 Met Gly Tyr Ile Thr Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 515 520 525 Glu Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Thr Asn Gln Phe Phe 530 535 540 Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys 545 550 555 560 Ala Arg Gly Gly Tyr Tyr Gly Ser Ser Trp Gly Val Phe Ala Tyr Trp 565 570 575 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly 580 585 590 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 595 600 605 Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly Glu Thr 610 615 620

Val Thr Ile Thr Cys Arg Val Ser Glu Asn Ile Tyr Ser Tyr Leu Ala 625 630 635 640 Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val Tyr Asn 645 650 655 Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 660 665 670 Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro Glu Asp 675 680 685 Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Trp Thr Phe 690 695 700 Gly Gly Gly Thr Lys Leu Glu Ile Lys 705 710 <210> SEQ ID NO 195 <211> LENGTH: 708 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 195 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gln Val Gln Leu Gln Gln Ser Ala Val Glu Leu Ala Arg Pro Gly Ala 465 470 475 480 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe 485 490 495 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 500 505 510 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Glu Tyr Asn Gln Lys Phe 515 520 525 Lys Asp Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 530 535 540 Met Gln Leu Asp Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 545 550 555 560 Val Arg Gly Ser Ser Arg Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 565 570 575 Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 580 585 590 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Ile Gln Ser 595 600 605 Pro Ala Ser Leu Ser Val Ser Val Gly Glu Thr Val Thr Ile Thr Cys 610 615 620 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Phe Gln Gln Lys 625 630 635 640 Gln Gly Lys Ser Pro Gln Leu Leu Val Tyr Ala Ala Thr Asn Leu Ala 645 650 655 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr 660 665 670 Ser Leu Lys Ile Asn Ser Leu Gln Ser Glu Asp Phe Gly Ile Tyr Tyr 675 680 685 Cys Gln His Phe Trp Gly Thr Pro Arg Thr Phe Gly Gly Gly Thr Lys 690 695 700 Leu Glu Ile Lys 705 <210> SEQ ID NO 196 <400> SEQUENCE: 196 000 <210> SEQ ID NO 197 <211> LENGTH: 106 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 197 Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> SEQ ID NO 198 <211> LENGTH: 1653 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 198 tacaacttct tcccacggaa acccaagtgg gacaagaacc agatcaccta ccggatcatc 60 ggctacaccc ctgacctgga tcctgagaca gtggacgatg ccttcgccag agccttccaa 120 gtttggagcg acgtgacccc tctgcggttc tccagaatcc atgatggcga ggccgacatc 180 atgatcaact tcggcagatg ggagcacggc gacggctacc cttttgatgg caaggatggc 240 ctgctggccc acgcttttgc ccctggaaca ggtgttggcg gcgactctca cttcgacgac 300 gatgagttgt ggaccctcgg cgaaggacag gtcgtcagag tgaagtacgg caacgccgat 360 ggcgagtact gcaagttccc cttcctgttc aacggcaaag agtacaactc ctgcaccgac 420 accggcagat ctgacggctt cctgtggtgc tccaccacct acaactttga gaaggacggc 480 aaatacggct tctgccctca cgaggccctg tttaccatgg gcggaaatgc tgagggccag 540 ccatgcaagt ttccattccg gttccaaggg acctcctacg acagctgtac caccgaggga 600 agaaccgatg gctatcgttg gtgcggcacc acagaggact acgacagaga caagaagtat 660 ggcttctgtc ccgagacagc catgtctacc gtcggcggca attctgaagg cgccccttgt 720 gtgttccctt tcaccttcct gggcaacaaa tacgagtcct gcacctccgc tggccgctct 780 gatggaaaaa tgtggtgcgc taccaccgcc aactacgacg acgacagaaa gtggggcttt 840 tgtcctgacc agggctactc cctgtttctg gtggccgctc acgagtttgg ccatgctatg 900 ggcctcgagc actctcaaga tcccggtgca ctgatggccc ctatctacac ctacaccaag 960 aacttccggc tgtcccagga cgacatcaag ggcatccaag agctgtacgg cgcctctcct 1020

gatatcgatc tcggcaccgg acctactcct acactgggac ctgtgacacc cgagatctgc 1080 aagcaggaca tcgtgttcga cggaatcgcc cagatccggg gcgagatctt cttttttaag 1140 gaccggttca tctggcggac agtgacccct agagacaagc ctatgggacc tctgctggtg 1200 gctaccttct ggcctgagct gcctgagaag atcgacgccg tgtacgaggc ccctcaagag 1260 gaaaaggccg tctttttcgc cggcaacgag tactggatct actccgcttc taccctggaa 1320 cggggctacc ccaagcctct gacatctctg ggactgcctc cagacgtgca gagagtggac 1380 gccgccttca actggtccaa gaacaagaaa acctacatct tcgccgggga caagttctgg 1440 cggtacaacg aagtgaagaa aaagatggac cctggcttcc ccaagctgat cgccgatgcc 1500 tggaacgcta tccccgataa cctggacgct gtggtggatc tccaaggcgg cggacactcc 1560 tactttttca agggcgccta ctacctgaag ctggaaaacc agagcctgaa gtccgtgaag 1620 ttcggctcca tcaagtccga ctggctcgga tgt 1653 <210> SEQ ID NO 199 <211> LENGTH: 1242 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 199 ttcagaggcc ctctgctgcc caacagaccc ttcaccaccg tgtggaacgc caacacccag 60 tggtgcctgg aaagacacgg cgtggacgtg gacgtgtccg tgttcgatgt ggtggccaac 120 cccggccaga ccttcagggg ccctgacatg accatcttct actccagcca gctgggcacc 180 tacccctact acacccctac aggcgagcct gtgtttggcg gcctgcctca gaacgcctct 240 ctgatcgctc acctggcccg gaccttccag gacatcctgg ctgctatccc tgcccccgac 300 ttttctggcc tggccgtgat cgattgggag gcctggcgac ctagatgggc cttcaactgg 360 gacaccaagg acatctaccg gcagcggtcc agagccctgg tgcaggctca gcatcctgat 420 tggcctgccc ctcaggtgga agccgtggcc caggatcagt ttcagggcgc tgccagagct 480 tggatggctg gcacactgca gctgggaagg gccctgaggc ctagaggact gtggggcttc 540 tacggcttcc ccgactgcta caactacgac ttcctgtccc ccaactacac cggccagtgc 600 ccctctggaa tccgggccca gaatgatcag ctgggctggc tgtggggcca gtctagagcc 660 ctgtacccct ccatctacat gcccgccgtg ctggaaggca ccggcaagtc ccagatgtac 720 gtgcagcaca gagtggccga ggccttcagg gtggcagtgg ctgctggcga tcctaacctg 780 cccgtgctgc cctacgtgca gatcttctac gataccacca accactttct gcccctggac 840 gagctggaac actccctggg agagtctgct gctcagggtg ctgcaggcgt ggtgctgtgg 900 gtgtcctggg agaacacccg gaccaaagag tcctgccagg ccatcaaaga gtacatggac 960 accaccctgg gccccttcat cctgaacgtg acctctggcg ccctgctgtg tagccaggct 1020 ctgtgttctg gccacggcag atgcgtgcgg agaacctctc accctaaggc tctgctgctg 1080 ctgaaccccg cctccttcag catccagctg acacctggcg gcggacccct gtctctgaga 1140 ggtgctctgt ccctggaaga tcaggcccag atggccgtgg aattcaagtg ccggtgctac 1200 cctggctggc aggccccttg gtgcgagcgg aaatctatgt gg 1242 <210> SEQ ID NO 200 <211> LENGTH: 372 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 200 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 120 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 180 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 240 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 300 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 360 accgtgtcct ct 372 <210> SEQ ID NO 201 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 201 gacatcgtga tgacccagtc tccagactct ctggccgtgt ctctgggcga gagagccacc 60 atcaactgca agtcctctca gtccctgctg tactcccgga accagaagaa ctacctggcc 120 tggtatcagc agaagcccgg ccagcctcct aagctgctga tcttctgggc ctccaccaga 180 gaatctggcg tgcccgatag attctccggc tctggctttg gcaccgactt taccctgacc 240 atcagctccc tgcaggccga ggatgtggcc gtgtactact gccagcagta cttcagctac 300 cctctgacct ttggccaggg caccaaggtg gaaatcaag 339 <210> SEQ ID NO 202 <211> LENGTH: 1428 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 202 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct agggaacccc aggtttacac cctgcctcca 1140 tgccgggaag agatgaccaa gaaccaggtg tccctgtggt gcctcgtgaa gggcttctac 1200 ccttccgata tcgccgtgga atgggagagc aatggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgt acagcaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca agtgatga 1428 <210> SEQ ID NO 203 <211> LENGTH: 726 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 203 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 gacatcgtga tgacccagtc tccagactct ctggccgtgt ctctgggcga gagagccacc 120 atcaactgca agtcctctca gtccctgctg tactcccgga accagaagaa ctacctggcc 180 tggtatcagc agaagcccgg ccagcctcct aagctgctga tcttctgggc ctccaccaga 240 gaatctggcg tgcccgatag attctccggc tctggctttg gcaccgactt taccctgacc 300 atcagctccc tgcaggccga ggatgtggcc gtgtactact gccagcagta cttcagctac 360 cctctgacct ttggccaggg caccaaggtg gaaatcaagc ggacagtggc cgctccttcc 420 gtgttcatct tcccaccttc cgacgagcag ctgaagtctg gcacagcctc tgtcgtgtgc 480 ctgctgaaca acttctaccc tcgggaagcc aaggtgcagt ggaaggtgga caatgccctg 540 cagtccggca actcccaaga gtctgtgacc gagcaggact ccaaggacag cacctacagc 600 ctgtcctcca cactgaccct gtccaaggcc gactacgaga agcacaaggt gtacgcctgc 660 gaagtgaccc atcagggcct gtctagccct gtgaccaagt ctttcaaccg gggcgagtgc 720 tgatga 726 <210> SEQ ID NO 204 <211> LENGTH: 3126 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 204 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420

accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct cgggaacctc aagtctgtac cctgcctcct 1140 agccgggaag agatgaccaa gaaccaggtg tccctgagct gcgccgtgaa gggcttctac 1200 ccttctgata tcgccgtgga atgggagagc aacggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca aaggtggcgg aggatctggc 1440 ggaggtggaa gcggcggagg cggctcttac aacttcttcc cacggaaacc caagtgggat 1500 aagaaccaga tcacctaccg gatcatcggc tacacccctg acctggatcc tgagactgtg 1560 gacgatgcct tcgccagggc cttccaagtt tggagcgacg tgacccctct gcggttctcc 1620 agaatccatg atggcgaggc cgacatcatg atcaacttcg gcagatggga gcacggcgac 1680 ggctaccctt ttgatggcaa ggatggcctg ctggcccacg cttttgcccc tggaacaggt 1740 gttggcggcg actctcactt cgacgacgat gagttgtgga ccctcggcga aggacaggtc 1800 gtcagagtga agtacggcaa cgccgatggc gagtactgca agttcccctt cctgttcaat 1860 gggaaagagt ataactcctg caccgacacc ggcagatctg acggcttcct gtggtgctcc 1920 accacctaca acttcgagaa ggacggcaaa tacggcttct gccctcacga ggctctgttc 1980 accatgggcg gaaatgctga gggacagccc tgcaagtttc cattcagatt ccaagggacc 2040 tcctacgact cttgcaccac cgagggaaga accgatggct atcgttggtg cggcaccaca 2100 gaggactacg accgggacaa gaagtatggc ttctgtcccg agacagccat gtctaccgtc 2160 ggcggcaatt ctgagggtgc cccttgcgtg ttccctttca ccttcctggg caacaaatac 2220 gagtcctgca cctccgctgg cagatccgat ggaaagatgt ggtgcgctac caccgccaac 2280 tacgacgacg acagaaagtg gggcttttgt cctgaccagg gctacagcct gtttctggtg 2340 gccgctcacg agttcggcca tgctatggga ctcgagcact ctcaagatcc cggcgcactg 2400 atggccccta tctacaccta caccaagaac ttccggctgt cccaggacga catcaagggc 2460 atccaagagc tgtacggcgc ctctcctgat atcgatctcg gcaccggacc tactcctaca 2520 ctgggacctg tgacacccga gatctgcaag caggatatcg tgttcgacgg aatcgcccag 2580 atccggggcg agatcttctt ttttaaggac cgcttcattt ggcggaccgt gactcctcgg 2640 gacaagccta tgggacctct gctggtggct accttctggc ctgaactgcc cgagaagatc 2700 gatgccgtgt acgaggcccc tcaagaggaa aaggccgtct ttttcgccgg caacgagtac 2760 tggatctact ccgctagcac cctggaacgg ggctacccta agcctctgac ttctctggga 2820 ctgccacctg acgtgcagcg agtggatgcc gccttcaact ggtccaagaa caagaaaacc 2880 tatatcttcg ccggggacaa gttctggcgg tacaacgaag tcaagaaaaa gatggaccct 2940 ggcttcccca agctgatcgc cgatgcctgg aacgctatcc ccgataacct ggacgctgtg 3000 gtggacttgc aaggcggcgg acactcctac tttttcaagg gcgcctacta cctgaagctg 3060 gaaaaccaga gcctgaagtc cgtgaagttc ggctccatca agtccgactg gctgggctgc 3120 tgatga 3126 <210> SEQ ID NO 205 <211> LENGTH: 2445 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 205 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg ctctaccggc 60 tacaacttct tcccacggaa acccaagtgg gacaagaacc agatcaccta ccggatcatc 120 ggctacaccc ctgacctgga tcctgagaca gtggacgatg ccttcgccag agccttccaa 180 gtttggagcg acgtgacccc tctgcggttc tccagaatcc atgatggcga ggccgacatc 240 atgatcaact tcggcagatg ggagcacggc gacggctacc cttttgatgg caaggatggc 300 ctgctggccc acgcttttgc ccctggaaca ggtgttggcg gcgactctca cttcgacgac 360 gatgagttgt ggaccctcgg cgaaggacag gtcgtcagag tgaagtacgg caacgccgat 420 ggcgagtact gcaagttccc cttcctgttc aacggcaaag agtacaactc ctgcaccgac 480 accggcagat ctgacggctt cctgtggtgc tccaccacct acaactttga gaaggacggc 540 aaatacggct tctgccctca cgaggccctg tttaccatgg gcggaaatgc tgagggccag 600 ccatgcaagt ttccattccg gttccaaggg acctcctacg acagctgtac caccgaggga 660 agaaccgatg gctatcgttg gtgcggcacc acagaggact acgacagaga caagaagtat 720 ggcttctgtc ccgagacagc catgtctacc gtcggcggca attctgaagg cgccccttgt 780 gtgttccctt tcaccttcct gggcaacaaa tacgagtcct gcacctccgc tggccgctct 840 gatggaaaaa tgtggtgcgc taccaccgcc aactacgacg acgacagaaa gtggggcttt 900 tgtcctgacc agggctactc cctgtttctg gtggccgctc acgagtttgg ccatgctatg 960 ggcctcgagc actctcaaga tcccggtgca ctgatggccc ctatctacac ctacaccaag 1020 aacttccggc tgtcccagga cgacatcaag ggcatccaag agctgtacgg cgcctctcct 1080 gatatcgatc tcggcaccgg acctactcct acactgggac ctgtgacacc cgagatctgc 1140 aagcaggaca tcgtgttcga cggaatcgcc cagatccggg gcgagatctt cttttttaag 1200 gaccggttca tctggcggac agtgacccct agagacaagc ctatgggacc tctgctggtg 1260 gctaccttct ggcctgagct gcctgagaag atcgacgccg tgtacgaggc ccctcaagag 1320 gaaaaggccg tctttttcgc cggcaacgag tactggatct actccgcttc taccctggaa 1380 cggggctacc ccaagcctct gacatctctg ggactgcctc cagacgtgca gagagtggac 1440 gccgccttca actggtccaa gaacaagaaa acctacatct tcgccgggga caagttctgg 1500 cggtacaacg aagtgaagaa aaagatggac cctggcttcc ccaagctgat cgccgatgcc 1560 tggaacgcta tccccgataa cctggacgct gtggtggatc tccaaggcgg cggacactcc 1620 tactttttca agggcgccta ctacctgaag ctggaaaacc agagcctgaa gtccgtgaag 1680 ttcggctcca tcaagtccga ctggctcgga tgtggtggcg gaggaagcgg aggcggagga 1740 tctggcggtg gcggatctga taagacccac acctgtccac cttgtcctgc tccagaactg 1800 ctcggcggac cttccgtgtt cctgtttcct ccaaagccta aggacaccct gatgatctct 1860 cggacccctg aagtgacctg cgtggtggtg gatgtgtccc acgaggaccc agaagtgaag 1920 ttcaattggt acgtggacgg cgtggaagtg cacaacgcca agaccaagcc tagagaggaa 1980 cagtacaaca gcacctacag agtggtgtcc gtgctgaccg tgctgcacca ggattggctg 2040 aatgggaaag agtataagtg caaggtgtcc aacaaggccc tgcctgctcc tatcgaaaag 2100 accatcagca aggccaaggg acagccccgg gaacctcaag tctgtaccct gcctcctagc 2160 cgggaagaga tgaccaagaa tcaggtgtcc ctgtcttgcg ccgtgaaggg cttttacccc 2220 tccgatatcg ccgtggaatg ggagtctaat ggccagcctg agaacaacta caagaccaca 2280 cctcctgtgc tggactccga cggctcattc ttcctggtgt ccaagctgac tgtggacaag 2340 tccagatggc agcagggcaa cgtgttctcc tgctccgtga tgcacgaggc tctgcacaac 2400 cactacacac agaagtctct gagcctgtct cctggcaagt gatga 2445 <210> SEQ ID NO 206 <211> LENGTH: 1872 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 206 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct agggaacccc aggtttacac cctgcctcca 1140 tgccgggaag agatgaccaa gaaccaggtg tccctgtggt gcctcgtgaa gggcttctac 1200 ccttccgata tcgccgtgga atgggagagc aatggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgt acagcaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca aaggtggcgg aggatctggc 1440 ggaggtggaa gcggcggagg cggatctgct cctacatcct ccagcaccaa gaaaacccag 1500 ctgcagttgg agcatctgct gctggacctg cagatgatcc tgaatggcat caacaattac 1560 aagaacccca agctgacccg gatgctgacc gccaagtttg ccatgcctaa gaaggccacc 1620

gagctgaaac atctgcagtg cctggaagag gaactgaagc ccctggaaga agtgctgaat 1680 ctggcccagt ccaagaactt ccacctgagg cctcgggacc tgatctccaa catcaacgtg 1740 atcgtgctcg agctgaaggg ctccgagaca accttcatgt gcgagtacgc cgacgagaca 1800 gctaccatcg tggaatttct gaaccggtgg atcaccttct gccagtccat catcagcacc 1860 ctgacctgat ga 1872 <210> SEQ ID NO 207 <211> LENGTH: 2715 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 207 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtgcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 120 tcctgcaaga cctctcggta cacctttacc gagtacacca tccactgggt ccgacaggct 180 ccaggccaga gactggaatg gatcggcggc atcaacccca acaacggcat ccccaactac 240 aaccagaaat tcaagggccg cgtgaccatc accgtggaca cctctgcttc taccgcctac 300 atggaactgt ccagcctgag atctgaggac accgccgtgt actactgcgc cagaagaaga 360 atcgcctacg gctacgatga gggccacgcc atggattatt ggggccaggg aacactggtc 420 accgtgtcct ctgcctctac aaagggcccc tctgtgttcc ctctggctcc ttccagcaag 480 tctacctctg gcggaacagc tgctctgggc tgcctggtca aggactactt tcctgagcct 540 gtgaccgtgt cttggaactc tggcgctctg acatccggcg tgcacacctt tccagctgtg 600 ctgcaatctt ccggcctgta ctccctgtcc tccgtcgtga cagtgccttc tagctctctg 660 ggcacccaga cctacatctg caatgtgaac cacaagcctt ccaacaccaa ggtggacaag 720 agagtggaac ccaagtcctg cgacaagacc cacacctgtc caccatgtcc tgctccagaa 780 ctgctcggcg gaccttccgt gttcctgttt cctccaaagc ctaaggacac cctgatgatc 840 tctcggaccc ctgaagtgac ctgcgtggtg gtggatgtgt ctcacgagga cccagaagtg 900 aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcctagagag 960 gaacagtaca actccaccta cagagtggtg tccgtgctga ccgtgctgca ccaggattgg 1020 ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc tcctatcgaa 1080 aagaccatct ccaaggccaa gggccagcct cgggaacctc aagtctgtac cctgcctcct 1140 agccgggaag agatgaccaa gaaccaggtg tccctgagct gcgccgtgaa gggcttctac 1200 ccttctgata tcgccgtgga atgggagagc aacggccagc cagagaacaa ctacaagaca 1260 acccctcctg tgctggactc cgacggctca ttcttcctgg tgtccaagct gacagtggac 1320 aagtccagat ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1380 aatcactaca cacagaagtc cctgtctctg tcccctggca aaggtggcgg aggatctggc 1440 ggaggtggaa gcggcggagg cggatctttt agaggacctc tgctgcccaa ccggcctttc 1500 accacagtgt ggaacgctaa cacccagtgg tgcctggaaa gacacggcgt tgacgtggac 1560 gtgtccgtgt tcgatgtggt ggctaatccc ggccagacct tcagaggccc tgacatgacc 1620 atcttctact ccagccagct gggcacctat ccttactaca cccctacagg cgagcccgtg 1680 tttggaggct tgcctcagaa tgccagcctg atcgctcacc tggccagaac ctttcaggac 1740 atcctggctg ctatccccgc tcctgacttt tccggactgg ccgtgatcga ttgggaagcc 1800 tggcgaccta gatgggcctt caactgggac accaaggaca tctaccggca gcggtctaga 1860 gcactggtgc aggctcaaca tcctgactgg cctgctccac aggttgaggc tgttgcccag 1920 gatcagtttc agggcgctgc cagagcttgg atggctggaa cattgcagct ggggagagcc 1980 ctgaggccta gaggactgtg gggcttttac ggcttccccg actgctacaa ctacgacttc 2040 ctgtctccta actacaccgg ccagtgtcct tccggcatca gagcccagaa tgatcagctc 2100 ggatggctct ggggacagtc cagggctctg tacccctcca tctacatgcc tgctgtcctg 2160 gaaggcaccg gcaagtccca gatgtacgtg cagcatagag tggccgaggc cttcagagtg 2220 gctgttgctg ctggcgatcc taacctgcct gtgctgcctt acgtgcagat cttctacgat 2280 accaccaacc actttctgcc cctggacgag ctggaacact ccctgggaga atctgctgct 2340 caaggtgctg caggcgtggt gttgtgggtg tcctgggaaa acacccggac caaagagtcc 2400 tgccaggcca tcaaagagta tatggacacc acactgggcc ccttcatcct gaacgtgaca 2460 tctggcgcac tgctgtgcag ccaggcactg tgttctggac acggaagatg cgtgcggaga 2520 acctctcatc ccaaggctct gctgctgctg aaccctgcca gcttctccat ccagttgaca 2580 ccaggcggag gccctctgtc tttgagaggt gcactgtccc tggaagatca ggcccagatg 2640 gctgtggaat tcaagtgcag atgctacccc ggctggcaag ctccttggtg cgagagaaag 2700 tccatgtggt agtga 2715 <210> SEQ ID NO 208 <211> LENGTH: 1416 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 208 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaggtgcagc tgttggaatc tggcggagga ttggttcagc ctggcggctc tctgagactg 120 tcttgtgccg cttccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 180 cctggcaaag gactggaatg ggtgtcctct atctacccct ctggcggcat caccttttac 240 gccgacaccg tgaagggcag attcaccatc tctcgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc cagaatcaag 360 ctgggcaccg tgaccaccgt ggattattgg ggacagggca ccctggtcac cgtgtcctct 420 gcttctacca agggacccag cgtgttccct ctggctcctt ccagcaagtc tacctccggt 480 ggaacagctg ctctgggctg cctggtcaag gactactttc ctgagcctgt gaccgtgtct 540 tggaactccg gcgctctgac atctggcgtg cacacatttc cagccgtgct gcagtcctcc 600 ggcctgtact ctctcagctc tgtcgtgacc gtgccttcca gctctctggg aacccagacc 660 tacatctgca atgtgaacca caagccttcc aacaccaagg tggacaagag agtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 780 ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatctc tcggacccct 840 gaagtgacct gcgtggtggt ggatgtgtct cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctaca gagtggtgtc cgtgctgaca gtgctgcacc aggattggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgaaaa gaccatctcc 1080 aaggccaagg gccagcctag ggaaccccag gtttacaccc tgcctccatg ccgggaagag 1140 atgaccaaga accaggtgtc cctgtggtgc ctggttaagg gcttctaccc ttccgatatc 1200 gccgtggaat gggagagcaa tggccagcct gagaacaact acaagacaac ccctcctgtg 1260 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtccagatgg 1320 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa tcactacacc 1380 cagaagtccc tgtctctgag ccccggcaag tgatga 1416 <210> SEQ ID NO 209 <211> LENGTH: 1860 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 209 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacaggc 60 gaggtgcagc tgttggaatc tggcggagga ttggttcagc ctggcggctc tctgagactg 120 tcttgtgccg cttccggctt caccttctcc agctatatca tgatgtgggt ccgacaggcc 180 cctggcaaag gactggaatg ggtgtcctct atctacccct ctggcggcat caccttttac 240 gccgacaccg tgaagggcag attcaccatc tctcgggaca actccaagaa caccctgtac 300 ctgcagatga actccctgag agccgaggac accgccgtgt actactgcgc cagaatcaag 360 ctgggcaccg tgaccaccgt ggattattgg ggacagggca ccctggtcac cgtgtcctct 420 gcttctacca agggacccag cgtgttccct ctggctcctt ccagcaagtc tacctccggt 480 ggaacagctg ctctgggctg cctggtcaag gactactttc ctgagcctgt gaccgtgtct 540 tggaactccg gcgctctgac atctggcgtg cacacatttc cagccgtgct gcagtcctcc 600 ggcctgtact ctctcagctc tgtcgtgacc gtgccttcca gctctctggg aacccagacc 660 tacatctgca atgtgaacca caagccttcc aacaccaagg tggacaagag agtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 780 ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatctc tcggacccct 840 gaagtgacct gcgtggtggt ggatgtgtct cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctaca gagtggtgtc cgtgctgaca gtgctgcacc aggattggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgaaaa gaccatctcc 1080 aaggccaagg gccagcctag ggaaccccag gtttacaccc tgcctccatg ccgggaagag 1140 atgaccaaga accaggtgtc cctgtggtgc ctggttaagg gcttctaccc ttccgatatc 1200 gccgtggaat gggagagcaa tggccagcct gagaacaact acaagacaac ccctcctgtg 1260 ctggactccg acggctcatt cttcctgtac tccaagctga ccgtggacaa gtccagatgg 1320 cagcagggca acgtgttctc ctgctccgtg atgcacgagg ccctgcacaa tcactacacc 1380 cagaagtccc tgtctctgtc tcccggaaaa ggcggaggtg gaagcggcgg aggcggatct 1440 ggtggcggtg gatctgctcc tacctcctcc agcaccaaga aaacccagct gcagttggag 1500 catctgctgc tggacctcca gatgatcctg aatggcatca acaattacaa gaaccccaag 1560 ctcacccgga tgctgaccgc caagtttgcc atgcctaaga aggccaccga gctgaaacat 1620 ctgcagtgcc tggaagagga actgaagccc ctggaagaag tgctgaatct ggcccagtcc 1680 aagaacttcc acctgaggcc tcgggacctg atctccaaca tcaacgtgat cgtgctcgag 1740 ctgaagggct ccgagacaac cttcatgtgc gagtacgccg acgagacagc taccatcgtg 1800 gaatttctga accggtggat caccttctgt cagtccatca tcagcaccct gacctgatga 1860 <210> SEQ ID NO 210

<211> LENGTH: 2703 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 210 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctacagga 60 caggtccagc tgcagcagtc tggccctgaa cttgtgaagc ctggcgcctc cgtgaagatg 120 tcctgcaagg cttctggcta caccttcacc gactacgtga tcaactgggg caagcagaga 180 tctggccagg gcctcgagtg gatcggcgag atctatcctg gctccggcac caactactac 240 aacgagaagt tcaaggccaa ggctaccctg accgccgaca agtcctccaa tatcgcctac 300 atgcagctgt ccagcctgac ctctgaggac tccgccgtgt acttctgcgc cagaagaggc 360 agatacggcc tgtacgccat ggactattgg ggccagggca cctctgtgac cgtgtcctct 420 gcttctacca agggacccag cgtgttccct ctggctcctt ccagcaagtc tacctctggc 480 ggaacagctg ctctgggctg cctggtcaag gactactttc ctgagcctgt gacagtgtct 540 tggaactctg gcgccctgac atccggcgtg cacacatttc cagctgtgct gcagtcctct 600 ggcctgtact ctctgtcctc cgtcgtgacc gtgccttcta gctctctggg cacccagacc 660 tacatctgca atgtgaacca caagccttcc aacaccaagg tggacaagag agtggaaccc 720 aagtcctgcg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 780 ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatctc tcggacccct 840 gaagtgacct gcgtggtggt ggatgtgtct cacgaggatc ccgaagtgaa gttcaattgg 900 tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaac 960 tccacctaca gagtggtgtc cgtgctgacc gtgctgcacc aggattggct gaacggcaaa 1020 gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgaaaa gaccatctcc 1080 aaggctaagg gccagcctcg cgaaccccaa gtctgtacac tgcctcctag ccgggaagag 1140 atgaccaaga accaggtgtc cctgtcctgc gccgtgaagg gcttctaccc ttctgatatc 1200 gccgtggaat gggagtccaa cggccagcct gagaacaact acaagacaac ccctcctgtg 1260 ctggactccg acggctcatt cttcctggtg tccaagctga cagtggacaa gtcccgatgg 1320 cagcagggca acgtgttctc ctgctctgtg atgcacgagg ctctgcacaa ccactacacc 1380 cagaagtccc tgtctctgtc ccctggaaaa ggcggcggag gatctggcgg aggtggaagc 1440 ggaggcggtg gatcttttag aggacctctg ctgcccaacc ggcctttcac cacagtgtgg 1500 aacgctaaca cccagtggtg cctggaaaga catggcgtcg acgtggacgt gtccgtgttc 1560 gatgtggtgg ctaatcccgg ccagaccttc agaggccccg acatgaccat cttctactcc 1620 agccagctgg gcacctatcc ttactacacc cctacaggcg agcccgtgtt tggtggcttg 1680 cctcagaatg cctctctgat cgcccacctg gctagaacct tccaggatat tctggctgct 1740 atccccgctc ctgacttttc tggcctggcc gtgatcgatt gggaagcttg gaggcctaga 1800 tgggccttca actgggacac caaggacatc taccggcagc ggtctagagc actggtgcag 1860 gctcaacatc ctgactggcc tgctccacag gttgaggctg ttgcccagga tcagtttcag 1920 ggcgctgcca gagcttggat ggctggaaca ttgcagctgg ggagagccct gaggccaaga 1980 ggattgtggg gcttttacgg cttccccgac tgctacaact acgacttcct gtctcctaac 2040 tacaccggcc agtgtccttc cggcatcaga gcccagaatg atcagctcgg atggctctgg 2100 ggacagtcca gggctctgta cccctccatc tacatgcctg ctgtgctcga aggcaccggc 2160 aagtcccaga tgtacgtgca gcatagagtg gccgaggcct tcagagtggc tgttgctgct 2220 ggcgatccta acctgcctgt gctgccttac gtgcagatct tctacgatac caccaaccac 2280 tttctgcccc tggacgagct ggaacactcc ctgggagaat ctgctgctca aggtgctgca 2340 ggcgtggtgt tgtgggtgtc ctgggaaaac acccggacca aagagtcctg ccaggccatc 2400 aaagagtata tggacaccac actgggcccc ttcatcctga acgtgacatc tggcgctctg 2460 ctgtgcagcc aggctctgtg ttctggccat ggtagatgcg tgcggagaac ctctcatccc 2520 aaggctctgc tgctgctgaa ccctgccagc ttctccatcc agttgacacc aggcggaggc 2580 cctctgtctt tgagaggtgc actgtccctg gaagatcagg cccagatggc tgtggaattc 2640 aagtgcagat gctaccccgg ctggcaagct ccttggtgcg agagaaagtc catgtggtag 2700 tga 2703 <210> SEQ ID NO 211 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 211 atggaaaccg acacactgct gctgtgggtg ctgctcttgt gggtgccagg atctaccggc 60 gacatccaga tgacccagac cacctctagc ctgtctgcct ctctgggcga cagagtgacc 120 atctcctgta gagccagcca ggacatctcc aactacctga actggtatca gcagaaaccc 180 gacggcaccg tgaagctgct gatctactac acctctcggc tgcactctgg cgtgccctct 240 agattttctg gctccggctc tggcaccgac tactccctga ccatcaacaa cctggaacaa 300 gaggatatcg ctacctactt ctgccagcaa ggcaacaccc ggccttggac atttggcggc 360 ggaacaaagc tggaaatcaa gcggacagtg gccgctcctt ccgtgttcat cttcccacct 420 tccgacgagc agctgaagtc cggcacagct tctgtcgtgt gcctgctgaa caacttctac 480 cctcgggaag ccaaggtgca gtggaaggtg gacaatgccc tgcagtccgg caactcccaa 540 gagtctgtga ccgagcagga ctccaaggac agcacctaca gcctgtcctc cacactgacc 600 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccatcagggc 660 ctgtctagcc ctgtgaccaa gtctttcaac cggggcgagt gctgatga 708 <210> SEQ ID NO 212 <211> LENGTH: 2037 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 212 atggctgctc atctgctgcc tatctgcgcc ctgttcctga ccctgctgga tatggcccag 60 ggcttcagag gccctctgct gcccaacaga cccttcacca ccgtgtggaa cgccaacacc 120 cagtggtgcc tggaaagaca cggcgtggac gtggacgtgt ccgtgttcga tgtggtggcc 180 aaccccggcc agaccttcag gggccctgac atgaccatct tctactccag ccagctgggc 240 acctacccct actacacccc tacaggcgag cctgtgtttg gcggcctgcc tcagaacgcc 300 tctctgatcg ctcacctggc ccggaccttc caggacatcc tggctgctat ccctgccccc 360 gacttttctg gcctggccgt gatcgattgg gaggcctggc gacctagatg ggccttcaac 420 tgggacacca aggacatcta ccggcagcgg tccagagccc tggtgcaggc tcagcatcct 480 gattggcctg cccctcaggt ggaagccgtg gcccaggatc agtttcaggg cgctgccaga 540 gcttggatgg ctggcacact gcagctggga agggccctga ggcctagagg actgtggggc 600 ttctacggct tccccgactg ctacaactac gacttcctgt cccccaacta caccggccag 660 tgcccctctg gaatccgggc ccagaatgat cagctgggct ggctgtgggg ccagtctaga 720 gccctgtacc cctccatcta catgcccgcc gtgctggaag gcaccggcaa gtcccagatg 780 tacgtgcagc acagagtggc cgaggccttc agggtggcag tggctgctgg cgatcctaac 840 ctgcccgtgc tgccctacgt gcagatcttc tacgatacca ccaaccactt tctgcccctg 900 gacgagctgg aacactccct gggagagtct gctgctcagg gtgctgcagg cgtggtgctg 960 tgggtgtcct gggagaacac ccggaccaaa gagtcctgcc aggccatcaa agagtacatg 1020 gacaccaccc tgggcccctt catcctgaac gtgacctctg gcgccctgct gtgtagccag 1080 gctctgtgtt ctggccacgg cagatgcgtg cggagaacct ctcaccctaa ggctctgctg 1140 ctgctgaacc ccgcctcctt cagcatccag ctgacacctg gcggcggacc cctgtctctg 1200 agaggtgctc tgtccctgga agatcaggcc cagatggccg tggaattcaa gtgccggtgc 1260 taccctggct ggcaggcccc ttggtgcgag cggaaatcta tgtggggcgg aggcggatca 1320 ggcggcggag gatctggggg tggtggctct gataagaccc acacctgtcc tccctgccct 1380 gcccctgaac tgctgggagg cccttccgtg ttcctgttcc ccccaaagcc caaggacacc 1440 ctgatgatct cccggacccc cgaagtgacc tgcgtggtgg tggatgtgtc ccacgaggac 1500 cctgaagtga agttcaattg gtacgtggac ggggtggaag tgcacaacgc caagaccaag 1560 cccagagagg aacagtacaa ctccacctac agagtggtgt ccgtgctgac cgtgctgcat 1620 caggactggc tgaacggcaa agagtataag tgcaaggtgt ccaacaaggc cctgcccgct 1680 cccatcgaaa agaccatctc caaggccaag ggccagcccc gggaacctca agtgtgcacc 1740 ctgcctccat cccgggaaga gatgaccaag aaccaggtgt ccctgtcctg cgccgtgaag 1800 ggcttttacc cctccgatat cgctgtggaa tgggagtcca acggccagcc tgagaacaac 1860 tacaagacca ccccccctgt gctggactcc gacggctcat tcttcctggt gtccaagctg 1920 acagtggaca agtcccggtg gcagcagggc aacgtgttct cctgctccgt gatgcacgag 1980 gccctgcaca accactacac ccagaagtcc ctgagcctgt cccctggcaa gtgatga 2037 <210> SEQ ID NO 213 <211> LENGTH: 2385 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polynucleotide <400> SEQUENCE: 213 atgaagacct gggtcaagat cgtgtttggc gtggccacct ctgctgtgct ggctctgctg 60 gtcatgtgca tcgtgctgcg gccttccaga gtgcacaact ccgaagagaa caccatgcgg 120 gctctgaccc tgaaggacat cctgaacggc accttcagct acaagacctt ctttcccaac 180 tggatctccg gccaagagta cctgcaccag tccgccgaca acaatatcgt gctgtacaac 240 atcgagacag gccagtccta caccatcctg tccaaccgga ccatgaagtc cgtgaacgcc 300 tccaactacg gactgtctcc tgaccggcag ttcgtgtacc tggaatccga ctactccaag 360 ctgtggcggt actcctacac cgccacctac tacatctacg acctgagcaa cggcgagttc 420 gtgcggggaa atgagctgcc cagacctatc cagtacctgt gctggtcccc tgtgggctct 480 aagctggctt acgtgtacca gaacaacatc tacctgaagc agcggcctgg cgaccctcca 540 ttccagatca ccttcaacgg cagagagaac aagatcttta acggcatccc cgactgggtg 600 tacgaggaag agatgctgcc cactaagtac gccctctggt ggtcccctaa cggcaagttt 660

ctggcctacg ccgagttcaa cgacaaggat atccccgtga tcgcctactc ctactacggc 720 gacgagcagt accctcggac catcaacatc ccttatccta aggctggcgc caagaatccc 780 gtcgtgcgga tcttcatcat cgacaccacc tatcctgcct acgtgggccc tcaagaggtg 840 ccagtgcctg ctatgatcgc ctccagcgac tactacttct cctggctgac atgggtcacc 900 gacgagcgag tttgtctgca gtggctgaag cgggtgcaga acgtgtccgt gctgtccatc 960 tgcgacttca gagaggactg gcagacctgg gactgcccca agacacaaga gcacatcgag 1020 gaatctcgga ccggatgggc tggcggcttc ttcgtgtcta gacccgtgtt ctcctacgac 1080 gccatcagct actataagat cttctccgac aaggacggct acaagcacat ccactacatc 1140 aaggacaccg tcgagaacgc catccagatt acctccggca agtgggaagc catcaatatc 1200 ttcagagtga cccaggactc cctgttctac tcctccaacg agttcgagga ataccccggc 1260 agacggaaca tctacagaat ctccatcggc agctaccctc catccaagaa atgcgtgacc 1320 tgccacctga gaaaagagcg gtgccagtac tataccgcca gcttctctga ctacgccaag 1380 tactacgccc tcgtgtgtta cggccctggc atccctatct ctaccctgca cgatggcaga 1440 accgaccaag agatcaagat cctggaagaa aacaaagagc tggaaaacgc cctgaagaac 1500 attcagctgc ccaaagagga aatcaagaag ctggaagtcg acgagatcac cctgtggtac 1560 aagatgatcc tgcctcctca gttcgaccgg tccaagaagt accctctgct gatccaggtg 1620 tacggcggac cttgctctca gtccgtcaga tctgtgttcg ccgtgaattg gatctcctac 1680 ctggcctcca aagaaggcat ggttatcgcc ctggtggacg gcagaggcac agcttttcaa 1740 ggcgacaagc tgctgtacgc cgtgtacaga aagctgggcg tgtacgaagt ggaagatcag 1800 atcaccgccg tgcggaagtt catcgagatg ggcttcatcg acgagaagcg gatcgctatc 1860 tggggctggt cttacggcgg ctacgtttcc tctctggccc tggcttctgg caccggcctg 1920 ttcaagtgtg gaatcgctgt tgcccctgtg tcctcctggg agtactatgc ctctgtgtac 1980 accgagcggt tcatgggcct gcctaccaag gacgacaacc tggaacacta caagaacagc 2040 accgtgatgg ccagagccga gtacttccgg aacgtggact acctgctgat tcacggcacc 2100 gccgacgaca acgtgcactt ccaaaacagc gcccagatcg ccaaggctct ggtcaatgcc 2160 caggtggact ttcaggccat gtggtactcc gaccagaacc acggcctgtc tggcctgagc 2220 accaatcacc tgtacaccca catgacccac tttctgaagc agtgcttctc cctgtctgat 2280 ggcggcggag gctctggact gaacgatatc ttcgaggccc agaaaatcga gtggcacgaa 2340 ggcggaggcg gctcccacca tcatcatcac caccatcact gatga 2385 <210> SEQ ID NO 214 <211> LENGTH: 454 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 214 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <210> SEQ ID NO 215 <211> LENGTH: 220 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 215 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> SEQ ID NO 216 <211> LENGTH: 1020 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 216 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Tyr Asn Phe Phe Pro Arg Lys Pro Lys Trp Asp 465 470 475 480 Lys Asn Gln Ile Thr Tyr Arg Ile Ile Gly Tyr Thr Pro Asp Leu Asp 485 490 495 Pro Glu Thr Val Asp Asp Ala Phe Ala Arg Ala Phe Gln Val Trp Ser 500 505 510 Asp Val Thr Pro Leu Arg Phe Ser Arg Ile His Asp Gly Glu Ala Asp 515 520 525 Ile Met Ile Asn Phe Gly Arg Trp Glu His Gly Asp Gly Tyr Pro Phe 530 535 540 Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe Ala Pro Gly Thr Gly 545 550 555 560 Val Gly Gly Asp Ser His Phe Asp Asp Asp Glu Leu Trp Thr Leu Gly 565 570 575 Glu Gly Gln Val Val Arg Val Lys Tyr Gly Asn Ala Asp Gly Glu Tyr 580 585 590 Cys Lys Phe Pro Phe Leu Phe Asn Gly Lys Glu Tyr Asn Ser Cys Thr 595 600 605 Asp Thr Gly Arg Ser Asp Gly Phe Leu Trp Cys Ser Thr Thr Tyr Asn 610 615 620 Phe Glu Lys Asp Gly Lys Tyr Gly Phe Cys Pro His Glu Ala Leu Phe 625 630 635 640 Thr Met Gly Gly Asn Ala Glu Gly Gln Pro Cys Lys Phe Pro Phe Arg 645 650 655 Phe Gln Gly Thr Ser Tyr Asp Ser Cys Thr Thr Glu Gly Arg Thr Asp 660 665 670 Gly Tyr Arg Trp Cys Gly Thr Thr Glu Asp Tyr Asp Arg Asp Lys Lys 675 680 685 Tyr Gly Phe Cys Pro Glu Thr Ala Met Ser Thr Val Gly Gly Asn Ser 690 695 700 Glu Gly Ala Pro Cys Val Phe Pro Phe Thr Phe Leu Gly Asn Lys Tyr 705 710 715 720 Glu Ser Cys Thr Ser Ala Gly Arg Ser Asp Gly Lys Met Trp Cys Ala 725 730 735 Thr Thr Ala Asn Tyr Asp Asp Asp Arg Lys Trp Gly Phe Cys Pro Asp 740 745 750 Gln Gly Tyr Ser Leu Phe Leu Val Ala Ala His Glu Phe Gly His Ala 755 760 765 Met Gly Leu Glu His Ser Gln Asp Pro Gly Ala Leu Met Ala Pro Ile 770 775 780 Tyr Thr Tyr Thr Lys Asn Phe Arg Leu Ser Gln Asp Asp Ile Lys Gly 785 790 795 800 Ile Gln Glu Leu Tyr Gly Ala Ser Pro Asp Ile Asp Leu Gly Thr Gly 805 810 815 Pro Thr Pro Thr Leu Gly Pro Val Thr Pro Glu Ile Cys Lys Gln Asp 820 825 830 Ile Val Phe Asp Gly Ile Ala Gln Ile Arg Gly Glu Ile Phe Phe Phe 835 840 845 Lys Asp Arg Phe Ile Trp Arg Thr Val Thr Pro Arg Asp Lys Pro Met 850 855 860 Gly Pro Leu Leu Val Ala Thr Phe Trp Pro Glu Leu Pro Glu Lys Ile 865 870 875 880 Asp Ala Val Tyr Glu Ala Pro Gln Glu Glu Lys Ala Val Phe Phe Ala 885 890 895 Gly Asn Glu Tyr Trp Ile Tyr Ser Ala Ser Thr Leu Glu Arg Gly Tyr 900 905 910 Pro Lys Pro Leu Thr Ser Leu Gly Leu Pro Pro Asp Val Gln Arg Val 915 920 925 Asp Ala Ala Phe Asn Trp Ser Lys Asn Lys Lys Thr Tyr Ile Phe Ala 930 935 940 Gly Asp Lys Phe Trp Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro 945 950 955 960 Gly Phe Pro Lys Leu Ile Ala Asp Ala Trp Asn Ala Ile Pro Asp Asn 965 970 975 Leu Asp Ala Val Val Asp Leu Gln Gly Gly Gly His Ser Tyr Phe Phe 980 985 990 Lys Gly Ala Tyr Tyr Leu Lys Leu Glu Asn Gln Ser Leu Lys Ser Val 995 1000 1005 Lys Phe Gly Ser Ile Lys Ser Asp Trp Leu Gly Cys 1010 1015 1020 <210> SEQ ID NO 217 <211> LENGTH: 793 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 217 Tyr Asn Phe Phe Pro Arg Lys Pro Lys Trp Asp Lys Asn Gln Ile Thr 1 5 10 15 Tyr Arg Ile Ile Gly Tyr Thr Pro Asp Leu Asp Pro Glu Thr Val Asp 20 25 30 Asp Ala Phe Ala Arg Ala Phe Gln Val Trp Ser Asp Val Thr Pro Leu 35 40 45 Arg Phe Ser Arg Ile His Asp Gly Glu Ala Asp Ile Met Ile Asn Phe 50 55 60 Gly Arg Trp Glu His Gly Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly 65 70 75 80 Leu Leu Ala His Ala Phe Ala Pro Gly Thr Gly Val Gly Gly Asp Ser 85 90 95 His Phe Asp Asp Asp Glu Leu Trp Thr Leu Gly Glu Gly Gln Val Val 100 105 110 Arg Val Lys Tyr Gly Asn Ala Asp Gly Glu Tyr Cys Lys Phe Pro Phe 115 120 125 Leu Phe Asn Gly Lys Glu Tyr Asn Ser Cys Thr Asp Thr Gly Arg Ser 130 135 140 Asp Gly Phe Leu Trp Cys Ser Thr Thr Tyr Asn Phe Glu Lys Asp Gly 145 150 155 160 Lys Tyr Gly Phe Cys Pro His Glu Ala Leu Phe Thr Met Gly Gly Asn 165 170 175 Ala Glu Gly Gln Pro Cys Lys Phe Pro Phe Arg Phe Gln Gly Thr Ser 180 185 190 Tyr Asp Ser Cys Thr Thr Glu Gly Arg Thr Asp Gly Tyr Arg Trp Cys 195 200 205 Gly Thr Thr Glu Asp Tyr Asp Arg Asp Lys Lys Tyr Gly Phe Cys Pro 210 215 220 Glu Thr Ala Met Ser Thr Val Gly Gly Asn Ser Glu Gly Ala Pro Cys 225 230 235 240 Val Phe Pro Phe Thr Phe Leu Gly Asn Lys Tyr Glu Ser Cys Thr Ser 245 250 255 Ala Gly Arg Ser Asp Gly Lys Met Trp Cys Ala Thr Thr Ala Asn Tyr 260 265 270 Asp Asp Asp Arg Lys Trp Gly Phe Cys Pro Asp Gln Gly Tyr Ser Leu 275 280 285 Phe Leu Val Ala Ala His Glu Phe Gly His Ala Met Gly Leu Glu His 290 295 300 Ser Gln Asp Pro Gly Ala Leu Met Ala Pro Ile Tyr Thr Tyr Thr Lys 305 310 315 320 Asn Phe Arg Leu Ser Gln Asp Asp Ile Lys Gly Ile Gln Glu Leu Tyr 325 330 335 Gly Ala Ser Pro Asp Ile Asp Leu Gly Thr Gly Pro Thr Pro Thr Leu 340 345 350 Gly Pro Val Thr Pro Glu Ile Cys Lys Gln Asp Ile Val Phe Asp Gly 355 360 365 Ile Ala Gln Ile Arg Gly Glu Ile Phe Phe Phe Lys Asp Arg Phe Ile 370 375 380 Trp Arg Thr Val Thr Pro Arg Asp Lys Pro Met Gly Pro Leu Leu Val 385 390 395 400

Ala Thr Phe Trp Pro Glu Leu Pro Glu Lys Ile Asp Ala Val Tyr Glu 405 410 415 Ala Pro Gln Glu Glu Lys Ala Val Phe Phe Ala Gly Asn Glu Tyr Trp 420 425 430 Ile Tyr Ser Ala Ser Thr Leu Glu Arg Gly Tyr Pro Lys Pro Leu Thr 435 440 445 Ser Leu Gly Leu Pro Pro Asp Val Gln Arg Val Asp Ala Ala Phe Asn 450 455 460 Trp Ser Lys Asn Lys Lys Thr Tyr Ile Phe Ala Gly Asp Lys Phe Trp 465 470 475 480 Arg Tyr Asn Glu Val Lys Lys Lys Met Asp Pro Gly Phe Pro Lys Leu 485 490 495 Ile Ala Asp Ala Trp Asn Ala Ile Pro Asp Asn Leu Asp Ala Val Val 500 505 510 Asp Leu Gln Gly Gly Gly His Ser Tyr Phe Phe Lys Gly Ala Tyr Tyr 515 520 525 Leu Lys Leu Glu Asn Gln Ser Leu Lys Ser Val Lys Phe Gly Ser Ile 530 535 540 Lys Ser Asp Trp Leu Gly Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly 545 550 555 560 Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 565 570 575 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 580 585 590 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 595 600 605 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 610 615 620 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 625 630 635 640 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 645 650 655 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 660 665 670 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 675 680 685 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 690 695 700 Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro 705 710 715 720 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 725 730 735 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 740 745 750 Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 755 760 765 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 770 775 780 Lys Ser Leu Ser Leu Ser Pro Gly Lys 785 790 <210> SEQ ID NO 218 <211> LENGTH: 602 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 218 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln 465 470 475 480 Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly 485 490 495 Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys 500 505 510 Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu 515 520 525 Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser 530 535 540 Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val 545 550 555 560 Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr 565 570 575 Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr 580 585 590 Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr 595 600 <210> SEQ ID NO 219 <211> LENGTH: 883 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 219 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe 465 470 475 480 Thr Thr Val Trp Asn Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly 485 490 495 Val Asp Val Asp Val Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln 500 505 510 Thr Phe Arg Gly Pro Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly 515 520 525 Thr Tyr Pro Tyr Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu 530 535 540 Pro Gln Asn Ala Ser Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp 545 550 555 560 Ile Leu Ala Ala Ile Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile 565 570 575 Asp Trp Glu Ala Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys 580 585 590 Asp Ile Tyr Arg Gln Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro 595 600 605 Asp Trp Pro Ala Pro Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln 610 615 620 Gly Ala Ala Arg Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala 625 630 635 640 Leu Arg Pro Arg Gly Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr 645 650 655 Asn Tyr Asp Phe Leu Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly 660 665 670 Ile Arg Ala Gln Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg 675 680 685 Ala Leu Tyr Pro Ser Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly 690 695 700 Lys Ser Gln Met Tyr Val Gln His Arg Val Ala Glu Ala Phe Arg Val 705 710 715 720 Ala Val Ala Ala Gly Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln 725 730 735 Ile Phe Tyr Asp Thr Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu 740 745 750 His Ser Leu Gly Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu 755 760 765 Trp Val Ser Trp Glu Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile 770 775 780 Lys Glu Tyr Met Asp Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr 785 790 795 800 Ser Gly Ala Leu Leu Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg 805 810 815 Cys Val Arg Arg Thr Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro 820 825 830 Ala Ser Phe Ser Ile Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu 835 840 845 Arg Gly Ala Leu Ser Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe 850 855 860 Lys Cys Arg Cys Tyr Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys 865 870 875 880 Ser Met Trp <210> SEQ ID NO 220 <211> LENGTH: 450 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 220 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> SEQ ID NO 221 <211> LENGTH: 598 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 221 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val

50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu 465 470 475 480 His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr 485 490 495 Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro 500 505 510 Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu 515 520 525 Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His 530 535 540 Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu 545 550 555 560 Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr 565 570 575 Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser 580 585 590 Ile Ile Ser Thr Leu Thr 595 <210> SEQ ID NO 222 <211> LENGTH: 879 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 222 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 50 55 60 Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 450 455 460 Ser Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp 465 470 475 480 Asn Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp 485 490 495 Val Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly 500 505 510 Pro Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr 515 520 525 Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala 530 535 540 Ser Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala 545 550 555 560 Ile Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala 565 570 575 Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg 580 585 590 Gln Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala 595 600 605 Pro Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg 610 615 620 Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg 625 630 635 640 Gly Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe 645 650 655 Leu Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln 660 665 670 Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro 675 680 685 Ser Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met 690 695 700 Tyr Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala 705 710 715 720

Gly Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp 725 730 735 Thr Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly 740 745 750 Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp 755 760 765 Glu Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met 770 775 780 Asp Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu 785 790 795 800 Leu Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg 805 810 815 Thr Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser 820 825 830 Ile Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu 835 840 845 Ser Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys 850 855 860 Tyr Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp 865 870 875 <210> SEQ ID NO 223 <211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 223 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 224 <211> LENGTH: 656 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 224 Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp Asn 1 5 10 15 Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp Val 20 25 30 Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly Pro 35 40 45 Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr Tyr 50 55 60 Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala Ser 65 70 75 80 Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala Ile 85 90 95 Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala Trp 100 105 110 Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg Gln 115 120 125 Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala Pro 130 135 140 Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg Ala 145 150 155 160 Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg Gly 165 170 175 Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe Leu 180 185 190 Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln Asn 195 200 205 Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro Ser 210 215 220 Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met Tyr 225 230 235 240 Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala Gly 245 250 255 Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp Thr 260 265 270 Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly Glu 275 280 285 Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp Glu 290 295 300 Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met Asp 305 310 315 320 Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu Leu 325 330 335 Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg Thr 340 345 350 Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser Ile 355 360 365 Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu Ser 370 375 380 Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys Tyr 385 390 395 400 Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp Gly Gly 405 410 415 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr 420 425 430 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 435 440 445 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 450 455 460 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 465 470 475 480 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 485 490 495 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 500 505 510 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 515 520 525 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 530 535 540 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 545 550 555 560 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys 565 570 575 Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 580 585 590 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 595 600 605 Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 610 615 620 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 625 630 635 640 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 645 650 655 <210> SEQ ID NO 225 <211> LENGTH: 775 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 225 Leu Leu Val Met Cys Ile Val Leu Arg Pro Ser Arg Val His Asn Ser 1 5 10 15 Glu Glu Asn Thr Met Arg Ala Leu Thr Leu Lys Asp Ile Leu Asn Gly 20 25 30 Thr Phe Ser Tyr Lys Thr Phe Phe Pro Asn Trp Ile Ser Gly Gln Glu 35 40 45 Tyr Leu His Gln Ser Ala Asp Asn Asn Ile Val Leu Tyr Asn Ile Glu 50 55 60 Thr Gly Gln Ser Tyr Thr Ile Leu Ser Asn Arg Thr Met Lys Ser Val 65 70 75 80 Asn Ala Ser Asn Tyr Gly Leu Ser Pro Asp Arg Gln Phe Val Tyr Leu 85 90 95 Glu Ser Asp Tyr Ser Lys Leu Trp Arg Tyr Ser Tyr Thr Ala Thr Tyr 100 105 110

Tyr Ile Tyr Asp Leu Ser Asn Gly Glu Phe Val Arg Gly Asn Glu Leu 115 120 125 Pro Arg Pro Ile Gln Tyr Leu Cys Trp Ser Pro Val Gly Ser Lys Leu 130 135 140 Ala Tyr Val Tyr Gln Asn Asn Ile Tyr Leu Lys Gln Arg Pro Gly Asp 145 150 155 160 Pro Pro Phe Gln Ile Thr Phe Asn Gly Arg Glu Asn Lys Ile Phe Asn 165 170 175 Gly Ile Pro Asp Trp Val Tyr Glu Glu Glu Met Leu Pro Thr Lys Tyr 180 185 190 Ala Leu Trp Trp Ser Pro Asn Gly Lys Phe Leu Ala Tyr Ala Glu Phe 195 200 205 Asn Asp Lys Asp Ile Pro Val Ile Ala Tyr Ser Tyr Tyr Gly Asp Glu 210 215 220 Gln Tyr Pro Arg Thr Ile Asn Ile Pro Tyr Pro Lys Ala Gly Ala Lys 225 230 235 240 Asn Pro Val Val Arg Ile Phe Ile Ile Asp Thr Thr Tyr Pro Ala Tyr 245 250 255 Val Gly Pro Gln Glu Val Pro Val Pro Ala Met Ile Ala Ser Ser Asp 260 265 270 Tyr Tyr Phe Ser Trp Leu Thr Trp Val Thr Asp Glu Arg Val Cys Leu 275 280 285 Gln Trp Leu Lys Arg Val Gln Asn Val Ser Val Leu Ser Ile Cys Asp 290 295 300 Phe Arg Glu Asp Trp Gln Thr Trp Asp Cys Pro Lys Thr Gln Glu His 305 310 315 320 Ile Glu Glu Ser Arg Thr Gly Trp Ala Gly Gly Phe Phe Val Ser Arg 325 330 335 Pro Val Phe Ser Tyr Asp Ala Ile Ser Tyr Tyr Lys Ile Phe Ser Asp 340 345 350 Lys Asp Gly Tyr Lys His Ile His Tyr Ile Lys Asp Thr Val Glu Asn 355 360 365 Ala Ile Gln Ile Thr Ser Gly Lys Trp Glu Ala Ile Asn Ile Phe Arg 370 375 380 Val Thr Gln Asp Ser Leu Phe Tyr Ser Ser Asn Glu Phe Glu Glu Tyr 385 390 395 400 Pro Gly Arg Arg Asn Ile Tyr Arg Ile Ser Ile Gly Ser Tyr Pro Pro 405 410 415 Ser Lys Lys Cys Val Thr Cys His Leu Arg Lys Glu Arg Cys Gln Tyr 420 425 430 Tyr Thr Ala Ser Phe Ser Asp Tyr Ala Lys Tyr Tyr Ala Leu Val Cys 435 440 445 Tyr Gly Pro Gly Ile Pro Ile Ser Thr Leu His Asp Gly Arg Thr Asp 450 455 460 Gln Glu Ile Lys Ile Leu Glu Glu Asn Lys Glu Leu Glu Asn Ala Leu 465 470 475 480 Lys Asn Ile Gln Leu Pro Lys Glu Glu Ile Lys Lys Leu Glu Val Asp 485 490 495 Glu Ile Thr Leu Trp Tyr Lys Met Ile Leu Pro Pro Gln Phe Asp Arg 500 505 510 Ser Lys Lys Tyr Pro Leu Leu Ile Gln Val Tyr Gly Gly Pro Cys Ser 515 520 525 Gln Ser Val Arg Ser Val Phe Ala Val Asn Trp Ile Ser Tyr Leu Ala 530 535 540 Ser Lys Glu Gly Met Val Ile Ala Leu Val Asp Gly Arg Gly Thr Ala 545 550 555 560 Phe Gln Gly Asp Lys Leu Leu Tyr Ala Val Tyr Arg Lys Leu Gly Val 565 570 575 Tyr Glu Val Glu Asp Gln Ile Thr Ala Val Arg Lys Phe Ile Glu Met 580 585 590 Gly Phe Ile Asp Glu Lys Arg Ile Ala Ile Trp Gly Trp Ser Tyr Gly 595 600 605 Gly Tyr Val Ser Ser Leu Ala Leu Ala Ser Gly Thr Gly Leu Phe Lys 610 615 620 Cys Gly Ile Ala Val Ala Pro Val Ser Ser Trp Glu Tyr Tyr Ala Ser 625 630 635 640 Val Tyr Thr Glu Arg Phe Met Gly Leu Pro Thr Lys Asp Asp Asn Leu 645 650 655 Glu His Tyr Lys Asn Ser Thr Val Met Ala Arg Ala Glu Tyr Phe Arg 660 665 670 Asn Val Asp Tyr Leu Leu Ile His Gly Thr Ala Asp Asp Asn Val His 675 680 685 Phe Gln Asn Ser Ala Gln Ile Ala Lys Ala Leu Val Asn Ala Gln Val 690 695 700 Asp Phe Gln Ala Met Trp Tyr Ser Asp Gln Asn His Gly Leu Ser Gly 705 710 715 720 Leu Ser Thr Asn His Leu Tyr Thr His Met Thr His Phe Leu Lys Gln 725 730 735 Cys Phe Ser Leu Ser Asp Gly Gly Gly Gly Ser Gly Leu Asn Asp Ile 740 745 750 Phe Glu Ala Gln Lys Ile Glu Trp His Glu Gly Gly Gly Gly Ser His 755 760 765 His His His His His His His 770 775 <210> SEQ ID NO 226 <211> LENGTH: 327 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 226 Met Lys Asp Asn Thr Val Pro Leu Lys Leu Ile Ala Leu Leu Ala Asn 1 5 10 15 Gly Glu Phe His Ser Gly Glu Gln Leu Gly Glu Thr Leu Gly Met Ser 20 25 30 Arg Ala Ala Ile Asn Lys His Ile Gln Thr Leu Arg Asp Trp Gly Val 35 40 45 Asp Val Phe Thr Val Pro Gly Lys Gly Tyr Ser Leu Pro Glu Pro Ile 50 55 60 Gln Leu Leu Asn Ala Lys Gln Ile Leu Gly Gln Leu Asp Gly Gly Ser 65 70 75 80 Val Ala Val Leu Pro Val Ile Asp Ser Thr Asn Gln Tyr Leu Leu Asp 85 90 95 Arg Ile Gly Glu Leu Lys Ser Gly Asp Ala Cys Ile Ala Glu Tyr Gln 100 105 110 Gln Ala Gly Arg Gly Arg Arg Gly Arg Lys Trp Phe Ser Pro Phe Gly 115 120 125 Ala Asn Leu Tyr Leu Ser Met Phe Trp Arg Leu Glu Gln Gly Pro Ala 130 135 140 Ala Ala Ile Gly Leu Ser Leu Val Ile Gly Ile Val Met Ala Glu Val 145 150 155 160 Leu Arg Lys Leu Gly Ala Asp Lys Val Arg Val Lys Trp Pro Asn Asp 165 170 175 Leu Tyr Leu Gln Asp Arg Lys Leu Ala Gly Ile Leu Val Glu Leu Thr 180 185 190 Gly Lys Thr Gly Asp Ala Ala Gln Ile Val Ile Gly Ala Gly Ile Asn 195 200 205 Met Ala Met Arg Arg Val Glu Glu Ser Val Val Asn Gln Gly Trp Ile 210 215 220 Thr Leu Gln Glu Ala Gly Ile Asn Leu Asp Arg Asn Thr Leu Ala Ala 225 230 235 240 Met Leu Ile Arg Glu Leu Arg Ala Ala Leu Glu Leu Phe Glu Gln Glu 245 250 255 Gly Leu Ala Pro Tyr Leu Ser Arg Trp Glu Lys Leu Asp Asn Phe Ile 260 265 270 Asn Arg Pro Val Lys Leu Ile Ile Gly Asp Lys Glu Ile Phe Gly Ile 275 280 285 Ser Arg Gly Ile Asp Lys Gln Gly Ala Leu Leu Leu Glu Gln Asp Gly 290 295 300 Ile Ile Lys Pro Trp Met Gly Gly Glu Ile Ser Leu Arg Ser Ala Glu 305 310 315 320 Lys Ser Gly Lys Asp Glu Leu 325 <210> SEQ ID NO 227 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 227 Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 228 <211> LENGTH: 133 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide

<400> SEQUENCE: 228 Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 1 5 10 15 Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 20 25 30 Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 35 40 45 Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 50 55 60 Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu 65 70 75 80 Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 85 90 95 Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 100 105 110 Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile 115 120 125 Ile Ser Thr Leu Thr 130 <210> SEQ ID NO 229 <211> LENGTH: 518 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 229 Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser 515 <210> SEQ ID NO 230 <211> LENGTH: 340 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 230 Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro 1 5 10 15 Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg 20 25 30 Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu 35 40 45 Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala 50 55 60 Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala 65 70 75 80 Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu 85 90 95 Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu 100 105 110 Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe 115 120 125 Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp 130 135 140 Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn 145 150 155 160 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 165 170 175 Gly Gly Gly Ser Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys 180 185 190 Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp 195 200 205 Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp 210 215 220 Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu 225 230 235 240 Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val 245 250 255 Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn 260 265 270 Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys 275 280 285 His Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val 290 295 300 Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met 305 310 315 320 Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met 325 330 335 Lys Ile Arg Asn 340 <210> SEQ ID NO 231 <211> LENGTH: 166 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 231 Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro 1 5 10 15 Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg 20 25 30 Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu 35 40 45 Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala 50 55 60 Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala 65 70 75 80 Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu 85 90 95 Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu 100 105 110

Pro Cys Glu Asn Gly Gly Gly Ser Gly Gly Lys Ser Lys Ala Val Glu 115 120 125 Gln Val Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys 130 135 140 Ala Met Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met 145 150 155 160 Thr Met Lys Ile Arg Asn 165 <210> SEQ ID NO 232 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 232 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His 20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln 35 40 45 Val Ile Ser Leu Ala Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu 50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Ala Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn 100 105 110 Thr Ser <210> SEQ ID NO 233 <211> LENGTH: 365 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 233 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu 20 25 30 Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser 35 40 45 Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu 50 55 60 Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp 65 70 75 80 Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn 85 90 95 Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu 100 105 110 Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met 115 120 125 Phe Ile Asn Thr Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 130 135 140 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 145 150 155 160 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 165 170 175 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 180 185 190 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 195 200 205 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 210 215 220 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 225 230 235 240 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 245 250 255 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys 260 265 270 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys 275 280 285 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 290 295 300 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 305 310 315 320 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 325 330 335 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 340 345 350 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 355 360 365 <210> SEQ ID NO 234 <211> LENGTH: 375 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 234 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu 50 55 60 Glu Trp Ile Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn 65 70 75 80 Gln Lys Phe Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Phe Cys Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys 260 265 270 Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr 275 280 285 Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe 290 295 300 Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile 305 310 315 320 His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser 325 330 335 Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu 340 345 350 Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val 355 360 365 Gln Met Phe Ile Asn Thr Ser 370 375 <210> SEQ ID NO 235 <211> LENGTH: 401 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 235 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile 20 25 30 Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser 35 40 45 Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser 50 55 60 Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro 65 70 75 80 Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile 85 90 95 Ser Ser Val Glu Ala Glu Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp 100 105 110 Ser Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 115 120 125 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 130 135 140

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 165 170 175 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 180 185 190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 195 200 205 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 210 215 220 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Val Pro Ser Gly 225 230 235 240 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Gln Lys Gly 245 250 255 Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser Glu Ala Ser Ser 260 265 270 Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met 275 280 285 Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln Leu Thr Val Lys 290 295 300 Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn 305 310 315 320 Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys 325 330 335 Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala Ala Asn Thr His 340 345 350 Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His Leu Gly Gly Val 355 360 365 Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn Val Thr Asp Pro 370 375 380 Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys 385 390 395 400 Leu <210> SEQ ID NO 236 <211> LENGTH: 414 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 236 Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe Thr Thr Val Trp Asn 1 5 10 15 Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly Val Asp Val Asp Val 20 25 30 Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln Thr Phe Arg Gly Pro 35 40 45 Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr Tyr Pro Tyr Tyr 50 55 60 Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala Ser 65 70 75 80 Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp Ile Leu Ala Ala Ile 85 90 95 Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala Trp 100 105 110 Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp Ile Tyr Arg Gln 115 120 125 Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro Asp Trp Pro Ala Pro 130 135 140 Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln Gly Ala Ala Arg Ala 145 150 155 160 Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala Leu Arg Pro Arg Gly 165 170 175 Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr Asn Tyr Asp Phe Leu 180 185 190 Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly Ile Arg Ala Gln Asn 195 200 205 Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala Leu Tyr Pro Ser 210 215 220 Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly Lys Ser Gln Met Tyr 225 230 235 240 Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala Val Ala Ala Gly 245 250 255 Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln Ile Phe Tyr Asp Thr 260 265 270 Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu His Ser Leu Gly Glu 275 280 285 Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp Val Ser Trp Glu 290 295 300 Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile Lys Glu Tyr Met Asp 305 310 315 320 Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser Gly Ala Leu Leu 325 330 335 Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg Arg Thr 340 345 350 Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro Ala Ser Phe Ser Ile 355 360 365 Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu Arg Gly Ala Leu Ser 370 375 380 Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe Lys Cys Arg Cys Tyr 385 390 395 400 Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys Ser Met Trp 405 410 <210> SEQ ID NO 237 <211> LENGTH: 507 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 237 Gln Gln Gln Thr Leu Pro Lys Pro Phe Ile Trp Ala Glu Pro His Phe 1 5 10 15 Met Val Pro Lys Glu Lys Gln Val Thr Ile Cys Cys Gln Gly Asn Tyr 20 25 30 Gly Ala Val Glu Tyr Gln Leu His Phe Glu Gly Ser Leu Phe Ala Val 35 40 45 Asp Arg Pro Lys Pro Pro Glu Arg Ile Asn Lys Val Lys Phe Tyr Ile 50 55 60 Pro Asp Met Asn Ser Arg Met Ala Gly Gln Tyr Ser Cys Ile Tyr Arg 65 70 75 80 Val Gly Glu Leu Trp Ser Glu Pro Ser Asn Leu Leu Asp Leu Val Val 85 90 95 Thr Glu Met Tyr Asp Thr Pro Thr Leu Ser Val His Pro Gly Pro Glu 100 105 110 Val Ile Ser Gly Glu Lys Val Thr Phe Tyr Cys Arg Leu Asp Thr Ala 115 120 125 Thr Ser Met Phe Leu Leu Leu Lys Glu Gly Arg Ser Ser His Val Gln 130 135 140 Arg Gly Tyr Gly Lys Val Gln Ala Glu Phe Pro Leu Gly Pro Val Thr 145 150 155 160 Thr Ala His Arg Gly Thr Tyr Arg Cys Phe Gly Ser Tyr Asn Asn His 165 170 175 Ala Trp Ser Phe Pro Ser Glu Pro Val Lys Leu Leu Val Thr Gly Asp 180 185 190 Ile Glu Asn Thr Ser Leu Ala Pro Glu Asp Pro Thr Phe Pro Asp Thr 195 200 205 Trp Gly Thr Tyr Leu Leu Thr Thr Glu Thr Gly Leu Gln Lys Asp His 210 215 220 Ala Leu Trp Asp His Thr Ala Gln Asn Gly Gly Gly Gly Ser Gly Gly 225 230 235 240 Gly Gly Ser Glu Pro Arg Thr Asp Thr Asp Thr Cys Pro Asn Pro Pro 245 250 255 Asp Pro Cys Pro Thr Cys Pro Thr Pro Asp Leu Leu Gly Gly Pro Ser 260 265 270 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Met Ile Ser Leu 275 280 285 Thr Pro Lys Ile Thr Cys Val Val Val Asp Val Ser Glu Glu Glu Pro 290 295 300 Asp Val Gln Phe Asn Trp Tyr Val Asn Asn Val Glu Asp Lys Thr Ala 305 310 315 320 Gln Thr Glu Thr Arg Gln Arg Gln Tyr Asn Ser Thr Tyr Arg Val Val 325 330 335 Ser Val Leu Pro Ile Lys His Gln Asp Trp Met Ser Gly Lys Val Phe 340 345 350 Lys Cys Lys Val Asn Asn Asn Ala Leu Pro Ser Pro Ile Glu Lys Thr 355 360 365 Ile Ser Lys Pro Arg Gly Gln Val Arg Val Pro Gln Ile Tyr Thr Phe 370 375 380 Pro Pro Pro Ile Glu Gln Thr Val Lys Lys Asp Val Ser Val Thr Cys 385 390 395 400 Leu Val Thr Gly Phe Leu Pro Gln Asp Ile His Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Gln Pro Glu Gln Asn Tyr Lys Asn Thr Gln Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val Pro 435 440 445 Lys Ser Arg Trp Asp Gln Gly Asp Ser Phe Thr Cys Ser Val Ile His 450 455 460 Glu Ala Leu His Asn His His Met Thr Lys Thr Ile Ser Arg Ser Leu 465 470 475 480 Gly Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Leu Asn Asp 485 490 495 Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu 500 505 <210> SEQ ID NO 238 <211> LENGTH: 375

<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 238 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Gln Gln Ser Gly Arg Glu Leu Glu Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45 Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu 50 55 60 Glu Trp Ile Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn 65 70 75 80 Gln Lys Phe Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Phe Cys Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys 260 265 270 Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr 275 280 285 Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Ala 290 295 300 Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile 305 310 315 320 His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser 325 330 335 Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu 340 345 350 Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val 355 360 365 Gln Met Phe Ile Asn Thr Ser 370 375 <210> SEQ ID NO 239 <211> LENGTH: 242 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 239 Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala 1 5 10 15 Ala Gln Pro Ala Met Ala Asp Ile Val Met Thr Gln Ser Pro Asp Ser 20 25 30 Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser 35 40 45 Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr 50 55 60 Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser 65 70 75 80 Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly 85 90 95 Thr Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala 100 105 110 Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln 115 120 125 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe 130 135 140 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 145 150 155 160 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 165 170 175 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 180 185 190 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 195 200 205 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 210 215 220 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 225 230 235 240 Glu Cys <210> SEQ ID NO 240 <211> LENGTH: 716 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 240 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Phe Arg Gly 1 5 10 15 Val Gln Cys Glu Val Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 20 25 30 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 35 40 45 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 50 55 60 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 65 70 75 80 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 85 90 95 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 100 105 110 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 115 120 125 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 130 135 140 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser 145 150 155 160 Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 165 170 175 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 180 185 190 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 195 200 205 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln 210 215 220 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 225 230 235 240 Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 245 250 255 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 260 265 270 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 275 280 285 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 290 295 300 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 305 310 315 320 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 325 330 335 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 340 345 350 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 355 360 365 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu 370 375 380 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 385 390 395 400 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 405 410 415 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 420 425 430 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 435 440 445 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 450 455 460 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser 465 470 475 480 Asp Leu Lys Val Glu Met Met Ala Gly Gly Thr Gln Ile Thr Pro Leu 485 490 495 Asn Asp Asn Val Thr Ile Phe Cys Asn Ile Phe Tyr Ser Gln Pro Leu 500 505 510 Asn Ile Thr Ser Met Gly Ile Thr Trp Phe Trp Lys Ser Leu Thr Phe 515 520 525

Asp Lys Glu Val Lys Val Phe Glu Phe Phe Gly Asp His Gln Glu Ala 530 535 540 Phe Arg Pro Gly Ala Ile Val Ser Pro Trp Arg Leu Lys Ser Gly Asp 545 550 555 560 Ala Ser Leu Arg Leu Pro Gly Ile Gln Leu Glu Glu Ala Gly Glu Tyr 565 570 575 Arg Cys Glu Val Val Val Thr Pro Leu Lys Ala Gln Gly Thr Val Gln 580 585 590 Leu Glu Trp Ala Ser Pro Ala Ser Arg Leu Leu Leu Asp Gln Val Gly 595 600 605 Met Lys Glu Asn Glu Asp Lys Tyr Met Cys Glu Ser Ser Gly Phe Tyr 610 615 620 Pro Glu Ala Ile Asn Ile Thr Trp Glu Lys Gln Thr Gln Lys Phe Pro 625 630 635 640 His Pro Ile Glu Ile Ser Glu Asp Val Ile Thr Gly Pro Thr Ile Lys 645 650 655 Asn Met Asp Gly Thr Phe Asn Val Thr Ser Cys Leu Lys Leu Asn Ser 660 665 670 Ser Gln Glu Asp Pro Gly Thr Val Tyr Gln Cys Trp Arg His Ala Ser 675 680 685 Leu His Thr Pro Leu Arg Ser Asn Phe Thr Leu Thr Ala Ala Arg His 690 695 700 Ser Leu Ser Glu Thr Glu Lys Thr Asp Asn Phe Ser 705 710 715 <210> SEQ ID NO 241 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 241 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> SEQ ID NO 242 <211> LENGTH: 215 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 242 His Arg Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp 1 5 10 15 Phe Val Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser 20 25 30 Leu Ser Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe 35 40 45 Val Lys Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser 50 55 60 Phe Glu Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val 65 70 75 80 Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu 85 90 95 Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly 100 105 110 Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln 115 120 125 Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile 130 135 140 Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu 145 150 155 160 Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser 165 170 175 Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe 180 185 190 Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr 195 200 205 Ser Phe Gly Leu Leu Lys Leu 210 215

Claims

1.-192. (canceled)

193. A multifunctional polypeptide molecule comprising: (i) a first antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof; and (ii) a second moiety selected from the group consisting of a tumor-targeting moiety, a cytokine molecule, a stromal modifying moiety, and a second antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof; wherein the multifunctional polypeptide molecule comprises one or more second moieties; wherein the multifunctional polypeptide molecule further comprises a dimerization module comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region; wherein the first antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof is linked to the first immunoglobulin chain constant region; and wherein the second moiety is linked to the first immunoglobulin chain constant region, the second immunoglobulin chain constant region, or a combination thereof.

194. The multifunctional polypeptide molecule of claim 193, wherein the first immunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region).

195. The multifunctional polypeptide molecule of claim 194, wherein dimerization of the first Fc region and the second Fc region is enhanced by providing an Fc interface of the first Fc region and the second Fc region with one or more of a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, such that a greater ratio of heteromultimer:homomultimer forms relative to a non-engineered interface.

196. The multifunctional polypeptide molecule of claim 193, wherein the cytokine molecule is selected from the group consisting of interleukin-2 (TL-2) or a functional variant thereof, interleukin-7 (TL-7) or a functional variant thereof, interleukin-12 (IL-12) or a functional variant thereof, interleukin-15 (IL-15) or a functional variant thereof, interleukin-18 (IL-18) or a functional variant thereof, interleukin-21 (IL-21) or a functional variant thereof, and interferon gamma or a functional variant thereof.

197. The multifunctional polypeptide molecule of claim 196, wherein the cytokine molecule comprises a receptor dimerizing domain.

198. The multifunctional polypeptide molecule of claim 193, wherein the stromal modifying moiety is selected from the group consisting of a hyaluronidase, a collagenase, a chondroitinase, and a matrix metalloproteinase.

199. The multifunctional polypeptide molecule of claim 193, wherein the multifunctional polypeptide molecule further comprises: a linker between the first antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof and the first immunoglobulin chain constant region, a linker between the second moiety and the first immunoglobulin chain constant region, a linker between the second moiety and the second immunoglobulin chain constant region, or any combination thereof.

200. The multifunctional polypeptide molecule of claim 193, wherein the multifunctional polypeptide molecule further comprises a cytokine molecules, a stromal modifying moiety, or a combination thereof linked to the first antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof, the tumor-targeting moiety, the second antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof, or any combination thereof.

201. The multifunctional polypeptide molecule of claim 200, wherein the cytokine molecule is selected from the group consisting of interleukin-2 (TL-2) or a functional variant thereof, interleukin-7 (TL-7) or a functional variant thereof, interleukin-12 (IL-12) or a functional variant thereof, interleukin-15 (IL-15) or a functional variant thereof, interleukin-18 (IL-18) or a functional variant thereof, interleukin-21 (IL-21) or a functional variant thereof, and interferon gamma or a functional variant thereof.

202. The multifunctional polypeptide molecule of claim 201, wherein the cytokine molecule comprises a receptor dimerizing domain.

203. The multifunctional polypeptide molecule of claim 200, wherein the stromal modifying moiety is selected from the group consisting of a hyaluronidase, a collagenase, a chondroitinase, and a matrix metalloproteinase.

204. The multifunctional polypeptide molecule of claim 200, wherein the multifunctional polypeptide molecule further comprises: a linker between the cytokine molecules, the stromal modifying moiety, or the combination thereof and the first antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof, a linker between the cytokine molecules, the stromal modifying moiety, or the combination thereof and the tumor-targeting moiety, a linker between the cytokine molecules, the stromal modifying moiety, or the combination thereof and the second antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof, or any combination thereof.

205. The multifunctional polypeptide molecule of claim 193, wherein the first antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof, the tumor-targeting moiety, the second antibody molecule that binds to NKp30 or NKp46 or antigen binding fragment thereof, or any combination thereof is a full length antibody, a dAb (domain antibody), an Fab, an Fab', an F(ab').sub.2 fragment, a single chain variable fragment (scFv), or a single domain antibody.

206. The multifunctional polypeptide molecule of claim 193, wherein the tumor-targeting moiety comprises an antibody molecule that binds to a cancer antigen or antigen binding fragment thereof, wherein the cancer antigen is: (i) present on a hematological cancer, a solid tumor, a metastatic cancer, soft tissue tumor, metastatic lesion, or any combination thereof; (ii) a tumor antigen, a stromal antigen, or a hematological antigen; or (iii) a tumor antigen or stromal antigen present on a fibrotic or desmoplastic solid tumor.

207. The multifunctional polypeptide molecule of claim 206, wherein the cancer antigen is: (i) selected from the group consisting of PDL1, mesothelin, CD47, prostate stem cell antigen (PSCA), GD2, prostate specific membrane antigen (PSMA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, Calcium-activated chloride channel 2, Cyclin-B1, 9D7, Ep-CAM, EphA3, Her2/neu, Telomerase, SAP-1, Survivin, Melan-A/MART-1, MART-2, Gp100/pmel17, Tyrosinase, MC1R, .beta.-catenin, BRCA1/2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, MAGE, AFP, ETA, CA-125, NY-ESO-1/LAGE-1, PRAME, SSX-2, BAGE, GAGE, CDC27, .alpha. actinin-4, TRP1/gp75, TRP2, a ganglioside, WT1, Epidermal growth factor receptor (EGFR), CD20, MUC1, MUC2, MUM1, MUM2, MUM3, NA88-1, NPM, OA1, OGT, RCC, RUI1, RUI2, SAGE, TRG, TSTA, Folate receptor alpha, BING-4, L1-CAM, CAIX, EGFRvIII, gpA33, GD3, GM2, VEGFR, an Integrin, a carbohydrate, IGF1R, TRAILR1, TRAILR2, and RANKL; (ii) a stromal antigen selected from the group consisting of fibroblast activating protease (FAP), TGF-beta, hyaluronic acid, collagen, tenascin C, and tenascin W; (iii) a hematological antigen selected from the group consisting of CD19, CD33, CD47, CD123, CD20, CD99, CD30, BCMA, CD38, CD22, SLAMF7, and NY-ESO1; or (iv) a solid tumor antigen selected from the group consisting of PDL1, Mesothelin, HER3, IGF-1R, GD2, PSMA, CEA, Ron Kinase, and c-Met.

208. The multifunctional polypeptide molecule of claim 193, wherein the multifunctional polypeptide molecule further comprises an immune cell engager selected from the group consisting of a T cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, and any combination thereof; and wherein the T cell engager binds to CD3, TCR.alpha., TCRO, TCR.gamma., TCR.zeta., ICOS, CD28, CD27, HVEM, 4-1BB, OX40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226; wherein the B cell engager is a CD40 ligand, an OX40 ligand, a CD70 ligand, an antibody molecule that binds to OX40, an antibody molecule that binds to CD40, or an antibody molecule that binds to CD70; wherein the dendritic cell engager is a CD2 agonist, an antibody molecule that binds to OX40, an OX40 ligand, a 41BB agonist, an agonist of a Toll-like receptor, a CD47 agonist, or a STING agonist; or wherein the macrophage cell engager is a CD2 agonist, a CD40 ligand, an OX40 ligand, an antibody molecule that binds to OX40, an antibody molecule that binds to CD40, an antibody molecule that binds to CD70, an agonist of a Toll-like receptor, CD47, or a STING agonist.

209. A pharmaceutical composition comprising the multifunctional polypeptide molecule of claim 193 and a pharmaceutically acceptable carrier, excipient, or stabilizer.

210. A method of treating cancer in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 209, wherein the administering is effective to treat the cancer in the subject.

211. The method of claim 210, wherein the cancer is: (i) a solid tumor cancer or a metastatic lesion; or (ii) a hematological cancer.

212. The method of claim 211, wherein: (i) the solid tumor is selected from the group consisting of pancreatic cancer, breast cancer, colorectal cancer, lung cancer, skin cancer, ovarian cancer, liver cancer, and any combination thereof; or (ii) the hematological cancer is selected from the group consisting of Hodgkin's lymphoma, Non-Hodgkin's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia.