METHODS OF MAKING AND USING GUIDANCE AND NAVIGATION CONTROL PROTEINS

Abstract

The application provides methods for generating a therapeutic composition. The method includes the steps of providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell, and formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic composition is substantially free of exogenous viral and non-viral DNA or RNA. The first GNC protein comprises a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor. The first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the first cytotoxic cell receptor.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of filing date of U.S. Provisional Patent Application No. 62/648,888 filed Mar. 27, 2018, and U.S. Provisional Patent Application No. 62/648,880 filed Mar. 27, 2018, the entire disclosures of which are expressly incorporated by reference herein.

TECHNICAL FIELD

[0002] The present application generally relates to the technical field of Guidance and Navigation Control (GNC) proteins with multi-specific binding activities against surface molecules on both immune cells and tumor cells, and more particularly relates to making and using GNC proteins.

BACKGROUND

[0003] Cancer cells develop various strategies to evade the immune system. One of the underlying mechanisms for the immune escape is the reduced recognition of cancer cells by the immune system. Defective presentation of cancer specific antigens or lack of thereof results in immune tolerance and cancer progression. In the presence of effective immune recognition tumors use other mechanisms to avoid elimination by the immune system. Immunocompetent tumors create suppressive microenvironments to downregulate the immune response. Multiple players are involved in shaping the suppressive tumor microenvironment, including tumor cells, regulatory T cells, Myeloid-Derived Suppressor cells, stromal cells, and other cell types. The suppression of immune response can be executed in a cell contact-dependent format as well as in a contact-independent manner, via secretion of immunosuppressive cytokines or elimination of essential survival factors from the local environment. Cell contact-dependent suppression relies on molecules expressed on the cell surface, e.g. Programmed Death Ligand 1 (PD-L1), T-lymphocyte-associated protein 4 (CTLA-4) and others (Dunn, Old et al. 2004, Adachi and Tamada 2015).

[0004] As the mechanisms by which tumors evade recognition by the immune system continue to be better understood, new treatment modalities that target these mechanisms have recently emerged. On Mar. 25, 2011, the U. S. Food and Drug Administration (FDA) approved ipilimumab injection (Yervoy, Bristol-Myers Squibb) for the treatment of unresectable or metastatic melanoma. Yervoy binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on activated T cells and blocks the interaction of CTLA-4 with CD80/86 on antigen-presenting cells thereby blocking the negative or inhibitory signal delivered into the T cell through CTLA-4 resulting in re-activation of the antigen-specific T cell leading to, in many patients, eradication of the tumor. A few years later in 2014 the FDA approved Keytruda (Pembrolizumab, Merck) and Opdivo (Nivolumab, Bristol-Myers Squibb) for treatment of advanced melanoma. These monoclonal antibodies bind to PD-1 which is expressed on activated and/or exhausted T cells and block the interaction of PD-1 with PD-L1 expressed on tumors thereby eliminating the inhibitory signal through PD-1 into the T cell resulting in re-activation of the antigen-specific T cell leading to again, in many patients, eradication of the tumor. Since then additional clinical trials have been performed comparing the single monoclonal antibody Yervoy to the combination of the monoclonal antibodies Yervoy and Opdivo in the treatment of advanced melanoma which showed improvement in overall survival and progression-free survival in the patients treated with the combination of antibodies. (Hodi, Chesney et al. 2016, Hellmann, Callahan et al. 2018). However, as many clinical trials have shown a great benefit of treating cancer patients with monoclonal antibodies that are specific for one or more immune checkpoint molecules data has emerged that only those patients with a high mutational burden that generates a novel T cell epitope(s) which is recognized by antigen-specific T cells show a clinical response (Snyder, Makarov et al. 2014). Those patients that have a low tumor mutational load mostly do not show an objective clinical response (Snyder, Makarov et al. 2014, Hellmann, Callahan et al. 2018).

[0005] In recent years other groups have developed an alternate approach that does not require the presence of neoepitope presentation by antigen-presenting cells to activate T cells. One example is the development of a bi-specific antibody where the binding domain of an antibody which is specific for a tumor associated antigen, e.g., CD19, is linked to an antibody binding domain specific for CD3 on T cells thus creating a bi-specific T cell engager or BiTe molecule. In 2014, the FDA approved a bi-specific antibody called Blinatumumab for the treatment of Precursor B-Cell Acute Lymphoblastic Leukemia. Blinatumumab links the single-chain variable fragment (scFv) specific for CD19 expressed on leukemic cells with the scFv specific for CD3 expressed on T cells (Benjamin and Stein 2016). However, despite an initial response rate of >50% in patients with relapsed or refractory ALL many patients are resistant to Blinatumumab therapy or relapse after successful treatment with Blinatumumab. Evidence is emerging that the resistance to Blinatumumab or relapse after Blinatumumab treatment is attributable to the expression of immune checkpoint inhibitory molecules expressed on tumor cells, such as PD-L1 that drives an inhibitory signal through PD-1 expressed on activated T cells (Feucht, Kayser et al. 2016). In a case study of a patient who was resistant to therapy with Blinatumumab, a second round of Blinatumumab therapy was performed but with the addition of a monoclonal antibody, pembrolizumab (Keytruda, Merck). Pembrolizumab specifically binds to PD-1 and blocks the interaction of T cell-expressed PD-1 with tumor cell expressed PD-L1, which resulted in a dramatic response and reduction of tumor cells in the bone marrow from 45% to less than 5% in this one patient (Feucht, Kayser et al. 2016). These results show that combining a bi-specific BiTe molecule with one or more monoclonal antibodies can significantly increase clinical activity compared to either agent alone. Despite the promising outcome, the cost leading to the combined therapy must be high due to multiple clinical trials and the difficulty in recruiting representative populations.

[0006] Adoptive cell therapy with chimeric antigen receptor T cells (CAR-T) is another promising immunotherapy for treating cancer. The clinical success of CAR-T therapy has revealed durable complete remissions and prolonged survival of patients with CD19-positive treatment-refractory B cell malignancies (Gill and June 2015). However, the cost and complexity associated with the manufacture of a personalized and genetically modified CAR-T immunotherapy has restricted their production and use to specialized centers for treating relatively small numbers of patients. Cytokine release syndrome (CRS), also known as cytokine storm, is considered as the major adverse effect after the infusion of engineered CAR-T cells (Bonifant, Jackson et al. 2016). In many cases, the onset and severity of CRS seems to be personally specific to the patient. Current options of mitigating CRS are mainly focused on rapid response and management care because the option of controlling CRS prior to T cell infusion is limited.

[0007] While the efficacy of CAR-T therapy specific for a CD19-positive B cell malignancy is now clearly established, the efficacy of CAR-T therapy against solid tumors has not been unequivocally demonstrated to date. Currently, many clinical trials are in progress to explore a variety of solid tumor-associated antigens (TAA) for CAR-T therapy. Inefficient T cell trafficking into the tumors, an immunosuppressive tumor micro-environment, suboptimal antigen recognition specificity, and lack of control over treatment-related adverse events are currently considered as the main obstacles in solid tumor CAR-T therapy (Li, Li et al. 2018). The option of managing the therapeutic effect, as well as any adverse effect before and after the CAR-T cell infusion, is limited.

SUMMARY

[0008] The application provides, among others, methods for generating therapeutic compositions containing a guidance and navigation (GNC) proteins, methods for treating cancer conditions using a guidance and navigation control (GNC) proteins, and therapeutic compositions containing GNC proteins or therapeutic cells having cytotoxic cells coated (or bound) with GNC proteins.

[0009] In one aspect, the application provides therapeutic compositions. In one embodiment, the therapeutic composition comprises a cytotoxic cell, a GNC protein, and a therapeutic cell. The therapeutic cell comprises the GNC protein bound to the cytotoxic cell through the binding interaction with the cytotoxic cell receptor, and the therapeutic cell composition is substantially free exogenous of viral and non-viral DNA and RNA.

[0010] In one embodiment, the therapeutic composition may further comprise a second GNC protein, a second therapeutic cell, or a combination thereof, wherein the second therapeutic cell comprises the cytotoxic cells with the second GNC protein bound thereupon or with both the first and the second GNC proteins bound thereupon.

[0011] GNC protein includes a cytotoxic binding moiety and a cancer targeting moiety. The cytotoxic binding moiety has a binding specificity to a cytotoxic cell receptor and is configured to activate the cytotoxic cell through the binding with the cytotoxic cell receptor. The cancer targeting moiety has a binding specificity to a cancer cell receptor.

[0012] In one embodiment, the GNC protein includes a binding domain for T-cell receptors. Examples T-cell receptor include without limitation CD3, CD28, PDL1, PD1, OX40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40L, VISTA, ICOS, BTLA, Light, CD30, NKp30, CD28H, CD27, CD226, CD96, CD112R, A2AR, CD160, CD244, CECAM1, CD200R, TNFRSF25 (DR3), or a combination thereof. In one embodiment, the GNC protein is capable of activating a T-cell by binding the T-cell binding moiety to a T-cell receptor on the T-cell. In one embodiment, the GNC protein is capable of activating a T-cell by binding multiple T-cell binding moieties on the T-cell.

[0013] In one embodiment, the GNC protein includes a binding domain for a NK cell receptor. Examples NK cell receptor include, without limitation, receptors for activation of NK cell such as CD16, NKG2D, KIR2DS1, KIR2DS2, KIR2DS4, KIR3DS1, NKG2C, NKG2E, NKG2H; agonist receptors such as NKp30a, NKp30b, NKp46, NKp80, DNAM-1, CD96, CD160, 4-1BB, GITR, CD27, OX-40, CRTAM; and antagonist receptors such as KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, KIR3DL2, KIR3DL3, NKG2A, NKp30c, TIGIT, SIGLEC7, SIGLEC9, LILR, LAIR-1, KLRG1, PD-1, CTLA-4, CD161.

[0014] In one embodiment, the GNC protein includes a binding domain for a macrophage receptor. Examples macrophage receptor include, without limitation, agonist receptor on macrophage such as TLR2, TLR4, CD16, CD64, CD40, CD80, CD86, TREM-1, TREM-2, ILT-1, ILT-6a, ILT-7, ILT-8, EMR2, Dectin-1, CD69; antagonist receptors such as CD32b, SIRPa, LAIR-1, VISTA, TIM-3, CD200R, CD300a, CD300f, SIGLEC1, SIGLEC3, SIGLEC5, SIGLEC7, SIGLEC9, ILT-2, ILT-3, ILT-4, ILT-5, LILRB3, LILRB4, DCIR; and other surface receptors such as CSF-1R, LOX-1, CCR2, FRP, CD163, CR3, DC-SIGN, CD206, SR-A, CD36, MARCO.

[0015] In one embodiment, the GNC protein includes a binding domain for a dendritic cell receptor. Examples dendritic cell receptor include, without limitation, agonist receptors on dendritic cell such as TLR, CD16, CD64, CD40, CD80, CD86, HVEM, CD70; antagonist receptors such as VISTA, TIM-3, LAG-3, BTLA; and other surface receptors such as CSF-1R, LOX-1, CCR7, DC-SIGN, GM-CSF-R, IL-4R, IL-10R, CD36, CD206, DCIR, RIG-1, CLEC9A, CXCR4.

[0016] In one embodiment, the GNC protein may include a T-cell binding moiety and a cancer-targeting moiety. In one embodiment, the T-cell binding moiety has a binding specificity to a T-cell receptor comprising CD3, CD28, PDL1, PDL2, PD1, OX40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40L, VISTA, ICOS, BTLA, Light, CD30, CD27, or a combination thereof. In one embodiment, the cancer targeting moiety has a binding specificity to a cancer cell receptor. In one embodiment, the cancer cell receptor may include BCMA, CD19, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, HER2, EGFR, EGFRvIII, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, as yet to be discovered tumor associated antigens or a combination thereof.

[0017] In one embodiment, the GNC protein may have multi-specific antigen binding activities to the surface molecules of a T cell and a tumour cell. In one embodiment, the guidance and navigation control (GNC) protein comprises a binding domain for a T cell activating receptor, a binding domain for a tumor associated antigen, a bind domain for an immune checkpoint receptor, and a binding domain for a T cell co-stimulating receptor.

[0018] In one embodiment, the binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor. In one embodiment, the binding domain for the T cell activating receptor is adjacent to the binding domain for the tumor associated antigen (TAA). The T cell activating receptor may include without limitation CD3. The T cell co-stimulating receptor may include without limitation 4-1BB, CD28, OX40, GITR, CD40L, ICOS, Light, CD27, CD30, or a combination thereof. The immune checkpoint receptor may include without limitation PD-L1, PD-1, TIGIT, TIM-3, LAG-3, CTLA4, BTLA, VISTA, PDL2, or a combination thereof.

[0019] The tumor associated antigen (TAA) may include without limitation ROR1, CD19, EGFRVIII, BCMA, CD20, CD33, CD123, CD22, CD30, CEA, HER2, EGFR, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, or a combination thereof. In one embodiment, the tumor associated antigen may be ROR1. In one embodiment, the tumor associated antigen may be CD19. In one embodiment, the tumor associated antigen may be EGFRVIII.

[0020] In one embodiment, the guidance and navigation control (GNC) protein may be an antibody or an antibody monomer or a fragment thereof. In one embodiment, the GNC protein may be a tri-specific antibody. In one embodiment, the GNC protein may be a tetra-specific antibody. In one embodiment, the GNC protein includes Fc domain or a fragment thereof. Any Fc domain from an antibody may be used. Example Fc domains may include Fc domains from IgG, IgA, IgD, IgM, IgE, or a fragment or a combination thereof. Fc domain may be natural or engineered. In one embodiment, the Fc domain may contain an antigen binding site.

[0021] In one embodiment, the GNC protein comprises a bi-specific antibody, a tri-specific antibody, a tetra-specific antibody, or a combination thereof yielding up to eight binding motifs on the GNC protein. Examples of antibodies, antibody monomers, antigen-binding fragment thereof are disclosed herein. In one embodiment, GNC proteins may include an immunoglobulin G (IgG) moiety with two heavy chains and two light chains, and at least two scFv moieties being covalently connected to either C or N terminals of the heavy or light chains. The IgG moiety may provide stability to the scFv moiety, and a tri-specific GNC protein may have two moieties for binding the surface molecules on T cells.

[0022] In one embodiment, the guidance and navigation control (GNC) protein may be an antibody. In one embodiment, the tumor associated antigen comprises ROR1, CD19, or EGRFVIII. In on embodiment, the T cell activating receptor comprises CD3 and the binding domain for CD3 may be linked to the binding domain for the tumor associated (TAA) antigen through a linker to form a CD3-TAA pair. In one embodiment, the IgG Fc domain may intermediate the CD3-TAA pair and the binding domain for the immune checkpoint receptor. In one embodiment, the immune checkpoint receptor may be PD-L1.

[0023] The linker may be a covalent bond or a peptide linker. In one embodiment, the peptide linker may have from about 2 to about 100 amino acid residues.

[0024] In on embodiment, the guidance and navigation control (GNC) protein has a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, the binding domain for CD3, the binding domain for EGFRVI, IgG Fc domain, the bind domain for PD-L1, and the binding domain for 41-BB. In one embodiment, the guidance and navigation control (GNC) protein has a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, the binding domain for 4-1BB, the binding domain for PD-L1, IgG Fc domain, the bind domain for ROR1, and the binding domain for CD3. In one embodiment, the guidance and navigation control (GNC) protein has a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, the binding domain for CD3, the binding domain for CD19, IgG Fc domain, the bind domain for PD-L1, and the binding domain for 4-1BB.

[0025] In one embodiment, the GNC protein comprises an amino acid having a percentage homology to SEQ ID NO. 50, 52, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, and 110. The percentage homology is not less than 70%. 80%, 90%, 95%, 98% or 99%.

[0026] In another aspect, the application provides nucleic acid sequences encoding the GNC protein or its fragments disclosed thereof. In one embodiment, the nucleic acid has a percentage homology to SEQ ID NO. 49, 51, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, and 109. The percentage homology is not less than 70%. 80%, 90%, 95%, 98% or 99%.

[0027] In another aspect, the application provides methods for generating a therapeutic composition. In one embodiment, the method may include the steps of providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, and formulating the activated cell composition to provide a therapeutic composition. The activated cell composition contains a first therapeutic cell. The first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the binding interaction with the first cytotoxic cell receptor. The therapeutic composition is substantially free of exogenous viral and non-viral DNA or RNA.

[0028] In one embodiment, the cell material may include or be derived from PBMC.

[0029] The first GNC protein may include a first cytotoxic binding moiety and a first cancer targeting moiety. The first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell through the binding with the first cytotoxic cell receptor. The first cancer targeting moiety has a specificity to a first cancer cell receptor.

[0030] In one embodiment, the method may repeat the incubating step by incubating a second GNC protein with the activated cell composition. The second GNC protein comprising a second cytotoxic binding moiety and a second cancer targeting moiety, the second cytotoxic binding moiety has a specificity to a second cytotoxic cell receptor, and the second cancer targeting moiety has a specificity to a second cancer cell receptor. The activated cell composition comprises a second therapeutic cell, and the second therapeutic cell comprises the second GNC protein bound to the cytotoxic cell or the first therapeutic cell through the binding interaction with the second cytotoxic cell receptor.

[0031] In one embodiment, the first and the second cancer-targeting moiety independently has a specificity for CD19, PDL1, or a combination thereof. In one embodiment, the first and the second cytotoxic binding moiety independently has a specificity for CD3, PDL1, 41BB, or a combination thereof.

[0032] The method may further include the repeated incubating steps by incubating additional GNC proteins with the activated composition. The additional GNC proteins may be a third GNC protein, a fourth GNC protein, etc. to provide addition therapeutic cells, each having the additional protein bound to the cytotoxic cell.

[0033] The first, second, and the additional GNC protein may be the same or may be different. The therapeutic cells may have one GNC protein, multiple same GNC proteins, or multiple different GNC proteins bound thereupon. In one embodiment, the therapeutic cell may have the first GNC protein bound thereupon. In one embodiment, the therapeutic cell may have both the first and the second GNC proteins bound thereupon. In one embodiment, the therapeutic cell may have the first, the second and the additional GNC proteins bound thereupon.

[0034] In one embodiment, the therapeutic cell comprises the cytotoxic cell having at least one bound GNC protein. In one embodiment, the therapeutic cell comprises the cytotoxic cell having at least 10, 20, 50, 100, 200, 300, 400 bound GNC proteins.

[0035] The therapeutic composition may include the first therapeutic cell, the first GNC protein, the cytotoxic cell, or a combination thereof. In one embodiment, the therapeutic composition may include the second therapeutic cell, the second GNC protein, comprises the first therapeutic cell, the first GNC protein, the cytotoxic cell, or a combination thereof. In one embodiment, the therapeutic composition may include additional GNC proteins and additional therapeutic cells.

[0036] In one embodiment, the incubating step may serve to expand the therapeutic cells. In one embodiment, expanding the therapeutic cell may include incubating the therapeutic cells with an additional amount of the GNC protein to provide an expanded cell population. In one embodiment, the expanded cell population comprises at least 10.sup.2, at least 103, at least 10.sup.4, at least 10.sup.5, at least 10.sup.6, at least 10.sup.7, at least 10.sup.8, at least 10.sup.9, at least 10.sup.10 cells per ml. In one embodiment, the expanded cell population comprises the GNC bound cell, the GNC protein, the cytotoxic cell, or a combination thereof. In one embodiment, in order to deplete PD-1+ T cells, a GNC protein may be added to the expansion culture that redirects killing to PD-1+ T cells therefore resulting in reduction in PD-1+ exhausted T cells. In one embodiment, in order to preferentially support PD-1+ T cells, a GNC protein may be added to the expansion culture that relieves checkpoint signaling through PD-1 on T cells therefore resulting in functional improvement of PD-1+ T cells. In one embodiment, in order to isolate 4-1BB mediated co-stimulation through 3.sup.rd gen CAR-T, a GNC protein may be added to the expansion culture that redirects killing to 4-1BB+ T cells or resulting in therapeutic composition with controlling level of 4-1BB stimulation in the therapeutic cells, such as CAR-T cells.

[0037] In one embodiment, the cancer targeting moiety has the specificity against B cell, and the therapeutic composition is substantially free of B cell. Therefore, the methods disclosed herein couple the activation and purification functions for the therapeutic cells, which allows the methods to produce B cell free therapeutic composition without the need to introduce any foreign materials (such as beads) nor any foreign genetic materials (such as viral and non-viral DNA or RNA vectors).

[0038] In one embodiment, the ratio of the GNC protein and the cytotoxic cell is at least 30 to 1 when incubating the cell material with the GNC protein.

[0039] In one embodiment, the therapeutic composition may include at least 10.sup.7 cells per ml.

[0040] In a further aspect, the application provides methods for using guidance and navigation control (GNC) proteins for cancer treatment. In one embodiment, the method of treating a subject having a cancer, comprises providing a cytotoxic cell, combining a GNC protein with the cytotoxic cell to provide a therapeutic cell, optionally expanding the therapeutic cell to provide an expanded cell population, and administering the therapeutic cell or the expanded cell population to the subject.

[0041] In one embodiment, the method include the step of providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell, formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic composition is substantially free exogenous of viral and non-viral DNA or RNA, and administering the therapeutic composition to the subject.

[0042] In one embodiment, the method may further include the steps of incubating a second GNC protein with the activated cell composition to provide the activated cell composition further comprising a second therapeutic cell. In one embodiment, the method may further include the step of incubating additional GNC proteins with the activated cell composition to provide the activated cell composition further comprising additional therapeutic cells.

[0043] In one embodiment, the method may further comprise isolating the cytotoxic cell from peripheral blood mononuclear cells (PBMC) before providing the cytotoxic cell. In one embodiment, the method may further comprise isolating the peripheral blood mononuclear cells (PBMC) from a blood. In one embodiment, the blood is from the subject. In one embodiment, the blood is not from the subject. In one embodiment, the cytotoxic cells may be from the patient that is under treatment or a different individual, such as a universal donor.

[0044] In one embodiment, the cytotoxic cell may be an autologous T cell, an alloreactive T cell, or a universal donor T cell. In one embodiment, when autologous donor T cells are used, in order to prevent infusion of contaminating cancer cells, a GNC protein may be added to the expansion culture that redirects killing to tumor antigens, example tumor antigen may include CD19 for B cell malignancies, Epcam for Breast carcinoma, MCP1 for melanoma.

[0045] In one embodiment, the method includes steps of providing a blood from the subject, isolating peripheral blood mononuclear cells (PBMC) from the blood, isolating a cytotoxic cell from the PBMC, combining a GNC protein with the cytotoxic cell to provide a therapeutic cell, optionally expanding the therapeutic cell to provide an expanded cell population, and administering the therapeutic cell or the expanded cell population to the subject.

[0046] In one embodiment, the method further comprises administering additional GNC protein to the subject after administering the therapeutic composition to the subject. In one embodiment, the cytotoxic cell may include CD3+ T cell, NK cell, or a combination thereof.

[0047] In one embodiment, the isolating of the cytotoxic cell comprises isolating at least one subpopulation of cytotoxic cells to provide the therapeutic T cells. In one embodiment, the subpopulation of cytotoxic cells comprises CD4+ cells, CD8+ cells, CD56+ cells, CD69+ cells, CD107a+ cells, CD45RA+ cells, CD45RO+ cells, CD2+ cells, CD178+ cells, Granzyme+ cells, or a combination thereof.

[0048] In one embodiment, the combining of a GNC protein with the cytotoxic cell comprises incubating the GNC protein with the cytotoxic cell for a period of time from about 2 hours to about 14 days, from about 1 day to about 7 days, from about 8 hours to about 24 hours, from about 4 days to about 7 days, or from about 10 days to about 14 days. In one embodiment, the incubating period may be more than 14 days. In one embodiment, the incubating period may be less than 2 hours.

[0049] In one embodiment, the ratio between the GNC protein and the cytotoxic cell is at least 600 to 1, 500 to 1, 400 to 1, 300 to 1, 200 to 1, 100 to 1, or 1 to 1. In one embodiment, the ratio between the GNC protein and the cytotoxic cell is from about 1 to 1, 10 to 1, 100 to 1, or to about 1000 to 1 ratio.

[0050] In one embodiment, the method may further comprise evaluating therapeutic efficacy after the administering step. In one embodiment, the evaluating therapeutic efficacy includes checking one or more biomarkers of the cancer, monitoring the life span of the therapeutic cells, or a combination thereof. In one embodiment, evaluating therapeutic efficacy comprises checking one or more biomarkers of the cancer, monitoring the life span of the therapeutic cells, or a combination thereof. In one embodiment, the biomarker comprises a tumor antigen, release of cytokines e.g., gamma interferon, IL-2, IL-8, and/or chemokines, and/or CD markers on the surface of various cell types e.g., CD69, PD-1, TIGIT, and/or mutated nucleic acid released into the bloodstream by tumors upon death, circulating tumor cells and their associated nucleic acid, or exosome associated nucleic acid, host inflammatory mediators, or tumor derived analytes, or a combination thereof. In one embodiment, the biomarker comprises a tumor antigen, tumor-associated apoptotic bodies, small molecule metabolites, release of cytokines, lymphocyte surface marker expression, phosphorylated/dephosphorylated signaling molecules, transcription factors, or a combination thereof.

[0051] The method disclosed herein is free of the step of transfecting the cytotoxic cell with a DNA vector or a viral vector. In one embodiment, the therapeutic cell or the expanded cell population is substantially free of a DNA vector or a viral vector.

[0052] The method may be used to treat a human subject suffering from cancer. In one embodiment, the cancer comprises cells expressing ROR1, CEA, HER2, EGFR, EGFRvIII, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, BCMA, CD20, CD33, CD123, CD22, CD30, CD19, as yet to be identified tumor associated antigens, or a combination thereof. In one embodiment, the method may be used to treat mammals.

[0053] Varieties of cancer may be treated using the methods disclosed herein. Example cancers includes without limitation breast cancer, colorectal cancer, anal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, head and neck cancer, nasopharyngeal cancer, skin cancer, melanoma, ovarian cancer, prostate cancer, urethral cancer, lung cancer, non-small lung cell cancer, small cell lung cancer, brain tumor, glioma, neuroblastoma, esophageal cancer, gastric cancer, liver cancer, kidney cancer, bladder cancer, cervical cancer, endometrial cancer, thyroid cancer, eye cancer, sarcoma, bone cancer, leukemia, myeloma or lymphoma.

[0054] In one embodiment, the method may further include administering an effective amount of a therapeutic agent after the administering the therapeutic cell or the expanded cell population to the subject. In one embodiment, the therapeutic agent comprises a monoclonal antibody, a chemotherapy agent, an enzyme, a protein, a co-stimulator, or a combination thereof. In one embodiment, the co-stimulator is configured to increase the amount of cytotoxic T cells in the subject.

[0055] The application further provides a solution comprising an effective concentration of the GNC protein. In one embodiment, the solution is blood plasma in the subject under treatment. In one embodiment, the solution includes the GNC protein bound cells. In one embodiment, the solution includes a GNC cluster including a GNC protein, a T-cell bound to the T-cell binding moiety of the GNC protein, and a cancer cell is bound to the caner-targeting moiety of the GNC protein.

[0056] The objectives and advantages of the present application will become apparent from the following detailed description of preferred embodiments thereof in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0057] The foregoing and other features of this disclosure will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings.

[0058] Understanding that these drawings depict only several embodiments arranged in accordance with the disclosure and are, therefore, not to be considered limiting of its scope, the disclosure will be described with additional specificity and detail through use of the accompanying drawings, in which:

[0059] FIG. 1 shows a GNC protein comprising four antigen-specific binding domains in an antibody structure with targeting specificity to CD19 positive cells;

[0060] FIG. 2 illustrates that a tetra-specific GNC antibody mediates multi-specific binding between a T cell and a tumor cell;

[0061] FIG. 3 is a flowchart comparing manufacturing processes for GNC-T cell therapy (left) and CAR-T cell therapy (right);

[0062] FIG. 4 is a diagram showing sources of cell material for preparing GNC-activated therapeutic cell composition;

[0063] FIG. 5 is a diagram showing sources of selected T cells for preparing GNC-activated therapeutic composition;

[0064] FIG. 6 is a diagram showing the preparation of GNC-activated therapeutic T cell composition;

[0065] FIG. 7 is a diagram showing the incubating and formulating steps for preparing the first GNC-activated T cells for GNC-T cell therapy;

[0066] FIG. 8 shows that GNC proteins (SI-35E class) induce IL-2 secretion from PBMC;

[0067] FIG. 9 shows that GNC proteins (SI-35E class) induce granzyme B secretion from PBMC;

[0068] FIG. 10 shows that GNC proteins (SI-35E class) induce expression of the activation marker CD69 on CD4+ T cells;

[0069] FIG. 11 shows that GNC proteins (SI-35E class) induce expression of the activation marker CD69 on CD8+ T cells;

[0070] FIG. 12 shows that GNC proteins (SI-35E class) induce expression of the activation marker CD69 on CD56+NK cells;

[0071] FIG. 13 shows that GNC proteins (SI-35E class) induce expression of the marker of cytotoxic degranulation CD107a on CD4+ T cells;

[0072] FIG. 14 shows that GNC proteins (SI-35E class) induce expression of the marker of cytotoxic degranulation CD107a on CD8+ T cells;

[0073] FIG. 15 shows that GNC proteins (SI-35E class) induce expression of the marker of cytotoxic degranulation CD107a on CD56+NK cells;

[0074] FIG. 16 shows that GNC proteins (SI-35E class) activate CD3+ T cells to proliferate;

[0075] FIG. 17 shows that GNC proteins (SI-35E class) activate CD3+ T cells to secrete gamma interferon;

[0076] FIG. 18 shows that GNC proteins (SI-35E class) activate naive CD8+/CD45RA+ T cells to proliferate;

[0077] FIG. 19 shows that GNC proteins (SI-35E class) activate naive CD8+/CD45RA+ T cells to secrete gamma interferon;

[0078] FIG. 20 shows Images of GNC activated cell growth in 6-well G-Rex plates over time;

[0079] FIG. 21 shows the example process of making the therapeutic composition as disclosed thereof (A), and cell viability of PBMC, GET, and GNC-T cells after thawing (B);

[0080] FIG. 22 shows the result of flow cytometry analyses of PBMC-derived, the first GNC (SI-38E17)-activated therapeutic cell composition (Product A) (22A), the second GNC (SI-38E17)-coated therapeutic cell composition (Product B) (22B), and input PBMC cell material (22C).

[0081] FIG. 23 shows GNC-T therapeutic cell composition of GET cells and formulated GNC-T cells from G-Rex 100M bioreactor after thawing;

[0082] FIG. 24 shows the result of RTCC of CHO-ROR1 cells by using GNC (SI-35E class)-coated PBMC cells;

[0083] FIG. 25 shows kinetics of PBMC-derived, SI-38E17 GNC-activated therapeutic cells on killing precursor B cell leukemia Kasumi over time;

[0084] FIG. 26 shows efficacy of killing Nalm-6, MEC-1, Daudi, and Jurkat cells by using PMBC-derived, SI-38E17 GNC-activated therapeutic cells; and

[0085] FIG. 27 shows the killing of Nalm-6, MEC-1, Daudi, and Jurkat leukemic cells by using PBMC-derived, SI-38E17 GNC-activated therapeutic cells in a spike-in model.

DETAILED DESCRIPTION

[0086] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0087] In one embodiment, the guidance navigation control (GNC) proteins are characterized by their composition of multiple antigen-specific binding domains (AgBDs) and by their ability of directing T cells (or other effector cells) to cancer cells (or other target cells such as bystander suppressor cells) through the binding of multiple surface molecules on a T cell and a tumor cell. In one embodiment, GNC proteins are composed of Moiety 1 for binding at least one surface molecule on a T cell and Moiety 2 for binding at least one surface antigen on a cancer cell as shown in TABLE 1. FIG. 1 shows the structure of an example tetra-specific GNC antibody comprising AgBDs for binding to both a T cell expressing CD3, PD-L1, and/or 4-1BB and a target B cell expressing CD19, as illustrated in FIG. 2.

[0088] In a T cell therapy, the cytotoxic T cells are regulated by T cell receptor complex proteins, as well as co-stimulation signaling proteins via either agonist receptors or antagonist receptors on their surface. To regulate this signaling, as well as the interaction between a T cell and a cancer cell, multiple AgBDs may compose Moiety 1 and Moiety 2, respectively. Examples of molecules that can be targeted by agonistic or antagonistic binding domains in Moiety 1 and 2 are shown in TABLE 1. In one embodiment, the GNC proteins may have at least one linker to link Moiety 1 and Moiety 2. In one example GNC protein, any linker molecule can be used to link two or more AgBDs together either in vitro or in vivo by using complementary linkers of DNA/RNA or protein-protein interactions, including but not limited to, that of biotin-avidin, leucine-zipper, and any two-hybrid positive protein. In some embodiments, the linkers may be an antibody backbone structure or antibody fragments, so that GNC protein and GNC antibody may have the same meaning, e.g. the structure of the example tetra-specific GNC antibody in FIG. 1.

[0089] GNC proteins or antibodies are capable of directing a T cell to a cancer cell, in vivo or ex vivo, through the binding function of multiple AgBDs (FIG. 2). The T cells may be derived from the same patient or different individuals, and the cancer cell may exist in vivo, in vitro, or ex vivo. The examples provided in the present application enable GNC proteins as a prime agent in a T cell therapy, i.e. GNC-T cell therapy, for activating and controlling cytotoxic T cells ex vivo, prior to adoptive transfer.

[0090] The present application relates to methods of making GNC-activated therapeutic cell composition. Multiple AgBDs can be divided into Moiety 1 and Moiety 2 due to their interface with a T cell and a cancer cell, respectively (TABLE 1). A GNC protein with two AgBDs may simultaneously bind to a surface molecule, such as CD3 on a T cell, and a tumor antigen, such as ROR1 on a tumor cell, for re-directing the T cell to the tumor cell.

[0091] The addition of a third AgBD, for example, one that specifically binds to 41BB, may help enhance anti-CD3-induced T cell activation because 41BB is a co-stimulation factor and the binding stimulates its agonist activity to activated T cells. The addition of a fourth AgBD to a GNC protein, for example, one that specifically binds to PD-L1 on a tumor cell, may block the inhibitory pathway of PD-L1 on tumor cells or that is mediated through its binding to PD-1 on the T cells.

[0092] In some embodiments, with these basic principles, GNC proteins are constructed to acquire multiple AgBDs specifically for binding unequal numbers of T cell antagonists and agonists, not only to re-direct activated T cells to tumor cells but also to control their activity in vivo (TABLE 2). Therefore, in some embodiments, GNC proteins may be bi-specific, tri-specific, tetra-specific, penta-specific, hexa-specific, hepta-specific, or octa-specific proteins.

[0093] In one embodiment, the application relates to a GNC-T cell therapy where GNC proteins are used to expand the T cells ex vivo prior to adoptive transfer (FIG. 3). The ex vivo priming of autonomous T cells provides the cytotoxic T cells guidance and navigation control. For example, peripheral blood mononuclear cells (PBMC) or specific types of cell populations within PBMC e.g., CD8+, CD45RO+ memory T cells may be isolated and primed ex vivo by GNC proteins. These expanded cytotoxic T cells can be formulated and infused back to the patient through adoptive transfer. While attacking the cancer in vivo, additional GNC proteins may be infused into the patient for managing the efficacy and lifespan of cytotoxicity. Thus, GNC-T cell therapy is different from GNC protein-based immunotherapy, where GNC proteins are directly administered into patients. However, GNC-T cell therapy does not rule out the direct administration of GNC proteins for managing the efficacy of infused cytotoxic T cells in vivo in a controlled manner. Additional GNC protein can both promote cytolytic activity and encourage T cell proliferation dependent of the configuration of AgBDs.

[0094] In one aspect, the application relates to the production of therapeutic GNC-T cells. In comparison with and to distinguish from the production of therapeutic CAR-T cells, their general processes are shown in FIG. 3, for comparison purpose. In CAR-T therapy, cell material, for example patient leukocytes, are collected by apheresis, and a subset of CD3+ T cells is selected and activated to facilitate gene transfer to the cellular material, which is then expanded in number by the introduction of foreign material scaffold for support to the T cell populations, for example, by using anti-CD3/anti-CD28 antibody coated beads. Advantageously, GNC-T cell material does not require the introduction of scaffold impurities for T cell expansion from patient leukocytes.

[0095] The CAR-T therapy cellular material must undergo the gene transfer that involves the preparation and transfection of CAR-T vector DNA, which results in genetically modifying the genome of the T cells. Furthermore, these genetically modified T cells may undergo another round of T cell expansion before being transferred back into the patient. The random integration of CAR-T vector DNA carries a risk of transformation of the T cells leading to primary leukemogenesis or introduction of the CAR-T vector to leukemia cells increasing the risk of relapse by mechanism of internal sequestration of the CAR target antigen (Zhang, Liu et al. 2017).

[0096] In contrast, GNC-T cell therapy has the advantages of not involving the transfection of any vector DNA, therefore there is no risk of genetic modification prior to adoptive transfer, which provides one of the significant advantages and technical improvements over the existing CAR-T therapy. Besides the advantage of GNC-T cell therapy being free of exogenous generic material contamination and cancer risk, the efficacy of GNC-T cell therapy may be improved when PBMC or different T cell subsets are being primed and activated ex vivo as shown in FIGS. 5 & 6. Similar approaches have been explored in the use of CAR-T therapy, where selected specific ratios of some subsets of T cells may be transferred back to the patient (Turtle, Hanafi et al. 2016, Turtle, Hanafi et al. 2016).

[0097] In some embodiments, it may be beneficial to remove leukemia or other cancer cells from the cellular material prior to cell expansion (FIG. 7). The PBMC of a patient with circulating leukemic cells, in particular from B cell malignancy, may profoundly alter the cellular composition and thus affect the suitability of the final therapeutic cellular products. For example, a high level of circulating leukemic blast cells (greater that 10% of WBC) may require a depletion of leukemic cells prior to GNC mediated cell expansion. The percentage of leukemic cells in the PBMC derived from a patient may be reduced by using cell fractionation methods. These methods may include steps involving density gradient separation, or immunofluorescent cell separation or fluorescent activated cells sorting, immunomagnetic cell separation, or microfluidic flow chambers methods. These methods may be preceded by or follow centrifugation, cell washing, incubation, or temperature modulation. These methods may utilize non-cellular substrates (magnetic beads, Plastic, polymers), modification of non-cellular substrates (protein, antibodies, charge state), antibody treatment, multiple antibody treatments, multi-specific antigen binding proteins and cell surface antigen-based cell coupling. These methods may use enzymatic digestion or, ionic chelation, or mechanical agitation or cell vessel rotation. The method for reduction of leukemic blasts may utilize antibody drug conjugates, or leukemia sensitizing agents. The method may consist of a combination of these approaches.

[0098] In one embodiment, to enable the production of therapeutic T cells primed (or coated or bound) with GNC proteins, a tetra-specific antibody is produced and used as the GNC protein. In one embodiment, the tetra-specific antibody/GNC protein comprises 4 different binding domains linked by antibody fragments as its backbone. One binding domain is specific for CD3 on T cells, a second binding domain is specific for a tumor associated antigen, including but not limited to ROR1, CEA, HER2, EGFR, EGFRvIII, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, BCMA, CD19, CD20, CD33, CD123, CD22, CD30, and a third and fourth binding domains are specific for two distinct immune checkpoint modulators such as PD-L1, PD-L2, PD-1, OX40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40L, VISTA, ICOS, BTLA, Light, etc.

[0099] Without being bound by theory, the advantages of GNC protein-mediated GNC-T cell therapy over conventional CAR-T therapies include, but are not limited to, first, that inclusion of an IgG Fc domain may confer the characteristic of a longer half-life in serum compared to a bi-specific BiTe molecule; second, that inclusion of two binding domains specific for immune checkpoint modulators may inhibit the suppressive pathways and engage the co-stimulatory pathways at the same time; third, that cross-linking CD3 on T cells with tumor associated antigens re-directs and guides T cells to kill the tumor cells without the need of removing T cells from the patient and genetically modifying them to be specific for the tumor cells before re-introducing them back into the patient, also known as chimeric antigen receptor T cells (CAR-T) therapy; and fourth, that GNC protein-mediated antibody therapy or T cell therapy does not involve genetic modification of T cells, the latter of which may carry the risk of transforming modified T cells to clonal expansion, i.e. T cell leukemia.

[0100] The present disclosure may be understood more readily by reference to the following detailed description of specific embodiments and examples included herein. Although the present disclosure has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the disclosure.

EXAMPLES

[0101] While the following examples are provided by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same or similar results.

Example 1. GNC Proteins and Tetra-Specific GNC Antibodies

[0102] In the present application, the examples of GNC proteins are classes of tetra-specific GNC antibodies, of which 4 AgBDs are covalently linked using an IgG antibody as its backbone (FIG. 1). From the N-terminal of this protein, the first scFv is linked to the Fab domain of the constant domains C.sub.H1, 2, and 3 of IgG antibody which is then linked to another scFv at the C-terminal. Because each of the scFv domains display independent binding specificity, linking of these AgBDs does not need to be done using the constant domains of an IgG antibody. Structured as a tetra-specific GNC antibody, a GNC protein can directly bind to tumor-associated antigen (TAA) and engage the host endogenous T cells to kill tumor cells independent of tumor antigen presentation by MHC to the antigen specific T cell receptors (FIG. 2). As shown in FIG. 1, CD19 is a TAA targeting CD19 positive B cells and tumor cells. In addition, PD-L1 is an example of the immune checkpoint modulating component for tetra-specific GNC antibodies that may overcome the immunosuppressive tumor microenvironment and fully activate the exhausted T cells within the tumor microenvironment.

[0103] Of tetra-specific GNC antibodies, the SI-35E class comprises targets an anti-human CD3 binding domain (SEQ IDs 1-4), an anti-human PD-L1 (SEQ IDs 5-12), an anti-human 4-1BB (SEQ IDs 13-24), and targets a human ROR1 (SEQ IDs 25-32), i.e. a TAA. In this context, the classes of SI-38E and SI-39E target CD19 (SEQ IDs 47-50) and EGFR (SEQ ID 51-54), respectively.

[0104] To construct tetra-specific GNC antibodies, AgBDs were converted to scFv and VLVH for placement at the N-terminal Domain 1 (D1) or scFv and VHVL for placement at the C-terminal Domains 3 (D3) and 4 (D4) of the GNC protein. All scFv molecules described herein contain a 20 amino acid flexible gly-gly-gly-gly-ser (G4S) X4 linker that operably links the VH and VL, regardless of the V-region orientation (LH or HL). The remaining position in the tetra-specific GNC antibody, Domain 2 (D2), consists of an IgG1 heavy chain, VH-CH1-Hinge-CH2-CH3, and its corresponding light chain, VL-CL, which can be either a kappa or lambda chain. D1 and D2 are genetically linked through a 10 amino acid (G4S).times.2 linkers, as are D2, D3 and D4 resulting in a contiguous .about.150 kDa heavy chain monomer peptide. When co-transfected with the appropriate light chain, the final symmetric tetra-specific GNC peptide can be purified through the IgG1 Fc (Protein A/Protein G) and assayed to assess functional activity. Heavy and light chain gene "cassettes" were previously constructed such that V-regions could be easily cloned using either restriction enzyme sites (HindIII/NhelI for the heavy chain and HindIII/BsiWI for the light chain) or "restriction-free cloning" such as Gibson Assembly (SGI-DNA, La Jolla, Calif.), Infusion (Takara Bio USA) or NEBuilder (NEB, Ipswich, Mass.), the latter of which was used here.

[0105] The tetra-specific GNC antibodies can be produced through a process that involves design of the intact molecule, synthesis and cloning of the nucleotide sequences for each domain, expression in mammalian cells and purification of the final product. Herein, nucleotide sequences were assembled using the Geneious 10.2.3 software package (Biomatters, Auckland, NZ) and broken up into their component domains for gene synthesis (Genewiz, South Plainsfield, N.J.). In this example, SI-35E18 (SEQ ID 65 and 67) was split into its component domains where the anti-41BB scFv, VL-VH, occupies D1, anti-human PD-L1 clone PL230C6 occupies D2 (Fab position), anti-human ROR1 Ig domain-specific clone 323H7 VHVL scFv occupies D3, and anti-human CD3 scFv, VHVL, occupies the C-terminal D4. Using NEBuilder web-based tools, 5' and 3' nucleotides were appended to each of the domains depending on their position in the larger protein so that each domain overlaps its flanking domains by 20-30 nucleotides which direct site-specific recombination, thus genetically fusing each domain in a single gene assembly step. Due to the high number of homologous regions in the tetra-specific nucleotide sequence, the N-terminal domains 1 and 2 are assembled separately from the C-terminal D3 and D4. The N- and C-terminal fragments were then assembled together in a second NEBuilder reaction. A small aliquot was transformed into E. coli DH10b (Invitrogen, Carlsbad, Calif.) and plated on TB+carbenicillin 100 ug/ml plates (Teknova, Hollister, Calif.) and incubated at 37.degree. C. overnight. Resultant colonies were selected and 2 mL overnight cultures inoculated in TB+carbenicillin. DNA was prepared (Thermo-Fisher, Carlsbad, Calif.) from overnight cultures and subsequently sequenced (Genewiz, South Plainsfield, N.J.) using sequencing primers (Sigma, St. Louis, Mo.) flanking each domain. All DNA sequences were assembled and analyzed in Geneious.

[0106] In another tetra-specific GNC protein, SI-38E17 targeting human CD19 (SEQ IDs 47-50), multiple AgBDs carry an anti-human 4-1BB (scFv 466F6, SEQ IDs 17-20) as well as an anti-human PD-L1 (scFv PL221G5 SEQ IDs 9-13), and an anti-human CD3 binding domain (SEQ IDs 1-4). The methods and procedures for producing this tetra-specific antibody were the same.

[0107] GNC proteins are composed of Moiety 1 for binding at least one surface molecule on a T cell and Moiety 2 for binding at least one surface antigen on a cancer cell (TABLE 1A). The tetra-specific GNC antibodies can be used to directly engage the body's endogenous T cells to kill tumor cells independent of tumor antigen presentation by MHC to the antigen specific T cell receptors. This is in contrast to therapies based solely on immune checkpoint blockade, which have been limited by antigen recognition. In context, the immune checkpoint modulating component may be constructed as a part of tetra-specific GNC antibodies, which may provide benefits similar to that in a standard checkpoint blockade therapy.

[0108] In addition to T cells, other cytotoxic cells may also be targeted by GNC proteins for cancer killing or preventing purposes. TABLE 1B shows the example compositions of functional moieties (Moiety 1 and Moiety 2) and antigen binding domain in GNC proteins with NK cell binding domains. TABLE 1C shows the example compositions of functional moieties (Moiety 1 and Moiety 2) and antigen binding domain in GNC proteins with macrophage binding domains. TABLE 1D shows the example compositions of functional moieties (Moiety 1 and Moiety 2) and antigen binding domain in GNC proteins with dendritic cell binding domains.

[0109] GNC proteins are constructed to acquire multiple AgBDs specifically for binding unequal numbers of T cell antagonists and agonists. In this way, GNC proteins may re-direct activated T cells to tumor cells with certain levels of control of their activity in vivo (TABLE 2). Therefore, GNC proteins may be bi-specific, tri-specific, tetra-specific, penta-specific, hexa-specific, hepta-specific, or even octa-specific proteins. In the present invention, three classes of tetra-specific GNC antibodies, i.e. SI-39E, SI-35E, and SI-38E, were created to enable GNC-T cell therapy, of which antibody domains and its specificity is listed in TABLE 3. The structures of tetra-specific GNC antibodies targeting EGFRvIII (SI-39E), ROR1 (SI-35E), and CD19 (SI-38E) are listed in TABLE 4.

Example 2: GNC-Activated, PBMS-Derived Cell Composition

[0110] The SI-35 class listed in Table 4 were tested for their ability to activate and induce proliferation of different cell types, such as CD4+ and/or CD8+ T cells and/or CD56+ natural killer cells (NK) within PBMC. The tetra-specific GNC antibodies were prepared at 2.times. final concentration and titrated in 1:10 serial dilutions across 6 wells of a 96 well plate in 200 ul of RPMI+10% FBS. Human PBMC were purified by standard Ficoll density gradient from a "leukopak" which is an enriched leukapheresis product collected from normal human peripheral blood. In the final destination 96 well plate, the PBMC and serially titrated GNC proteins were combined by adding 100 .mu.L of PBMC (100,000), and 100 .mu.L of each antibody dilution to each well of the assay. The assay plate was incubated at 37.degree. C. for approximately 72 hours and then the contents of each assay well were harvested and analyzed by FACS for the number of CD4+ T cells, CD8+ T cells, and CD56+NK cells. Cells were harvested from each well and transferred to a new 96 well V-bottom plate then centrifuged at 400.times.g for 3 minutes. Supernatant was transferred to a 96 well plate for analysis of IL-2 and Granzyme B. Cells were re-suspended in 200 .mu.L of 2% FBS/PBS of FACS antibodies and incubated on ice for 30 minutes. The plate was centrifuged at 400.times.g for 3 minutes and the supernatant was aspirated. This wash step was repeated once more and then the cells were re-suspended in 100 .mu.L 2% FBS/PBS and analyzed on a BD LSR FORTESSA.

[0111] As shown in FIG. 8, all SI-35E tetra-specific GNC antibodies, with the exception of those that had the scFv binding domain replaced with FITC at positions 2 (SI-35E37) and 4 (SI-35E39), induced production of IL-2 from PBMC. These two proteins lacked the binding domains for PD-L1 or CD3 respectively. The secretion of Granzyme B into the culture supernatant followed a similar pattern as that for IL-2 production as shown in FIG. 9. Both SI-35E37 and SI-35E3 were also much less potent at inducing cell-surface expression of the activation marker CD69 on CD4+(FIG. 10), CD8+(FIG. 11), and CD56+(FIG. 12) cells in the PBMC culture. Surface expression of the cytotoxic degranulation marker CD107a (LAMP-1) was induced by all GNC proteins tested except those lacking binding at positions 2 and 4 on CD4+(FIG. 13), CD8+(FIG. 14), but less consistently on CD56+(FIG. 15) in the culture. At lower concentrations, 3 of the GNC proteins (SI-35E42, SI-35E43, and SI-35E46) induced expression of CD69 on CD4+ T cells, CD8+ T cells, and CD56+NK cells, which correlated well with the level of IL-2 and granzyme B secretion (FIGS. 8 and 9) induced by these GNC.

[0112] Proliferation and production of gamma interferon was measured from cultures of CD3+ or naive CD8+ T cells (70,000 cells/well) stimulated for 5 days with a panel of SI-35 class antibodies. Human CD3+ or CD8+CD45RA+naive T cells were enriched from peripheral blood mononuclear cells from a normal donor using the EasySep.TM. Human CD3+ or Naive CD8+ T Cell Isolation Kits (StemCell Technologies) as per the manufacturer protocols. The final cell populations were determined to be >98% CD3+ or CD8+CD45RA+ T cells by flow cytometry. Proliferation in the culture was measured after stain with Alamar blue (ThermoFisher Cat. No. DAL1100) for 1 hour at 37.degree. C., and then read on a Spectramax plus 384 well reader (Molecular Devices). Proliferation of GNC-expanded CD3+ T cells was expressed as a fold increase in cell number over background of CD3+ T cells in cell culture without GNC (FIG. 16). Proliferation was induced by all constructs tested except the one lacking CD3 binding domain. Culture supernatants were also collected from these cultures and analyzed for the presence of gamma interferon by ELISA. Secretion of gamma interferon (FIG. 17) was high unless CD3 or ROR1 binding domains were changed to FITC in the GNC constructs. Proliferation of naive CD8+CD45RA+ T cells (FIG. 18) was more sensitive to the presence or absence of 4-1BB binding domain compared to total CD3+ T cells as shown by addition of soluble anti-4-1BB monoclonal antibody to the culture in which 4-1BB binding on the GNC was absent. A similar pattern was found for secretion of gamma interferon from the naive CD8+ T cells (FIG. 19).

Example 3. Scale Up and Formulation of a First GNC-Activated Therapeutic Cell Composition

[0113] The manufacture of GNC-activated and -coated T cells at clinically significant dosage of 10E9 was achieved after 7 days culture. Human PBMC were isolated from LRS cone leukocytes by standard Ficoll density gradient from leukopaks which are enriched leukapheresis product collected from normal human peripheral blood. After collection the cells were frozen at -80.degree. C. and then later thawed before putting in culture. Using the G-Rex plate and bioreactor culture systems, the growth of SI-38E17 GNC-stimulated PBMC cultures was monitored for up to 14 days. The culture medium consisted of RPMI 1640, 10% fetal calf serum, 1% non-essential amino acids, 1% GlutaMax, 0.6% glutamine-alanine supplement, 15 ng/mL human IL-2, and 1 nM GNC protein. The 6-well G-Rex cultures tolerated seeding densities of 25-100 million PBMC/well for six days, which greatly exceeded recommended amounts, but was tolerated by the cells in the system with a single 50% medium change on day 7. Clustering of cells was indicative of their activation in the culture (FIG. 20). At least 250 million cells from one leukapheresis donor were seeded into two G-Rex 100M bioreactors and cultured in 1 liter of culture medium for seven days. The larger volume of medium allowed the culture to continue without needing to exchange the culture medium. Cell yield in each of the 100M bioreactors was between 1.2-1.4 billion cells with greater than 88% viability.

Example 4. A Second GNC-Activated Therapeutic Cell Composition

[0114] The cells from the bioreactor were harvested as the first GNC-activated therapeutic cell composition, which were optionally concentrated using LOVO Automated Cell Processing System (Fresenius Kabi). One sample (Product B) was exposed to 1 nM SI-38E17, which is identical to the first GNC in this case for preparing a second GNC-activated therapeutic cell composition, potential for being used to target treat patients harboring CD19 positive malignancies (FIG. 21A).

[0115] After the second concentration step (100 mL volume) during the processing in the LOVO system, the second GNC-activated therapeutic cells were washed twice before eluting to a final volume of 54 mL in a sterile processing bag. The other sample (Product A) was only exposed to the first GNC protein during the culture phase and not re-exposed during processing in the LOVO system (FIG. 21A). Cells were removed from bags, mixed 1:1 with CryoStor CS10 reagent, and frozen to -80.degree. C. The processed cells were thawed and compared to the thawed unstimulated PBMC from the same donor before culture.

[0116] Cell viability from the GNC-expanded T cell (GET) culture was >75% and was not affected by exposure to additional GNC reagent (GNC-T, Product B) during processing (FIG. 21B). The mean diameter of the cells increased during culture, indicative of cell activation. Flow cytometry was performed on the input PBMC cell material and the two formulations after thawing using a multi-color panel of antibodies to stain for: live/dead (e780), CD45, TCR.alpha./.beta., CD56, CD4, CD8, CD14, TCR.gamma./.delta., and CD20. Gating for quantification of the different cell subsets is shown on the GNC-activated T cells (Product A) and the additional GNC-coated GNC-T cells (Product B) (FIGS. 22A and 22B). The percentages of each subpopulation of cells were similar between Product A and Product B, but very different from those of input PBMC (FIG. 22C). FIG. 23 summaries the total number and percentage of each subpopulation of cells. Compared to the input PBMC cell material, while the total number of leukocytes increased from 250 to 1000 millions or four-fold, the total number of each subpopulation of T cells was vastly increased by 55-fold for .alpha./.beta. T cells, 45-fold for CD4+ T cells, and 78-fold for CD8+ T cells. In this context, the increase of .gamma./.delta. T cells was modest at 5-fold, and TCR.alpha./.beta.-/lo, .gamma./.delta.+, CD8+ T cells seemed to the most abundant. Finally, the characteristic feature of both Product A and Product B cell compositions is the fact that there were no detectable B cells.

[0117] This example illustrates a number of advantages of GNC-T cells in comparison to CAR-T cell preparations. First, the cell composition of the starting material was fresh PBMC from the donor and did not need to be pre-selected for particular subsets of cells or require addition of feeder cells or synthetic beads. The GNC protein was 100% non-nucleotide biological material, and did not require the transfer of RNA or DNA into the cells, or transfection with a viral vector. The GNC-induced expansion yielded a therapeutic dose in 9 days, compared to the average of 40 days for CAR-T cell expansion. The resulting cells were devoid of B cells and highly enriched for activated CD4+ and CD8+ T cells that had potent killing potential against their specific targets. The GNC therapeutic composition was viable and bioactive upon thaw from -80.degree. C. Together these advantages are expected to significantly lower waiting times, costs and issues related to infrastructure and training related to CAR-T cell therapy. Improvements in the purity, safety and quantity of the end product will be of significant benefit to the patient.

Example 5. PBMC Pre-Activated with GNC Proteins are Redirected to Potently Kill Tumor Cells

[0118] Six of the GNC SI-35 class proteins listed in Table 4 were tested for the ability to activate PBMC for redirected T cell cytotoxicity (RTCC) activity against a human ROR1-transduced CHO cell line (FIG. 24). GNC proteins were prepared at 2.times. final concentration and titrated 1:3 across 10 wells of a 96 well plate in 200 ul of RPMI+10% FBS. In the final destination 96 well plate, the PBMC and serially titrated antibodies were combined by adding 100 .mu.L of PBMC (200,000), and 100 .mu.L of each antibody dilution to each well of the assay. The assay plate was incubated at 37.degree. C. for approximately 72 hours before the addition of CFSE-labeled CHO-ROR1 cells. CHO-ROR1 target cells, 5.times.10e6, were labeled with CFSE (Invitrogen, #C34554) at 0.5 .mu.M in 10 mL of culture media for 20 minutes at 37.degree. C. The CHO-ROR1 cells were washed 3 times with 50 mL of culture media before resuspending in 10 mL, counted again and then 5,000 CFSE-labeled CHO-ROR1 cells were added to each well of GNC-activated PBMC. Cells were incubated for another 72 hours and then the contents of each assay well were harvested and analyzed for the number of CFSE-labeled target cells remaining. As shown on FIG. 24, all of the GNC proteins tested directed RTCC activity with SI-35E42, SI-35E43, and SI-35E46 being the most potent in reducing the number of CHO-ROR1 cells in the well.

[0119] To further demonstrate the killing effects of GNC-labeled PBMC against human tumor cells, a GNC-dose and effector:target ratio escalation experiment was performed using an IncuCyte S3 Live Cell Analysis System (Sartorius/Essen Biosciences) to monitor the cells over time. PBMC from a healthy donor were labeled with GNC protein SI-38E17 at 10-fold serial doses ranging from 0.01 to 100 nM for 30 minutes at 37.degree. C. and then washed prior to culture. The GNC SI-38E17 targets the CD19 antigen expressed on B cell surfaces, and therefore, the Kasumi-2 precursor B cell leukemia line was chosen as a target cell. The Kasumi-2 cell used was transduced to express green fluorescence protein (GFP) and therefore the presence of tumor cells was tracked by measuring the average green fluorescence in 4 images/well collected 9 times over a six-day period. The effector:target (E:T) ratios were escalated by adding GNC-labeled PBMC in a serial 2-fold dilution of 5,000 (1:1) to 160,000 (32:1) cells to duplicate wells. As shown in FIG. 25, Kasumi-2 cells increased in number in the wells that had from 1:1 to 8:1 E:T ratios of unlabeled PBMC. Exposure to as little as 0.1 nM GNC led to decreased growth of Kasumi-2 in the 1:1 culture with suppression increasing at each 2-fold increase in the E:T ratio. Coating of PBMC with 1 nM or greater concentrations of GNC led to nearly complete elimination of Kasumi-2 cells after 42 hours of culture at all E:T ratios.

[0120] As a follow up experiment, three other transformed B cell lines: NALM-6, MEC-1, and Daudi and the acute T cell leukemia line, Jurkat, were used as target cells. These target cells were previously transduced by lentivirus to constitutively express the NucRed 647 molecule. In this assay, PBMC were exposed to 10-fold doses of GNC protein SI-38E17 for 30 minutes at 37.degree. C. and then washed as before. PBMC were plated at 1.2.times.10.sup.6 cells/well and 50,000 target tumor cells were added. Cells were placed in IncuCyte S3 set to collect red fluorescence images (4 images/well) collected at 10 time points over a 5.5-day period (FIG. 26). Growth curves were established for all four tumor cell lines in the absence of PBMC (null). Labeling of PBMC with 1 nM or more of GNC protein SI-38E17 led to arrested growth of all three B cell lines but not Jurkat T cell leukemia. The B cell lines varied in their susceptibility to PBMC cells pre-exposed to 0.1 nM of GNC protein.

[0121] As a different method of quantifying the outcome of cultures of GNC-T cells with tumor cells, we established a limit of quantification (LOQ) curve for detection by flow cytometry. Daudi-Red cells were serially diluted 10-fold in a range from 200,000 to 20 cells and then mixed 1:1 with 1 million PBMC to create samples of 10%, 1.0%, 0.1%, 0.01% and 0.001% tumor cells, which were then analyzed by flow cytometry (FIG. 27). Next, cells were harvested from a 15 day 6-well G-Rex culture of 1 nM GNC-expanded T cells that had been spiked with 10%, 1% or 0.1% of NALM-6, MEC-1, Daudi, or Jurkat (all NucRed-transduced) tumor cells at time 0 and analyzed using the same flow cytometry settings as above. Tumor cells were reduced to less than 0.001% in all conditions with the exception of the culture in which the MEC-1 tumor line was spiked in at 10% were 44 cells were detected. In this condition the MEC-1 cells were reduced to <0.01% in the culture.

[0122] While the present disclosure has been described with reference to particular embodiments or examples, it may be understood that the embodiments are illustrative and that the disclosure scope is not so limited. Alternative embodiments of the present disclosure may become apparent to those having ordinary skill in the art to which the present disclosure pertains. Such alternate embodiments are considered to be encompassed within the scope of the present disclosure. Accordingly, the scope of the present disclosure is defined by the appended claims and is supported by the foregoing description. All references cited or referred to in this disclosure are hereby incorporated by reference in their entireties.

Tables

TABLE-US-00001

[0123] TABLE 1A Composition of example GNC proteins with T cell binding domains. Moiety 1 Activation Agonist Moiety 2 of T cells receptor Antagonist receptor Tumor Antigen CD3 CD28, 41BB, PDL1, PD1, TIGIT, BCMA, CD19, CD20, OX40, GITR, TIM-3, LAG-3, CD33, CD123, CD22, CD40L, ICOS, CTLA4, BTLA, CD30, ROR1, CEA, Light, CD27, VISTA, PDL2 HER2, EGFR, CD30 EGFRvIII, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2

TABLE-US-00002 TABLE 2 Examples of possible combinations of T cell activation, T cell agonist, T cell antagonist, and tumor antigen binding domains in a single GNC protein. T cell Tumor T cell T cell T cell T cell T cell T cell GNC protein activation antigen antagonist agonist antagonist antagonist antagonist agonist Bi-specific CD3 ROR1 Tri-specific CD3 ROR1 PD1 Tetra-specific CD3 ROR1 PD1 41BB Penta-specific CD3 ROR1 PD1 41BB LAG3 Hexa-specific CD3 ROR1 PD1 41BB LAG3 TIM3 Hepta-specific CD3 ROR1 PD1 41BB LAG3 TIM3 TIGIT Octa-specific CD3 ROR1 PD1 41BB LAG3 TIM3 TIGIT CD28

TABLE-US-00003 TABLE 3 Specificity of antibody binding domains used in GNC proteins. AgBD Specificity Antibody Name CD3.epsilon. 284A10 480C8 4-1BB 460C3 420H5 466F6 FITC 4420 PD-L1 PL230C6 CD19 21D4 ROR1 323H7 IgD Domain 330F11 Kringle Domain 338H4 Frizzled Domain 324C6 EGFRvIII 806

TABLE-US-00004 TABLE 4 Classes of tetra-specific GNC antibodies targeting EGFRvIII (SI-39E), ROR1 (SI-35E), and CD19 (SI-38E). GNC AgBD 1 Humanized AgBD 2 Humanized IgG1 AgBD 3 Humanized AgBD 4 Humanized ID (LH-scFv) Variant (Fab) Variant Fc (HL-scFv) Variant (HL-ScFv) Variant SI-39E18 284A10 L1H1 806 -- n2 PL221G5 H1L1 420H5 H3L3 SI-39E29 806 -- 284A10 H1L1 n2 PL221G5 H1L1 420H5 H3L3 SI-35E20 466F6 L5H2 PL230C6 H3L2 n2 323H7 H4L1 284A10 H1L1 SI-35E58 284A10 L1H1 PL230C6 H3L2 n2 323H7 H4L1 466F6 H2L5 SI-35E88 284A10 L1H1 323H7 H4L1 n2 PL230C6 H3L2 466F6 H2L5 SI-35E99 284A10 L1H1 323H7 H4L1 n2 PL221G5 H1L1 466F6 H2L5 SI-35E18 460C3 L1H1 PL230C6 H3L2 n2 323H7 H4L1 284A10 H1L1 SI-35E19 420H5 L3H3 PL230C6 H3L2 n2 323H7 H4L1 284A10 H1L1 SI-35E36 4420 -- PL230C6 H3L2 n2 338H4 H3L4 284A10 H1L1 SI-35E37 460C3 L1H1 4420 -- n2 338H4 H3L4 284A10 H1L1 SI-35E38 460C3 L1H1 PL230C6 H3L2 n2 4420 -- 284A10 H1L1 SI-35E39 460C3 L1H1 PL230C6 H3L2 n2 338H4 H3L4 4420 -- SI-38E17 284A10 H1L1 21D4 -- n2 PL221G5 H1L1 466F6 H2L5 SI-38E33 21D4 -- 284A10 H1L1 n2 PL221G5 H1L1 466F6 H2L5

TABLE-US-00005 SEQ ID Description 1 anti-CD3 284A10 VHv1 nt 2 anti-CD3 284A10 VHv1 aa 3 anti-CD3 284A10 VLv1 nt 4 anti-CD3 284A10 VLv1 aa 5 anti-PD-L1 PL23006 VHv3 nt 6 anti-PD-L1 PL23006 VHv3 aa 7 anti-PD-L1 PL23006 VLv2 nt 8 anti-PD-L1 PL23006 VLv2 aa 9 anti-PD-L1 PL221G5 VHv1 nt 10 anti-PD-L1 PL221G5 VHv1 aa 11 anti-PD-L1 PL221G5 VLv1 nt 12 anti-PD-L1 PL221G5 VLv1 aa 13 anti-4-1BB 420H5 VHv3 nt 14 anti-4-1BB 420H5 VHv3 aa 15 anti-4-1BB 420H5 VLv3 nt 16 anti-4-1BB 420H5 VHLv3 aa 17 anti-4-1BB 466F6 VHv2 nt 18 anti-4-1BB 466F6 VHv2 aa 19 anti-4-1BB 466F6 VLv5 nt 20 anti-4-1BB 466F6 VLv5 aa 21 anti-4-1BB 460C3 VHv1 nt 22 anti-4-1BB 460C3 VHv1 aa 23 anti-4-1BB 460C3 VLv1 nt 24 anti-4-1BB 460C3 VLv1 aa 25 anti-ROR1 323H7 VHv4 nt 26 anti-ROR1 323H7 VHv4 aa 27 anti-ROR1 323H7 VLv1 nt 28 anti-ROR1 323H7 VLv1 aa 29 anti-ROR1 338H4 VHv3 nt 30 anti-ROR1 338H4 VHv3 aa 31 anti-ROR1 338H4 VLv4 nt 32 anti-ROR1 338H4 VLv4 aa 33 anti-FITC 4-4-20 VH nt 34 anti-FITC 4-4-20 VH aa 35 anti-FITC 4-4-20 VL nt 36 anti-FITC 4-4-20 VL aa 37 human IgG1 null2 (G1m-fa with ADCC/CDC null mutations) nt 38 human IgG1 null2 (G1m-fa with ADCC/CDC null mutations) aa 39 human Ig Kappa nt 40 human Ig Kappa aa 41 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain nt 42 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain aa 43 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain nt 44 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain aa 45 anti-CD3 284A10 VHv1b nt 46 anti-CD3 284A10 VHv1b aa 47 anti-huCD19 21D4 VH nt 48 anti-huCD19 21D4 VH aa 49 anti-huCD19 21D4 VL nt 50 anti-huCD19 21D4 VL aa 51 anti-huEGFRvIII 806 VH nt 52 anti-huEGFRvIII 806 VH aa 53 anti-huEGFRvIII 806 VL nt 54 anti-huEGFRvIII 806 VL aa 55 GGGGSGGGGSG linker nt 56 GGGGSGGGGSG linker aa 57 GGGSGGGGS linker 01 nt 58 GGGSGGGGS linker 01 aa 59 GGGSGGGGS linker 02 nt 60 GGGSGGGGS linker 02 aa 61 GGGSGGGGSGGGSGGGGS linker nt 62 GGGSGGGGSGGGSGGGGS linker aa 63 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-sc Fv .times. 420H5-H3L3-scFv) heavy chain nt 64 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-sc Fv .times. 420H5-H3L3-scFv) heavy chain aa 65 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-sc Fv .times. 420H5-H3L3-scFv) light chain nt 66 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-sc Fv .times. 420H5-H3L3-scFv) light chain aa 67 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5-H3L3-scFv) heavy chain nt 68 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5-H3L3-scFv) heavy chain aa 69 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5-H3L3-scFv) light chain nt 70 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5-H3L3-scFv) light chain aa 71 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 3 23H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain nt 72 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain aa 73 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain nt 74 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain aa 75 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-sc Fv .times. 466F6-H2L5-scFv) heavy chain nt 76 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-sc Fv .times. 466F6-H2L5-scFv) heavy chain aa 77 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-sc Fv .times. 466F6-H2L5-scFv) light chain nt 78 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-sc Fv .times. 466F6-H2L5-scFv) light chain aa 79 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6-H3L2-sc Fv .times. 466F6-H2L5-scFv) heavy chain nt 80 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6-H3L2-sc Fv .times. 466F6-H2L5-scFv) heavy chain aa 81 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6-H3L2-sc Fv .times. 466F6-H2L5-scFv) light chain nt 82 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6-H3L2-sc Fv .times. 466F6-H2L5-scFv) light chain aa 83 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) heavy chain nt 84 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) heavy chain aa 85 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) light chain nt 86 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) light chain aa 87 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1-scFv .times. 466F6-H2L5-scFv) heavy chain nt 88 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1-scFv .times. 466F6-H2L5-scFv) heavy chain aa 89 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1-scFv .times. 466F6-H2L5-scFv) light chain nt 90 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1-scFv .times. 466F6-H2L5-scFv) light chain aa 91 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) heavy chain nt 92 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) heavy chain aa 93 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) light chain nt 94 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-sc Fv .times. 466F6-H2L5-scFv) light chain aa

GNC-T Sequence Listing of Tetra-Specific GNC Antibodies

TABLE-US-00006

[0124]>SEQ ID 01 anti-CD3 284A10 VHv1 nt GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC- TGG ATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCA- TTA CTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAAC- ACG CTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATC- TGC TATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCA >SEQ ID 02 anti-CD3 284A10 VHv1 aa EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNS- KNT LYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS >SEQ ID 03 anti-CD3 284A10 VLv1 nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGC- CAG TGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAG- CAT CCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGC- AGC CTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTC- TTT CGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 04 anti-CD3 284A10 VLv1 aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLT- ISS LQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK >SEQ ID 05 anti-PD-L1 PL230C6 VHv3 nt CAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGG- AAT CGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTA- CTT ATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACG- GTG TATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTC- CCA CTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGT >SEQ ID 06 anti-PD-L1 PL230C6 VHv3 aa QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKGRFTISKDNTK- NTV YLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSS >SEQ ID 07 anti-PD-L1 PL230C6 VLv2 nt GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGC- CAG TGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTG- CAT CCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC- AGC CTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGG- CGG AGGGACCAAGGTGGAGATCAAA >SEQ ID 08 anti-PD-L1 PL230C6 VLv2 aa AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLT- ISS LQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIK >SEQ ID 09 anti-PD-L1 PL221G5 VHv1 nt GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC- TGG ATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCAT- GCA TTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAAT- TCC AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGC- GTT TTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC >SEQ ID 10 anti-PD-L1 PL221G5 VHv1 aa EVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGITYDANWAKGRFTISR- DNS KNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSS >SEQ ID 11 anti-PD-L1 PL221G5 VLv1 nt GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGC- CAG TCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG- CAT CCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGC- AGC CTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGG- CGG AGGGACCAAGGTGGAGATCAAA >SEQ ID 12 anti-PD-L1 PL221G5 VLv1 aa DIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLT- ISS LQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK >SEQ ID 13 anti-4-1BB 420H5 VHv3 nt CAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGG- ATT CTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCA- TTT ATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCC- AAG AACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGATAGTAG- TAG TTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC >SEQ ID 14 anti-4-1BB 420H5 VHv3 aa QSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRD- NSK NTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGTLVTVSS >SEQ ID 15 anti-4-1BB 420H5 VLv3 nt GCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGC- CAG TGAGGACATTGATACCTATTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTATG- CAT CCGATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGC- AGC CTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGC- TTT CGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 16 anti-4-1BB 420H5 VLv3 aa ALVMTQSPSTLSASVGDRVTINCQASEDIDTYLAWYQQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLT- ISS LQPDDFATYYCQGGYYTSSADTRGAFGGGTKVEIK >SEQ ID 17 anti-4-1BB 466F6 VHv2 nt CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGG- ATT CACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTA- GTA GTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACG- GTG GATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGA- TCC TATGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC >SEQ ID 18 anti-4-1BB 466F6 VHv2 aa RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSK- NTV DLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSS >SEQ ID 19 anti-4-1BB 466F6 VLv5 nt GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGC- CAG TCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTG- CAG CCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC- GAC CTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTT- CGG CGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 20 anti-4-1BB 466F6 VLv5 aa DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT- ISD LEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIK >SEQ ID 21 anti-4-1BB 460C3 VHv1 nt GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC- TGG AATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCAT- GCA TATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAAT- TCC AAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGAGAAGG- TAG CCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC >SEQ ID 22 anti-4-1BB 460C3 VHv1 aa EVQLLESGGGLVQPGGSLRLSCAASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISR- DNS KNTLYLQMNSLRAEDTAVYYCAREGSLWGQGTLVTVSS >SEQ ID 23 anti-4-1BB 460C3 VLv1 nt GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTC- CAG TCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATT- CTG CATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATC- AGC AGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTT- CGG CGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 24 anti-4-1BB 460C3 VLv1 aa DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTL- TIS

SLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIK >SEQ ID 25 anti-ROR1 323H7 VHv4 nt GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC- TGG ATTCACCATCAGTCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATA- TTT ATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAG- AAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGG- TGG TGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA >SEQ ID 26 anti-ROR1 323H7 VHv4 aa EVQLLESGGGLVQPGGSLRLSCAASGETISRYHMTWVRQAPGKGLEWIGHIYVNNDDTDYASSAKGRFTISRDN- SKN TLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS >SEQ ID 27 anti-ROR1 323H7 VLv1 nt GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTC- CAG TCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCT- ATT ATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACC- ATC AGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTT- TGC TTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 28 anti-ROR1 323H7 VLv1 aa DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFT- LTI SSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIK >SEQ ID 29 anti-ROR1 338H4 VHv3 nt GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTC- TGG ATTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAGGGGGCTGGAGTGGATCGGAATCA- TTT ATGCTAGTGGTAGCACATACTACGCGAGCTCGGCGAAAGGCAGATTCACCATCTCCAAAGACAATACCAAGAAC- ACG GTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTTATGACGGCAT- GGA CCTCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA >SEQ ID 30 anti-ROR1 338H4 VHv3 aa EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMSWVRQAPGRGLEWIGIIYASGSTYYASSAKGRFTISKDNT- KNT VDLQMNSLRAEDTAVYYCARIYDGMDLWGQGTLVTVSS >SEQ ID 31 anti-ROR1 338H4 VLv4 nt GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGC- CAG TCAGAACATTTACAGCTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGTTCCTAAGCGCCTGATCTATCTGG- CAT CTACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTACACTCTCACCATCAGC- AGC CTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAGCAATTATAACGGTAATTATGGTTTCGGCGGAGGGAC- CAA GGTGGAGATCAAA >SEQ ID 32 anti-ROR1 338H4 VLv4 aa DIQMTQSPSSLSASVGDRVTINCQASQNIYSYLSWYQQKPGKVPKRLIYLASTLASGVPSRFSGSGSGTDYTLT- ISS LQPEDVATYYCQSNYNGNYGFGGGTKVEIK >SEQ ID 33 anti-FITC 4420 VH nt GAGGTGAAGCTGGATGAGACTGGAGGAGGCTTGGTGCAACCTGGGAGGCCCATGAAACTCTCCTGTGTTGCCTC- TGG ATTCACTTTTAGTGACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAAGGACTGGAGTGGGTAGCACAAA- TTA GAAACAAACCTTATAATTATGAAACATATTATTCAGATTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGAT- TCC AAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGAGTTGAAGACATGGGTATCTATTACTGTACGGGTTCTTA- CTA TGGTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA >SEQ ID 34 anti-FITC 4420 VH aa EVKLDETGGGLVQPGRPMKLSCVASGFTFSDYWMNWVRQSPEKGLEWVAQIRNKPYNYETYYSDSVKGRFTISR- DDS KSSVYLQMNNLRVEDMGIYYCTGSYYGMDYWGQGTSVTVSS >SEQ ID 35 anti-FITC 4420 VL nt GATGTCGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATC- TAG TCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACGTTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGG- TCC TGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTC- ACA CTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGAC- GTT CGGTGGAGGCACCAAGCTGGAAATCAAA >SEQ ID 36 anti-FITC 4420 VL aa DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLRWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGT- DFT LKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK >SEQ ID 37 human IgG1 null (G1m-fa with ADCC/CDC null mutations) nt GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCT- GGG CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC- ACA CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG- GGC ACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATC- TTG TGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCC- CAA AACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGAC- CCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA- CAA CAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCG- CGG TCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG- GTG TACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA- TCC CAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG- ACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA- TGC TCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT >SEQ ID 38 human IgG1 null (G1m-fa with ADCC/CDC null mutations) aa ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS- SLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLEPPKPKDTLMISRTPEVTCVVVDVSH- EDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPRE- PQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV- FSC SVMHEALHNHYTQKSLSLSPG >SEQ ID 39 human Ig Kappa nt CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGT- TGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTA- ACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAA- GCA GACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTT- CAA CAGGGGAGAGTGT >SEQ ID 40 human Ig Kappa aa RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL- SKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 41 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain nt GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGTC- CAG TCAGAGTGTTTATAGTAACTGGTTCTCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATT- CTG CATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATC- AGC AGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGCAGGCGGTTACAATACTGTTATTGATACTTTTGCTTT- CGG CGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCG- GTG GAGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGT- GCA GCCTCTGGAATCGACTTCAGTAGGAGATACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTG- GAT CGCATGCATATATACTGGTAGCCGCGATACTCCTCACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCA- GAG ACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCG- AGA GAAGGTAGCCTGTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATC- CCA GTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGAA- TCG ACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACT- TAT AGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGT- GTA TCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCC- ACT TGTGGGGCCAGGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC- TCC

TCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGT- GTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC- TCA GCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGC- AAC ACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA- AGC CGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGG- TCA CATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG- CAT AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCA- CCA GGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCA- TCT CCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAAC- CAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC- GGA GAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGG- ACA AGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG- AAG AGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGG- GGG AGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACA- TGA CTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACAGAC- TAC GCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAG- CCT GAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACA- TCT GGGGCCAGGGAACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGG- TCC GGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCAC- CAT CACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAAGTTC- CTA AGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACA- GAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGA- TGG TCTTGATACGTTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGAT- CCG AGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCT- GGA TTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCAT- TAC TGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACA- CGC TGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCT- GCT ATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGG- CGG TTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCAT- CTG TAGGAGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAA- CCA GGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAG- TGG ATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCT- ATT TTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 42 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain aa DIQMTQSPSTLSASVGDRVTITCQSSQSVYSNWFSWYQQKPGKAPKLLIYSASTLASGVPSRFSGSGSGTEFTL- TIS SLQPDDFATYYCAGGYNTVIDTFAFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL- SCA ASGIDFSRRYYMCWVRQAPGKGLEWIACIYTGSRDTPHYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY- CAR EGSLWGQGTLVTVSSGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGI- ITY SGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPL- APS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK- PSN TKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV- EVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT- KNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY- TQK SLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGETISRYHMTWVRQAPGKGLEWIGHIYVNNDD- TDY ASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSSGGGGSGGGGSGG- GGS GGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRFSGSGS- GTD FTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCA- ASG FTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGG- SSA ITSNNIWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQ- QKP GKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIK >SEQ ID 43 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain nt GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCAAGTGTCAGGC- CAG TGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTG- CAT CCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC- AGC CTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGG- CGG AGGGACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGT- TGA AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTG- GAT AACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAG- CAG CACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA- GCT CGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT >SEQ ID 44 SI-35E18 (460C3-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain aa AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLT- ISS LQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNEYPREAKVQW- KVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 45 anti-CD3 284A10 VHv1b nt GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC- TGG ATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCA- TTA CTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAAC- ACG CTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTC- TGC TATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA >SEQ ID 46 anti-CD3 284A10 VHv1b aa EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNS- KNT LYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVST >SEQ ID 47 anti-huCD19 21D4 VH nt GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTAAGGGTTC- TGG ATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCA- TCT ATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATC- AGG ACTGCCTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTAT- GAT TTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA >SEQ ID 48 anti-huCD19 21D4 VH aa EVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQGQVTISADK- SIR TAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSS >SEQ ID 49 anti-huCD19 21D4 VL nt GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGC- AAG TCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATG- CCT CCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGC- AGC CTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGAC- CAA AGTGGATATCAAA >SEQ ID 50 anti-huCD19 21D4 VL aa AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLT- ISS LQPEDFATYYCQQFNSYPFTFGPGTKVDIK

>SEQ ID 51 anti-huEGFRvIII 806 VH nt GATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCAC- TGG CTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAGCTGGAGTGGATGGGCT- ACA TAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGCGACACATCCAAG- AAC CAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGG- GTT TCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA >SEQ ID 52 anti-huEGFRvIII 806 VH aa DVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLKSRISITRDT- SKN QFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSA >SEQ ID 53 anti-huEGFRvIII 806 VL nt GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTC- AAG TCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATG- GAA CCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGC- AGC CTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCAC- CAA GCTGGAAATCAAA >SEQ ID 54 anti-huEGFRvIII 806 VL aa DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLT- ISS LESEDFADYYCVQYAQFPWTFGGGTKLEIK >SEQ ID 55 GGGGSGGGGSG linker nt GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGA >SEQ ID 56 GGGGSGGGGSG linker aa GGGGSGGGGSG >SEQ ID 57 GGGGSGGGGS linker 01 nt GGCGGTGGAGGGTCCGGCGGTGGTGGATCA >SEQ ID 58 GGGGSGGGGS linker 01 aa GGGGSGGGGS >SEQ ID 59 GGGGSGGGGS linker 02 nt GGCGGTGGAGGGTCCGGCGGTGGTGGATCC >SEQ ID 60 GGGGSGGGGS linker 02 aa GGGGSGGGGS >SEQ ID 61 GGGGSGGGGSGGGGSGGGGS linker nt GGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCA >SEQ ID 62 GGGGSGGGGSGGGGSGGGGS linker aa GGGGSGGGGSGGGGSGGGGS >SEQ ID 63 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) heavy chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAAGC- CAG TGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAG- CAT CCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGC- AGC CTGCAGCCTGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTC- TTT CGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCG- GCG GTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCC- TGT GCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTG- GAT CGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACA- ATT CCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGAC- GGT GGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGAGG- GTC CGGCGGTGGTGGATCCGATGTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCC- TCA CCTGCACTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAACAAG- CTG GAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAAAGTCGAATCTCTATCAC- TCG CGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGACTATTGAGGACACAGCCACATATTACTGTG- TAA CGGCGGGACGCGGGTTTCCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCTAGCACCAAGGGCCCA- TCG GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTA- CTT CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC- AGT CCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC- AAC GTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATG- CCC ACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA- TGA TCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG- TAC GTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT- CAG CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCC- CAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCC- CGG GATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA- GTG GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC- TCT ATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT- CTG CACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGA- GGT GCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAT- TCT CCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATT- GCT GCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAA- GAA CACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTT- CGT TCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGA- GGC GGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC- ATC TGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGA- AAC CAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC- AGT GGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACA- GGG TTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCG- GCG GTGGTGGATCCCAGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGT- GCA GCCTCTGGATTCTCCTTCAGTAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTG- GAT CGCATGTATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCA- GAG ACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCG- AGA GATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGG- TAG TGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGCCCTTGTGATGACCCAGTCTCCTTCCA- CCC TGTCTGCATCTGTAGGAGACAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGG- TAT CAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTACGCATCCGATCTGGCATCTGGGGTCCCATCAAG- GTT CAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT- ACT GCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 64 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) heavy chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLT- ISS LQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLR- LSC AASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA- RDG GSSAITSNNIWGQGTLVTVSSGGGGSGGGGSDVQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPG- NKL EWMGYISYSGNTRYNPSLKSRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSAASTK- GPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY- ICN VNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF- NWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLP- PSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH- EAL HNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIA- CIA AGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGS- GGG GSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRF- SGS

GSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRL- SCA ASGFSFSSNYWICWVRQAPGKGLEWIACIYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY- CAR DSSSYYMFNLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINCQASEDIDTYL- AWY QQKPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGAFGGGTKVE- IK >SEQ ID 65 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) light chain nt GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCACTTGCCATTC- AAG TCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATCATTTAAGGGCCTGATCTATCATG- GAA CCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGCAGTGGATCTGGAGCCGATTATTCTCTCACCATCAGC- AGC CTGGAATCTGAAGATTTTGCAGACTATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCAC- CAA GCTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG- GAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC- CTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCT- GAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCG- TCA CAAAGAGCTTCAACAGGGGAGAGTGT >SEQ ID 66 SI-39E18 (284A10-L1H1-scFv .times. 806-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) light chain aa DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSGSGSGADYSLT- ISS LESEDFADYYCVQYAQFPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD- NAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 67 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) heavy chain nt GACATCCTGATGACCCAATCTCCATCCTCCATGTCTGTATCTCTGGGAGACACAGTCAGCATCA CTTGCCATTCAAGTCAGGACATTAACAGTAATATAGGGTGGTTGCAGCAGAGACCAGGGAAATC ATTTAAGGGCCTGATCTATCATGGAACCAACTTGGACGATGAAGTTCCATCAAGGTTCAGTGGC AGTGGATCTGGAGCCGATTATTCTCTCACCATCAGCAGCCTGGAATCTGAAGATTTTGCAGACT ATTACTGTGTACAGTATGCTCAGTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAA AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAT GTGCAGCTTCAGGAGTCGGGACCTAGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCA CTGTCACTGGCTACTCAATCACCAGTGATTTTGCCTGGAACTGGATTCGGCAGTTTCCAGGAAA CAAGCTGGAGTGGATGGGCTACATAAGTTATAGTGGTAACACTAGGTACAACCCATCTCTCAAA AGTCGAATCTCTATCACTCGCGACACATCCAAGAACCAATTCTTCCTGCAGTTGAACTCTGTGA CTATTGAGGACACAGCCACATATTACTGTGTAACGGCGGGACGCGGGTTTCCTTATTGGGGCCA AGGGACTCTGGTCACTGTCTCTGCAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAG CTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCT CTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGA GTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTC ACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGG ACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTG GGGCCAAGGAACTCTGGTCACCGTTTCTTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTG GCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGC GGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACC CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGT ACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCAC GTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAG TGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGC AGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT GGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC TCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGT GGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGC CTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACAT GTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGT GCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCA AGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGC GAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTC TCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGAT CAGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAA GCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCG GCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAAC TTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAG GTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGCTGGTGGAGTCTGGGG GAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAG TAGCAACTACTGGATATGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGT ATTTATGTTGGTAGTAGTGGTGACACTTACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCT CCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGC CGTATATTACTGTGCGAGAGATAGTAGTAGTTATTATATGTTTAACTTGTGGGGCCAGGGAACC CTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCG GCGGTGGAGGATCAGCCCTTGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGA CAGAGTCACCATCAATTGCCAGGCCAGTGAGGACATTGATACCTATTTAGCCTGGTATCAGCAG AAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTTACGCATCCGATCTGGCATCTGGGGTCCCAT CAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGA TGATTTTGCAACTTATTACTGCCAAGGCGGTTACTATACTAGTAGTGCTGATACGAGGGGTGCT TTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 68 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) heavy chain aa DILMTQSPSSMSVSLGDTVSITCHSSQDINSNIGWLQQRPGKSFKGLIYHGTNLDDEVPSRFSG SGSGADYSLTISSLESEDFADYYCVQYAQFPWTFGGGTKLEIKGGGGSGGGGSGGGGSGGGGSD VQLQESGPSLVKPSQSLSLTCTVTGYSITSDFAWNWIRQFPGNKLEWMGYISYSGNTRYNPSLK SRISITRDTSKNQFFLQLNSVTIEDTATYYCVTAGRGFPYWGQGTLVTVSAGGGGSGGGGSEVQ LVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAKGRF IISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGG GGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGS AGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTV SSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGK APKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTK VEIKGGGGSGGGGSQSLVESGGGLVQPGGSLRLSCAASGFSFSSNYWICWVRQAPGKGLEWIAC IYVGSSGDTYYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSSSYYMFNLWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSALVMTQSPSTLSASVGDRVTINCQASEDIDTYLAWYQQ KPGKAPKLLIFYASDLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGGYYTSSADTRGA FGGGTKVEIK >SEQ ID 69 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) light chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGT >SEQ ID 70 SI-39E29 (806-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1-scFv .times. 420H5- H3L3-scFv) light chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC

>SEQ ID 71 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain nt GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTT ACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAA GGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGT GGAGGATCACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAC TCTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCC AGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCC GCGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACA GCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTAT GTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCC CAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTA CAGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGG GCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGC CGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAG CTGAGGACACGGCTGTGTATTACTGTGCCAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCA GGGAACCCTGGTCACCGTCTCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC TCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCG AACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGT CCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGC ACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGC ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGG ACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCG TGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCG GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCC GAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCA TGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGG TCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGG GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACA GACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGT TGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA GGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACA TCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTG CCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGGGAAA GTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTGGGGTCCCATCTCGGTTCAGTG GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAAC TTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGGGACC AAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGGAGT CTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAC CATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGA GTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAAGGCAGATTCACCATCTCCA GAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGT GTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTACTAGTAACAACATTTGGGGCCAAGGA ACTCTGGTCACCGTTTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGT CCGGCGGTGGAGGATCAGACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGG AGACAGAGTCACCATCAATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAG CAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCC TGATGATTTTGCAACTTATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAAT TCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 72 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) heavy chain aa DVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSG SGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEIKGGGGSGGGGSGGGGSGG GGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSGGNVYYASS ARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGS QSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGIITYSGSRYYANWAKG RFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCA VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGG SGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDT DYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS GGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGK VPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGT KVEIKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIG VITGRDITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQG TLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQ QKPGKAPKLLIYEASKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVN SFGGGTKVEIK >SEQ ID 73 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain nt GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCA AGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTT ACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGT GGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGT >SEQ ID 74 SI-35E20 (466F6-L5H2-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 284A10-H1L1-scFv) light chain aa AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 75 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 466F6-H2L5-scFv) heavy chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC GGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCG AGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAA TGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGC TATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGG TCCGGCGGTGGTGGATCCCAGTCGGTGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGT CCCTGAGACTCTCCTGTACCGCCTCTGGAATCGACCTTAATACCTACGACATGATCTGGGTCCG CCAGGCTCCAGGCAAGGGGCTAGAGTGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTAC GCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGC AAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGG TTCCCACTTGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGCTAGCACCAAGGGCCCATCG GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGG TCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG CCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCA AGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGC ACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCA

AGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCA GTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC AAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCArCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCTGAC CAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGAGAGGTGCAGCTGTTGGAGTCTGGGG GAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAG TCGCTACCACATGACTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATT TATGTTAATAATGATGACACAGACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAG ACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTA TTTCTGTGCGAGATTGGATGTTGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGA ACTCTGGTTACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGT CCGGCGGTGGAGGATCAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGG AGACAGAGTCACCATCACTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGG TATCAGCAGAAACCAGGGAAAGTTCCTAAGCTCCTGATCTATTATGCTTCCACTCTGGCATCTG GGGTCCCATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACrCTCACCATCAGCAGCCT GCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACG TTTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGGT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGArCTTCAAATGAACAGCCT GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTrATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA CCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT GGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 76 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 466F6-H2L5-scFv) heavy chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYA SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG SGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLEWVGsIITYSGSRYY+EE ANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGGGGGSGGGGSGEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHI YVNNDDTDYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQG TLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAW YQQKPGKVPKLLIYYASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDT FAFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG KGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYLS WYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYV GGAFGGGTKVEIK >SEQ ID 77 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 466F6-H2L5-scFv) light chain nt GCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCA AGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTT ACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGCGGAGGGACCAAGGT GGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGT >SEQ ID 78 SI-35E58 (284A10-L1H1-scFv .times. PL230C6-Fab .times. 323H7-H4L1-scFv .times. 466F6-H2L5-scFv) light chain aa AYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQKPGKAPKLLIHSASSLASGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 79 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6- H3L2-scFv .times. 466F6-H2L5-scFv) heavy chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC GGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCG AGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAA TGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGC TATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGG TCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGG GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACA GACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGT TGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCA CAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGA ATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCA CACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCA AAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA GCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCC CCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGC CTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCGG TGGAGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACCGCCTC TGGAATCGACCTTAATACCTACGACATGATCTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAG TGGGTTGGAATCATTACTTATAGTGGTAGTAGATACTACGCGAACTGGGCGAAAGGCCGATTCA CCATCTCCAAAGACAATACCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGA CACGGCTGTGTATTACTGTGCGAGAGATTATATGAGTGGTTCCCACTTGTGGGGCCAGGGAACC CTGGTCACCGTCTCTTCCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTCTG GAGGCGGCGGATCTGCCTATGATATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACCATCAAGTGTCAGGCCAGTGAGGACATTTATAGCTTCTTGGCCTGGTATCAGCAG AAACCAGGGAAAGCCCCTAAGCTCCTGATCCATTCTGCATCCTCTCTGGCATCTGGGGTCCCAT CAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCAACTTACTATTGTCAACAGGGTTATGGTAAAAATAATGTTGATAATGCTTTCGGC GGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGGTCCGGACGGTCGC TGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTC TGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAG TACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCA CCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGA CACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACC CTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCG

GCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAG AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCAT CAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGG CGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTC GGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 80 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6- H3L2-scFv .times. 466F6-H2L5-scFv) heavy chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYA SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG SGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDT DYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGGGGGSGGGGSQSVEESGGGLVQPGGSLRLSCTASGIDLNTYDMIWVRQAPGKGLE WVGIITYSGSRYYANWAKGRFTISKDNTKNTVYLQMNSLRAEDTAVYYCARDYMSGSHLWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSAYDMTQSPSSVSASVGDRVTIKCQASEDIYSFLAWYQQ KPGKAPKLLIHSASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGKNNVDNAFG GGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLE YIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQ KPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAF GGGTKVEIK >SEQ ID 81 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6- H3L2-scFv .times. 466F6-H2L5-scFv) light chain nt GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGG GAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCTCGGTTC AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTG CAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGG GACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT >SEQ ID 82 SI-35E88 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL230C6- H3L2-scFv .times. 466F6-H2L5-scFv) light chain aa DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVIEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 83 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5- H1L1-scFv .times. 466F6-H2L5-scFv) heavy chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC GGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCG AGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAA TGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGC TATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGG TCCGGCGGTGGTGGATCAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGG GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTCGCTACCACATGACTTGGGT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGACATATTTATGTTAATAATGATGACACA GACTACGCGAGCTCCGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCACCTATTTCTGTGCGAGATTGGATGT TGGTGGTGGTGGTGCTTATATTGGGGACATCTGGGGCCAGGGAACTCTGGTTACCGTCTCTTCA GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCA CAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGA ATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCA CACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCA AAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA GCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC CCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGC CTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGC AGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGC CTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGG CTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGA AAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCT GAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATG GACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTG GTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCAC CCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCC CACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCA CTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCAC CATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGT AATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCG GTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCT GAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAG GCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAA GCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAAT GAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGAT CCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCG GTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTC CGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACT TACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCA ATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCAC CATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACT GATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 84 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5- H1L1-scFv .times. 466F6-H2L5-scFv) heavy chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYA SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG SGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTISRYHMTWVRQAPGKGLEWIGHIYVNNDDT DYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTATYFCARLDVGGGGAYIGDIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKG LEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAM DLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISS HLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWG NVDNVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQ APGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSD PMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRT YLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGT

DYVGGAFGGGTKVEIK >SEQ ID 85 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5- H1L1-scFv .times. 466F6-H2L5-scFv) light chain nt GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CTTGCCAGTCCAGTCAGAGTGTTTATAACAACAACGACTTAGCCTGGTATCAGCAGAAACCAGG GAAAGTTCCTAAGCTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCTCGGTTC AGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTG CAACTTATTACTGTGCAGGCGGTTATGATACGGATGGTCTTGATACGTTTGCTTTCGGCGGAGG GACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT >SEQ ID 86 SI-35E99 (284A10-L1H1-scFv .times. 323H7-Fab .times. PL221G5- H1L1-scFv .times. 466F6-H2L5-scFv) light chain aa DIQMTQSPSSLSASVGDRVTITCQSSQSVYNNNDLAWYQQKPGKVPKLLIYYASTLASGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCAGGYDTDGLDTFAFGGGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVIEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID 87 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) heavy chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC GGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCG AGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAA TGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGC TATTACTAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGGCGGTGGAGGG TCCGGCGGTGGTGGATCCGAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAG AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGT GCGCCAGGCACCTGGGAAAGGCCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACC AGATACAGTCCATCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCT ACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTAC TATGATTTGGGGAGTTATTATTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCT AGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGG CGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATC ACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACAC ATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAA CCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCC ACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCA TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCC ATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC AGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTC CCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTG GCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG AAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGC TGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTC TGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTG GAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAG GCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAG AGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGAC CTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTT CCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCT GTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCAC TTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTC TGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCAT CAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAAT GTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTG GTGGATCCCGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACT CTCCTGTACAGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCA GGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCG CGAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAG CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATG TGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTG GCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTC TGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGG CATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAG CGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTAT GTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 88 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) heavy chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYA SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGG SGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDT RYSPSFQGQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGL EWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMD LWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSH LNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGN VDNVFGGGTKVEIKGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAP GKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYL SWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDY VGGAFGGGTKVEIK >SEQ ID 89 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) light chain nt GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC TCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTT ATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAA ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG TGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAG CACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GT >SEQ ID 90 SI-38E17 (284A10-L1H1-scFv .times. 21D4-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) light chain aa AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC >SEQ ID 91 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) heavy chain nt GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC TCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTT ATTACTGTCAACAGTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAA AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAG

GTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAGAAACCAGGAGAGTCTCTGAAGATCTCCTGTA AGGGTTCTGGATACAGCTTTAGCAGTTCATGGATCGGCTGGGTGCGCCAGGCACCTGGGAAAGG CCTGGAATGGATGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGTCCATCCTTCCAA GGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGGACTGCCTACCTGCAGTGGAGTAGCCTGA AGGCCTCGGACACCGCTATGTATTACTGTGCGAGACATGTTACTATGATTTGGGGAGTTATTAT TGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCGGTGGAGGGTCCGGCGGTGGT GGATCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGAC TCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCC AGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGG GCGAAAGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACA GCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGCGCGACGGTGGATCATCTGCTATTAC TAGTAACAACATTTGGGGCCAAGGAACTCTGGTCACCGTTTCTTCAGCTAGCACCAAGGGCCCA TCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCC TGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACC GTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA CCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCC AGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTC ATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGA GCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAT GGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCT CCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTATACCCTGCCCCCATCCCGGGATGAGCT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTG TCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGG GAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAG TAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGC ATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCT CCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGC CGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGA ACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCT CCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGG AGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTAAACTGGTATCAG CAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCC TGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTC GGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCGGTCGC TGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTC TGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAG TACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCGAGCTCCGCGAGAGGCAGATTCA CCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGA CACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACC CTGGTCACCGTCTCGAGCGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCG GCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATTAGGACTTACTTATCCTGGTATCAGCAG AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCAT CAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGG CGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTC GGCGGAGGGACCAAGGTGGAGATCAAA >SEQ ID 92 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) heavy chain aa AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIKGGGGSGGGGSGGGGSGGGGSE VQLVQSGAEVKKPGESLKISCKGSGYSFSSSWIGWVRQAPGKGLEWMGIIYPDDSDTRYSPSFQ GQVTISADKSIRTAYLQWSSLKASDTAMYYCARHVTMIWGVIIDFWGQGTLVTVSSGGGGSGGG GSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASW AKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIAC IAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQG TLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQ QKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVF GGGTKVEIKGGGGSGGGGSRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLE YIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQ KPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAF GGGTKVEIK SEQ ID 93 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) light chain nt GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGT SEQ ID 94 SI-38E33 (21D4-LH-scFv .times. 284A10-Fab .times. PL221G5-H1L1- scFv .times. 466F6-H2L5-scFv) light chain aa DVVMTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC

Sequence CWU 1

1

941360DNAArtificial Sequencesynthesized 1gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccatcagt accaatgcaa tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgcg cgacggtgga 300tcatctgcta ttactagtaa caacatttgg ggccaaggaa ctctggtcac cgtttcttca 3602120PRTArtificial Sequencesynthesized 2Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 1203336DNAArtificial Sequencesynthesized 3gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaa 3364112PRTArtificial Sequencesynthesized 4Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 1105345DNAArtificial Sequencesynthesized 5cagtcggtgg aggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60tgtacagcct ctggaatcga ccttaatacc tacgacatga tctgggtccg ccaggctcca 120ggcaaggggc tagagtgggt tggaatcatt acttatagtg gtagtagata ctacgcgaac 180tgggcgaaag gccgattcac catctccaaa gacaatacca agaacacggt gtatctgcaa 240atgaacagcc tgagagctga ggacacggct gtgtattact gtgccagaga ttatatgagt 300ggttcccact tgtggggcca gggaaccctg gtcaccgtct ctagt 3456115PRTArtificial Sequencesynthesized 6Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser1 5 10 15Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp 20 25 30Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 35 40 45Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln65 70 75 80Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 85 90 95Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 1157330DNAArtificial Sequencesynthesized 7gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300ttcggcggag ggaccaaggt ggagatcaaa 3308110PRTArtificial Sequencesynthesized 8Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45His Ser Ala Ser Ser Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Lys Asn Asn 85 90 95Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 1109366DNAArtificial Sequencesynthesized 9gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt ctccttcagt agcgggtacg acatgtgctg ggtccgccag 120gctccaggga aggggctgga gtggatcgca tgcattgctg ctggtagtgc tggtatcact 180tacgacgcga actgggcgaa aggccggttc accatctcca gagacaattc caagaacacg 240ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccgtatatta ctgtgcgaga 300tcggcgtttt cgttcgacta cgccatggac ctctggggcc agggaaccct ggtcaccgtc 360tcgagc 36610122PRTArtificial Sequencesynthesized 10Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Gly 20 25 30Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Ala Cys Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp Ala Asn 50 55 60Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp Leu Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12011330DNAArtificial Sequencesynthesized 11gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggccagtca gagcattagt tcccacttaa actggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctataag gcatccactc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaacag ggttatagtt ggggtaatgt tgataatgtt 300ttcggcggag ggaccaaggt ggagatcaaa 33012110PRTArtificial Sequencesynthesized 12Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn 85 90 95Val Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 11013360DNAArtificial Sequencesynthesized 13cagtcgctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc 60tgtgcagcct ctggattctc cttcagtagc aactactgga tatgctgggt ccgccaggct 120ccagggaagg ggctggagtg gatcgcatgc atttatgttg gtagtagtgg tgacacttac 180tacgcgagct ccgcgaaagg ccggttcacc atctccagag acaattccaa gaacacgctg 240tatctgcaaa tgaacagcct gagagccgag gacacggccg tatattactg tgcgagagat 300agtagtagtt attatatgtt taacttgtgg ggccagggaa ccctggtcac cgtctcgagc 36014120PRTArtificial Sequencesynthesized 14Gln Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser1 5 10 15Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Asn Tyr 20 25 30Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ala Cys Ile Tyr Val Gly Ser Ser Gly Asp Thr Tyr Tyr Ala Ser Ser 50 55 60Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu65 70 75 80Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Asp Ser Ser Ser Tyr Tyr Met Phe Asn Leu Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 12015336DNAArtificial Sequencesynthesized 15gcccttgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aggccagtga ggacattgat acctatttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatcttttat gcatccgatc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc ggttactata ctagtagtgc tgatacgagg 300ggtgctttcg gcggagggac caaggtggag atcaaa 33616112PRTArtificial Sequencesynthesized 16Ala Leu Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile Asp Thr Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Tyr Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Gly Tyr Tyr Thr Ser Ser 85 90 95Ala Asp Thr Arg Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 11017345DNAArtificial Sequencesynthesized 17cggtcgctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc 60tgtacagcct ctggattcac catcagtagc taccacatgc agtgggtccg ccaggctcca 120gggaaggggc tggagtacat cggaaccatt agtagtggtg gtaatgtata ctacgcgagc 180tccgcgagag gcagattcac catctccaga ccctcgtcca agaacacggt ggatcttcaa 240atgaacagcc tgagagccga ggacacggct gtgtattact gtgcgagaga ctctggttat 300agtgatccta tgtggggcca gggaaccctg gtcaccgtct cgagc 34518115PRTArtificial Sequencesynthesized 18Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser1 5 10 15Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser Ser Tyr His 20 25 30Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly 35 40 45Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser Ala Arg Gly 50 55 60Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val Asp Leu Gln65 70 75 80Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 85 90 95Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 11519333DNAArtificial Sequencesynthesized 19gacgttgtga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacctgtc aggccagtca gaacattagg acttacttat cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcagccaatc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcga cctggagcct 240ggcgatgctg caacttacta ttgtcagtct acctatcttg gtactgatta tgttggcggt 300gctttcggcg gagggaccaa ggtggagatc aaa 33320111PRTArtificial Sequencesynthesized 20Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro65 70 75 80Gly Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp 85 90 95Tyr Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 11021345DNAArtificial Sequencesynthesized 21gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggaat cgacttcagt aggagatact acatgtgctg ggtccgccag 120gctccaggga aggggctgga gtggatcgca tgcatatata ctggtagccg cgatactcct 180cactacgcga gctccgcgaa aggccggttc accatctcca gagacaattc caagaacacg 240ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccgtatatta ctgtgcgaga 300gaaggtagcc tgtggggcca gggaaccctg gtcaccgtct cgagc 34522115PRTArtificial Sequencesynthesized 22Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Asp Phe Ser Arg Arg 20 25 30Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Ala Cys Ile Tyr Thr Gly Ser Arg Asp Thr Pro His Tyr Ala Ser 50 55 60Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Glu Gly Ser Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 11523333DNAArtificial Sequencesynthesized 23gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc agtccagtca gagtgtttat agtaactggt tctcctggta tcagcagaaa 120ccagggaaag cccctaagct cctgatctat tctgcatcca ctctggcatc tggggtccca 180tcaaggttca gcggcagtgg atctgggaca gaattcactc tcaccatcag cagcctgcag 240cctgatgatt ttgcaactta ttactgcgca ggcggttaca atactgttat tgatactttt 300gctttcggcg gagggaccaa ggtggagatc aaa 33324111PRTArtificial Sequencesynthesized 24Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Ser Asn 20 25 30Trp Phe Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asn Thr Val 85 90 95Ile Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 11025366DNAArtificial Sequencesynthesized 25gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccatcagt cgctaccaca tgacttgggt ccgccaggct 120ccagggaagg ggctggagtg gatcggacat atttatgtta ataatgatga cacagactac 180gcgagctccg cgaaaggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccacct atttctgtgc gagattggat 300gttggtggtg gtggtgctta tattggggac atctggggcc agggaactct ggttaccgtc 360tcttca 36626122PRTArtificial Sequencesynthesized 26Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Arg Tyr 20 25 30His Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly His Ile Tyr Val Asn Asn Asp Asp Thr Asp Tyr Ala Ser Ser Ala 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Leu Asp Val Gly Gly Gly Gly Ala Tyr Ile Gly Asp Ile Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12027339DNAArtificial Sequencesynthesized 27gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc agtccagtca gagtgtttat aacaacaacg

acttagcctg gtatcagcag 120aaaccaggga aagttcctaa gctcctgatc tattatgctt ccactctggc atctggggtc 180ccatctcggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240cagcctgaag atgttgcaac ttattactgt gcaggcggtt atgatacgga tggtcttgat 300acgtttgctt tcggcggagg gaccaaggtg gagatcaaa 33928113PRTArtificial Sequencesynthesized 28Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Asn Asn 20 25 30Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu 35 40 45Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu65 70 75 80Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr 85 90 95Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys29345DNAArtificial Sequencesynthesized 29gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtactg cctctggatt ctccctcagt agctatgcaa tgagctgggt ccgccaggct 120ccagggaggg ggctggagtg gatcggaatc atttatgcta gtggtagcac atactacgcg 180agctcggcga aaggcagatt caccatctcc aaagacaata ccaagaacac ggtggatctt 240caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag aatttatgac 300ggcatggacc tctggggcca gggaactctg gttaccgtct cttca 34530115PRTArtificial Sequencesynthesized 30Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45Gly Ile Ile Tyr Ala Ser Gly Ser Thr Tyr Tyr Ala Ser Ser Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Asp Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Ile Tyr Asp Gly Met Asp Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 11531321DNAArtificial Sequencesynthesized 31gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aggccagtca gaacatttac agctacttat cctggtatca gcagaaacca 120gggaaagttc ctaagcgcct gatctatctg gcatctactc tggcatctgg ggtcccatct 180cggttcagtg gcagtggatc tgggacagat tacactctca ccatcagcag cctgcagcct 240gaagatgttg caacttatta ctgtcaaagc aattataacg gtaattatgg tttcggcgga 300gggaccaagg tggagatcaa a 32132107PRTArtificial Sequencesynthesized 32Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Ile Tyr Ser Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile 35 40 45Tyr Leu Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Ser Asn Tyr Asn Gly Asn Tyr 85 90 95Gly Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10533354DNAArtificial Sequencesynthesized 33gaggtgaagc tggatgagac tggaggaggc ttggtgcaac ctgggaggcc catgaaactc 60tcctgtgttg cctctggatt cacttttagt gactactgga tgaactgggt ccgccagtct 120ccagagaaag gactggagtg ggtagcacaa attagaaaca aaccttataa ttatgaaaca 180tattattcag attctgtgaa aggcagattc accatctcaa gagatgattc caaaagtagt 240gtctacctgc aaatgaacaa cttaagagtt gaagacatgg gtatctatta ctgtacgggt 300tcttactatg gtatggacta ctggggtcaa ggaacctcag tcaccgtctc ctca 35434118PRTArtificial Sequencesynthesized 34Glu Val Lys Leu Asp Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Pro Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val 35 40 45Ala Gln Ile Arg Asn Lys Pro Tyr Asn Tyr Glu Thr Tyr Tyr Ser Asp 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser65 70 75 80Val Tyr Leu Gln Met Asn Asn Leu Arg Val Glu Asp Met Gly Ile Tyr 85 90 95Tyr Cys Thr Gly Ser Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Ser Val Thr Val Ser Ser 11535336DNAArtificial Sequencesynthesized 35gatgtcgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60atctcttgca gatctagtca gagccttgta cacagtaatg gaaacaccta tttacgttgg 120tacctgcaga agccaggcca gtctccaaag gtcctgatct acaaagtttc caaccgattt 180tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttccg 300tggacgttcg gtggaggcac caagctggaa atcaaa 33636112PRTArtificial Sequencesynthesized 36Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly1 5 10 15Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30Asn Gly Asn Thr Tyr Leu Arg Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Lys Val Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 11037987DNAArtificial Sequencesynthesized 37gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgcgggggca 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcgcggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggt 98738329PRTArtificial Sequencesynthesized 38Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly 32539321DNAArtificial Sequencesynthesized 39cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300agcttcaaca ggggagagtg t 32140107PRTArtificial Sequencesynthesized 40Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu1 5 10 15Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu65 70 75 80Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105413681DNAArtificial Sequencesynthesized 41gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc agtccagtca gagtgtttat agtaactggt tctcctggta tcagcagaaa 120ccagggaaag cccctaagct cctgatctat tctgcatcca ctctggcatc tggggtccca 180tcaaggttca gcggcagtgg atctgggaca gaattcactc tcaccatcag cagcctgcag 240cctgatgatt ttgcaactta ttactgcgca ggcggttaca atactgttat tgatactttt 300gctttcggcg gagggaccaa ggtggagatc aaaggcggtg gcggtagtgg gggaggcggt 360tctggcggcg gagggtccgg cggtggagga tcagaggtgc agctgttgga gtctggggga 420ggcttggtac agcctggggg gtccctgaga ctctcctgtg cagcctctgg aatcgacttc 480agtaggagat actacatgtg ctgggtccgc caggctccag ggaaggggct ggagtggatc 540gcatgcatat atactggtag ccgcgatact cctcactacg cgagctccgc gaaaggccgg 600ttcaccatct ccagagacaa ttccaagaac acgctgtatc tgcaaatgaa cagcctgaga 660gccgaggaca cggccgtata ttactgtgcg agagaaggta gcctgtgggg ccagggaacc 720ctggtcaccg tctcgagcgg cggtggaggg tccggcggtg gtggatccca gtcggtggag 780gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tacagcctct 840ggaatcgacc ttaataccta cgacatgatc tgggtccgcc aggctccagg caaggggcta 900gagtgggttg gaatcattac ttatagtggt agtagatact acgcgaactg ggcgaaaggc 960cgattcacca tctccaaaga caataccaag aacacggtgt atctgcaaat gaacagcctg 1020agagctgagg acacggctgt gtattactgt gccagagatt atatgagtgg ttcccacttg 1080tggggccagg gaaccctggt caccgtctct agtgctagca ccaagggccc atcggtcttc 1140cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 1200aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 1260gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 1320accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 1380agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 1440ccaccgtgcc cagcacctga agccgcgggg gcaccgtcag tcttcctctt ccccccaaaa 1500cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1560agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1620gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1680accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcgcggt ctccaacaaa 1740gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1800caggtgtata ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 1860tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1920ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1980tatagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 2040gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 2100ggcggtggag ggtccggcgg tggtggatcc gaggtgcagc tgttggagtc tgggggaggc 2160ttggtacagc ctggggggtc cctgagactc tcctgtgcag cctctggatt caccatcagt 2220cgctaccaca tgacttgggt ccgccaggct ccagggaagg ggctggagtg gatcggacat 2280atttatgtta ataatgatga cacagactac gcgagctccg cgaaaggccg gttcaccatc 2340tccagagaca attccaagaa cacgctgtat ctgcaaatga acagcctgag agccgaggac 2400acggccacct atttctgtgc gagattggat gttggtggtg gtggtgctta tattggggac 2460atctggggcc agggaactct ggttaccgtc tcttcaggcg gtggcggtag tgggggaggc 2520ggttctggcg gcggagggtc cggcggtgga ggatcagaca tccagatgac ccagtctcca 2580tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccagtc cagtcagagt 2640gtttataaca acaacgactt agcctggtat cagcagaaac cagggaaagt tcctaagctc 2700ctgatctatt atgcttccac tctggcatct ggggtcccat ctcggttcag tggcagtgga 2760tctgggacag atttcactct caccatcagc agcctgcagc ctgaagatgt tgcaacttat 2820tactgtgcag gcggttatga tacggatggt cttgatacgt ttgctttcgg cggagggacc 2880aaggtggaga tcaaaggcgg tggagggtcc ggcggtggtg gatccgaggt gcagctggtg 2940gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tgcagcctct 3000ggattcacca tcagtaccaa tgcaatgagc tgggtccgcc aggctccagg gaaggggctg 3060gagtggatcg gagtcattac tggtcgtgat atcacatact acgcgagctg ggcgaaaggc 3120agattcacca tctccagaga caattccaag aacacgctgt atcttcaaat gaacagcctg 3180agagccgagg acacggctgt gtattactgt gcgcgcgacg gtggatcatc tgctattact 3240agtaacaaca tttggggcca aggaactctg gtcaccgttt cttcaggcgg tggcggtagt 3300gggggaggcg gttctggcgg cggagggtcc ggcggtggag gatcagacgt cgtgatgacc 3360cagtctcctt ccaccctgtc tgcatctgta ggagacagag tcaccatcaa ttgccaagcc 3420agtgagagca ttagcagttg gttagcctgg tatcagcaga aaccagggaa agcccctaag 3480ctcctgatct atgaagcatc caaactggca tctggggtcc catcaaggtt cagcggcagt 3540ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 3600tattactgcc aaggctattt ttattttatt agtcgtactt atgtaaattc tttcggcgga 3660gggaccaagg tggagatcaa a 3681421227PRTArtificial Sequencesynthesized 42Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Ser Asn 20 25 30Trp Phe Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45Ile Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asn Thr Val 85 90 95Ile Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly 100 105 110Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln 130 135 140Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Asp Phe145 150 155 160Ser Arg Arg Tyr Tyr Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175Leu Glu Trp Ile Ala Cys Ile Tyr Thr Gly Ser Arg Asp Thr Pro His 180 185 190Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 195 200 205Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 210 215 220Ala Val Tyr Tyr Cys Ala Arg Glu Gly Ser Leu Trp Gly Gln Gly Thr225 230 235 240Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser 260 265

270Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp 275 280 285Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 290 295 300Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly305 310 315 320Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln 325 330 335Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 340 345 350Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr 355 360 365Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 370 375 380Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val385 390 395 400Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 405 410 415Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 420 425 430Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 435 440 445Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 450 455 460Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys465 470 475 480Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu 485 490 495Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 500 505 510Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 515 520 525Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 530 535 540Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu545 550 555 560Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala 565 570 575Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 580 585 590Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 595 600 605Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 610 615 620Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln625 630 635 640Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 645 650 655Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 660 665 670Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 675 680 685His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly 690 695 700Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly705 710 715 720Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 725 730 735Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly 740 745 750Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr 755 760 765Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 770 775 780Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp785 790 795 800Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala 805 810 815Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 820 825 830Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 835 840 845Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 850 855 860Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser865 870 875 880Val Tyr Asn Asn Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 885 890 895Val Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val 900 905 910Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 915 920 925Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly 930 935 940Gly Tyr Asp Thr Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr945 950 955 960Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 965 970 975Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser 980 985 990Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn Ala 995 1000 1005Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 1010 1015 1020Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala 1025 1030 1035Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 1040 1045 1050Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 1055 1060 1065Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn 1070 1075 1080Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 1085 1090 1095Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1100 1105 1110Gly Ser Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala 1115 1120 1125Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser 1130 1135 1140Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 1145 1150 1155Pro Lys Leu Leu Ile Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val 1160 1165 1170Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu 1175 1180 1185Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys 1190 1195 1200Gln Gly Tyr Phe Tyr Phe Ile Ser Arg Thr Tyr Val Asn Ser Phe 1205 1210 1215Gly Gly Gly Thr Lys Val Glu Ile Lys 1220 122543651DNAArtificial Sequencesynthesized 43gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300ttcggcggag ggaccaaggt ggagatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 65144217PRTArtificial Sequencesynthesized 44Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45His Ser Ala Ser Ser Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Lys Asn Asn 85 90 95Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21545360DNAArtificial SequenceSynthesized 45gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccatcagt accaatgcaa tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg gatcggagtc attactggtc gtgatatcac atactacgcg 180agctgggcga aaggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agacggtggt 300tcttctgcta ttactagtaa caacatttgg ggccagggaa ccctggtcac cgtgtcgaca 36046120PRTArtificial SequenceSynthesized 46Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Thr 115 12047363DNAArtificial SequenceSynthesized 47gaggtgcagc tggtgcagtc tggagcagag gtgaagaaac caggagagtc tctgaagatc 60tcctgtaagg gttctggata cagctttagc agttcatgga tcggctgggt gcgccaggca 120cctgggaaag gcctggaatg gatggggatc atctatcctg atgactctga taccagatac 180agtccatcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag gactgcctac 240ctgcagtgga gtagcctgaa ggcctcggac accgctatgt attactgtgc gagacatgtt 300actatgattt ggggagttat tattgacttc tggggccagg gaaccctggt caccgtctcc 360tca 36348121PRTArtificial SequenceSynthesized 48Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu1 5 10 15Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Ser Ser 20 25 30Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Arg Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg His Val Thr Met Ile Trp Gly Val Ile Ile Asp Phe Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12049321DNAArtificial SequenceSynthesized 49gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300gggaccaaag tggatatcaa a 32150107PRTArtificial SequenceSynthesized 50Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 10551348DNAArtificial SequenceSynthesized 51gatgtgcagc ttcaggagtc gggacctagc ctggtgaaac cttctcagtc tctgtccctc 60acctgcactg tcactggcta ctcaatcacc agtgattttg cctggaactg gattcggcag 120tttccaggaa acaagctgga gtggatgggc tacataagtt atagtggtaa cactaggtac 180aacccatctc tcaaaagtcg aatctctatc actcgcgaca catccaagaa ccaattcttc 240ctgcagttga actctgtgac tattgaggac acagccacat attactgtgt aacggcggga 300cgcgggtttc cttattgggg ccaagggact ctggtcactg tctctgca 34852116PRTArtificial SequenceSynthesized 52Asp Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln1 5 10 15Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp 20 25 30Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp 35 40 45Met Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu 50 55 60Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe65 70 75 80Leu Gln Leu Asn Ser Val Thr Ile Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Val Thr Ala Gly Arg Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ala 11553321DNAArtificial SequenceSynthesized 53gacatcctga tgacccaatc tccatcctcc atgtctgtat ctctgggaga cacagtcagc 60atcacttgcc attcaagtca ggacattaac agtaatatag ggtggttgca gcagagacca 120gggaaatcat ttaagggcct gatctatcat ggaaccaact tggacgatga agttccatca 180aggttcagtg gcagtggatc tggagccgat tattctctca ccatcagcag cctggaatct 240gaagattttg cagactatta ctgtgtacag tatgctcagt ttccgtggac gttcggtgga 300ggcaccaagc tggaaatcaa a 32154107PRTArtificial SequenceSynthesized 54Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly1 5 10 15Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn 20 25 30Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile 35 40 45Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser65 70 75 80Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 1055533DNAArtificial SequenceSynthesized 55ggcggtggag ggtccggcgg tggtggctcc gga 335611PRTArtificial SequenceSynthesized 56Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly1 5 105730DNAArtificial SequenceSynthesized 57ggcggtggag ggtccggcgg tggtggatca 305810PRTArtificial SequenceSynthesized 58Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 105930DNAArtificial SequenceSynthesized 59ggcggtggag ggtccggcgg tggtggatcc 306010PRTArtificial SequenceSynthesized 60Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser1 5 106160DNAArtificial SequenceSynthesized 61ggcggtggcg gtagtggggg aggcggttct ggcggcggag ggtccggcgg tggaggatca 606220PRTArtificial SequenceSynthesized 62Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly1 5 10 15Gly Gly Gly Ser 20633693DNAArtificial SequenceSynthesized 63gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc

540ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660gacacggctg tgtattactg tgcgcgcgac ggtggatcat ctgctattac tagtaacaac 720atttggggcc aaggaactct ggtcaccgtt tcttcaggcg gtggagggtc cggcggtggt 780ggatccgatg tgcagcttca ggagtcggga cctagcctgg tgaaaccttc tcagtctctg 840tccctcacct gcactgtcac tggctactca atcaccagtg attttgcctg gaactggatt 900cggcagtttc caggaaacaa gctggagtgg atgggctaca taagttatag tggtaacact 960aggtacaacc catctctcaa aagtcgaatc tctatcactc gcgacacatc caagaaccaa 1020ttcttcctgc agttgaactc tgtgactatt gaggacacag ccacatatta ctgtgtaacg 1080gcgggacgcg ggtttcctta ttggggccaa gggactctgg tcactgtctc tgcagctagc 1140accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 1200gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 1260tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 1320tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 1380tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 1440tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 1500gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1560acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1620gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1680taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1740aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1800aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1860aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1920gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1980tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 2040gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 2100agcctctccc tgtctccggg tggcggtgga gggtccggcg gtggtggatc cgaggtgcag 2160ctgttggagt ctgggggagg cttggtacag cctggggggt ccctgagact ctcctgtgca 2220gcctctggat tctccttcag tagcgggtac gacatgtgct gggtccgcca ggctccaggg 2280aaggggctgg agtggatcgc atgcattgct gctggtagtg ctggtatcac ttacgacgcg 2340aactgggcga aaggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 2400caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgag atcggcgttt 2460tcgttcgact acgccatgga cctctggggc cagggaaccc tggtcaccgt ctcgagcggc 2520ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagac 2580atccagatga cccagtctcc ttccaccctg tctgcatctg taggagacag agtcaccatc 2640acttgccagg ccagtcagag cattagttcc cacttaaact ggtatcagca gaaaccaggg 2700aaagccccta agctcctgat ctataaggca tccactctgg catctggggt cccatcaagg 2760ttcagcggca gtggatctgg gacagaattt actctcacca tcagcagcct gcagcctgat 2820gattttgcaa cttattactg ccaacagggt tatagttggg gtaatgttga taatgttttc 2880ggcggaggga ccaaggtgga gatcaaaggc ggtggagggt ccggcggtgg tggatcccag 2940tcgctggtgg agtctggggg aggcttggta cagcctgggg ggtccctgag actctcctgt 3000gcagcctctg gattctcctt cagtagcaac tactggatat gctgggtccg ccaggctcca 3060gggaaggggc tggagtggat cgcatgtatt tatgttggta gtagtggtga cacttactac 3120gcgagctccg cgaaaggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 3180ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gagagatagt 3240agtagttatt atatgtttaa cttgtggggc cagggaaccc tggtcaccgt ctcttcaggc 3300ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagcc 3360cttgtgatga cccagtctcc ttccaccctg tctgcatctg taggagacag agtcaccatc 3420aattgccagg ccagtgagga cattgatacc tatttagcct ggtatcagca gaaaccaggg 3480aaagccccta agctcctgat cttttacgca tccgatctgg catctggggt cccatcaagg 3540ttcagcggca gtggatctgg gacagaattt actctcacca tcagcagcct gcagcctgat 3600gattttgcaa cttattactg ccaaggcggt tactatacta gtagtgctga tacgaggggt 3660gctttcggcg gagggaccaa ggtggagatc aaa 3693641231PRTArtificial SequenceSynthesized 64Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr145 150 155 160Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala 180 185 190Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 195 200 205Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn225 230 235 240Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 245 250 255Ser Gly Gly Gly Gly Ser Asp Val Gln Leu Gln Glu Ser Gly Pro Ser 260 265 270Leu Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Thr Gly 275 280 285Tyr Ser Ile Thr Ser Asp Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro 290 295 300Gly Asn Lys Leu Glu Trp Met Gly Tyr Ile Ser Tyr Ser Gly Asn Thr305 310 315 320Arg Tyr Asn Pro Ser Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr 325 330 335Ser Lys Asn Gln Phe Phe Leu Gln Leu Asn Ser Val Thr Ile Glu Asp 340 345 350Thr Ala Thr Tyr Tyr Cys Val Thr Ala Gly Arg Gly Phe Pro Tyr Trp 355 360 365Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro 370 375 380Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr385 390 395 400Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 405 410 415Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 420 425 430Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 435 440 445Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 450 455 460His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser465 470 475 480Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 485 490 495Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 500 505 510Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 515 520 525His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 530 535 540Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr545 550 555 560Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 565 570 575Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro 580 585 590Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 595 600 605Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 610 615 620Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val625 630 635 640Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 645 650 655Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 660 665 670Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 675 680 685Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 690 695 700Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln705 710 715 720Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg 725 730 735Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Gly Tyr Asp Met 740 745 750Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys 755 760 765Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp Ala Asn Trp Ala Lys 770 775 780Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu785 790 795 800Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 805 810 815Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp Leu Trp Gly Gln Gly 820 825 830Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 835 840 845Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 850 855 860Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile865 870 875 880Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln 885 890 895Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr 900 905 910Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 915 920 925Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr 930 935 940Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn Val Asp Asn Val Phe945 950 955 960Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly 965 970 975Gly Gly Ser Gln Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 980 985 990Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser 995 1000 1005Ser Asn Tyr Trp Ile Cys Trp Val Arg Gln Ala Pro Gly Lys Gly 1010 1015 1020Leu Glu Trp Ile Ala Cys Ile Tyr Val Gly Ser Ser Gly Asp Thr 1025 1030 1035Tyr Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp 1040 1045 1050Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala 1055 1060 1065Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Ser Ser Tyr 1070 1075 1080Tyr Met Phe Asn Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser 1085 1090 1095Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1100 1105 1110Ser Gly Gly Gly Gly Ser Ala Leu Val Met Thr Gln Ser Pro Ser 1115 1120 1125Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln 1130 1135 1140Ala Ser Glu Asp Ile Asp Thr Tyr Leu Ala Trp Tyr Gln Gln Lys 1145 1150 1155Pro Gly Lys Ala Pro Lys Leu Leu Ile Phe Tyr Ala Ser Asp Leu 1160 1165 1170Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 1175 1180 1185Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala 1190 1195 1200Thr Tyr Tyr Cys Gln Gly Gly Tyr Tyr Thr Ser Ser Ala Asp Thr 1205 1210 1215Arg Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1220 1225 123065642DNAArtificial SequenceSynthesized 65gacatcctga tgacccaatc tccatcctcc atgtctgtat ctctgggaga cacagtcagc 60atcacttgcc attcaagtca ggacattaac agtaatatag ggtggttgca gcagagacca 120gggaaatcat ttaagggcct gatctatcat ggaaccaact tggacgatga agttccatca 180aggttcagtg gcagtggatc tggagccgat tattctctca ccatcagcag cctggaatct 240gaagattttg cagactatta ctgtgtacag tatgctcagt ttccgtggac gttcggtgga 300ggcaccaagc tggaaatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 64266214PRTArtificial SequenceSynthesized 66Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly1 5 10 15Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn 20 25 30Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile 35 40 45Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser65 70 75 80Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210673678DNAArtificial SequenceSynthesized 67gacatcctga tgacccaatc tccatcctcc atgtctgtat ctctgggaga cacagtcagc 60atcacttgcc attcaagtca ggacattaac agtaatatag ggtggttgca gcagagacca 120gggaaatcat ttaagggcct gatctatcat ggaaccaact tggacgatga agttccatca 180aggttcagtg gcagtggatc tggagccgat tattctctca ccatcagcag cctggaatct 240gaagattttg cagactatta ctgtgtacag tatgctcagt ttccgtggac gttcggtgga 300ggcaccaagc tggaaatcaa aggcggtggc ggtagtgggg gaggcggttc tggcggcgga 360gggtccggcg gtggaggatc agatgtgcag cttcaggagt cgggacctag cctggtgaaa 420ccttctcagt ctctgtccct cacctgcact gtcactggct actcaatcac cagtgatttt 480gcctggaact ggattcggca gtttccagga aacaagctgg agtggatggg ctacataagt 540tatagtggta acactaggta caacccatct ctcaaaagtc gaatctctat cactcgcgac 600acatccaaga accaattctt cctgcagttg aactctgtga ctattgagga cacagccaca 660tattactgtg taacggcggg acgcgggttt ccttattggg gccaagggac tctggtcact 720gtctctgcag gcggtggagg gtccggcggt ggtggatccg aggtgcagct ggtggagtct 780gggggaggct tggtccagcc tggggggtcc ctgagactct cctgtgcagc ctctggattc 840accatcagta ccaatgcaat gagctgggtc cgccaggctc cagggaaggg gctggagtgg 900atcggagtca ttactggtcg tgatatcaca tactacgcga gctgggcgaa aggcagattc 960accatctcca gagacaattc caagaacacg ctgtatcttc aaatgaacag cctgagagcc 1020gaggacacgg ctgtgtatta ctgtgcgcgc gacggtggat catctgctat tactagtaac 1080aacatttggg gccaaggaac tctggtcacc gtttcttcag ctagcaccaa gggcccatcg 1140gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 1200ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 1260agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 1320gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 1380aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 1440acatgcccac cgtgcccagc acctgaagcc gcgggggcac cgtcagtctt cctcttcccc 1500ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 1560gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 1620cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1680gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg cgcggtctcc 1740aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1800gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1860ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1920gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1980ttcctctata gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 2040tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 2100ccgggtggcg gtggagggtc cggcggtggt ggatccgagg tgcagctgtt ggagtctggg 2160ggaggcttgg tacagcctgg ggggtccctg agactctcct gtgcagcctc tggattctcc 2220ttcagtagcg ggtacgacat gtgctgggtc cgccaggctc

cagggaaggg gctggagtgg 2280atcgcatgca ttgctgctgg tagtgctggt atcacttacg acgcgaactg ggcgaaaggc 2340cggttcacca tctccagaga caattccaag aacacgctgt atctgcaaat gaacagcctg 2400agagccgagg acacggccgt atattactgt gcgagatcgg cgttttcgtt cgactacgcc 2460atggacctct ggggccaggg aaccctggtc accgtctcga gcggcggtgg cggtagtggg 2520ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagacatcca gatgacccag 2580tctccttcca ccctgtctgc atctgtagga gacagagtca ccatcacttg ccaggccagt 2640cagagcatta gttcccactt aaactggtat cagcagaaac cagggaaagc ccctaagctc 2700ctgatctata aggcatccac tctggcatct ggggtcccat caaggttcag cggcagtgga 2760tctgggacag aatttactct caccatcagc agcctgcagc ctgatgattt tgcaacttat 2820tactgccaac agggttatag ttggggtaat gttgataatg ttttcggcgg agggaccaag 2880gtggagatca aaggcggtgg agggtccggc ggtggtggat cccagtcgct ggtggagtct 2940gggggaggct tggtacagcc tggggggtcc ctgagactct cctgtgcagc ctctggattc 3000tccttcagta gcaactactg gatatgctgg gtccgccagg ctccagggaa ggggctggag 3060tggatcgcat gtatttatgt tggtagtagt ggtgacactt actacgcgag ctccgcgaaa 3120ggccggttca ccatctccag agacaattcc aagaacacgc tgtatctgca aatgaacagc 3180ctgagagccg aggacacggc cgtatattac tgtgcgagag atagtagtag ttattatatg 3240tttaacttgt ggggccaggg aaccctggtc accgtctctt caggcggtgg cggtagtggg 3300ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagcccttgt gatgacccag 3360tctccttcca ccctgtctgc atctgtagga gacagagtca ccatcaattg ccaggccagt 3420gaggacattg atacctattt agcctggtat cagcagaaac cagggaaagc ccctaagctc 3480ctgatctttt acgcatccga tctggcatct ggggtcccat caaggttcag cggcagtgga 3540tctgggacag aatttactct caccatcagc agcctgcagc ctgatgattt tgcaacttat 3600tactgccaag gcggttacta tactagtagt gctgatacga ggggtgcttt cggcggaggg 3660accaaggtgg agatcaaa 3678681226PRTArtificial SequenceSynthesized 68Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly1 5 10 15Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn 20 25 30Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile 35 40 45Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser65 70 75 80Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 115 120 125Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln Ser 130 135 140Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Phe145 150 155 160Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 165 170 175Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu Lys 180 185 190Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 195 200 205Gln Leu Asn Ser Val Thr Ile Glu Asp Thr Ala Thr Tyr Tyr Cys Val 210 215 220Thr Ala Gly Arg Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr225 230 235 240Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln 245 250 255Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg 260 265 270Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn Ala Met Ser 275 280 285Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile 290 295 300Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala Lys Gly Arg Phe305 310 315 320Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn 325 330 335Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly 340 345 350Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp Gly Gln Gly Thr Leu 355 360 365Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 370 375 380Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys385 390 395 400Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 405 410 415Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 420 425 430Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 435 440 445Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 450 455 460Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His465 470 475 480Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val 485 490 495Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 500 505 510Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 515 520 525Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 530 535 540Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser545 550 555 560Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 565 570 575Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 580 585 590Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 595 600 605Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 610 615 620Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn625 630 635 640Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 645 650 655Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 660 665 670Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 675 680 685His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly 690 695 700Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly705 710 715 720Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 725 730 735Ser Gly Phe Ser Phe Ser Ser Gly Tyr Asp Met Cys Trp Val Arg Gln 740 745 750Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys Ile Ala Ala Gly Ser 755 760 765Ala Gly Ile Thr Tyr Asp Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile 770 775 780Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu785 790 795 800Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Ala Phe Ser 805 810 815Phe Asp Tyr Ala Met Asp Leu Trp Gly Gln Gly Thr Leu Val Thr Val 820 825 830Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 835 840 845Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr 850 855 860Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser865 870 875 880Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 885 890 895Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val 900 905 910Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr 915 920 925Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 930 935 940Gly Tyr Ser Trp Gly Asn Val Asp Asn Val Phe Gly Gly Gly Thr Lys945 950 955 960Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser 965 970 975Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg 980 985 990Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Asn Tyr Trp Ile 995 1000 1005Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala 1010 1015 1020Cys Ile Tyr Val Gly Ser Ser Gly Asp Thr Tyr Tyr Ala Ser Ser 1025 1030 1035Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 1040 1045 1050Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 1055 1060 1065Tyr Tyr Cys Ala Arg Asp Ser Ser Ser Tyr Tyr Met Phe Asn Leu 1070 1075 1080Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 1085 1090 1095Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1100 1105 1110Ser Ala Leu Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser 1115 1120 1125Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Asp Ile 1130 1135 1140Asp Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 1145 1150 1155Lys Leu Leu Ile Phe Tyr Ala Ser Asp Leu Ala Ser Gly Val Pro 1160 1165 1170Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr 1175 1180 1185Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln 1190 1195 1200Gly Gly Tyr Tyr Thr Ser Ser Ala Asp Thr Arg Gly Ala Phe Gly 1205 1210 1215Gly Gly Thr Lys Val Glu Ile Lys 1220 122569657DNAArtificial SequenceSynthesized 69gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 65770219PRTArtificial SequenceSynthesized 70Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215713681DNAArtificial SequenceSynthesized 71gacgttgtga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcacctgtc aggccagtca gaacattagg acttacttat cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcagccaatc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcga cctggagcct 240ggcgatgctg caacttacta ttgtcagtct acctatcttg gtactgatta tgttggcggt 300gctttcggcg gagggaccaa ggtggagatc aaaggcggtg gcggtagtgg gggaggcggt 360tctggcggcg gagggtccgg cggtggagga tcacggtcgc tggtggagtc tgggggaggc 420ttggtccagc ctggggggtc cctgagactc tcctgtacag cctctggatt caccatcagt 480agctaccaca tgcagtgggt ccgccaggct ccagggaagg ggctggagta catcggaacc 540attagtagtg gtggtaatgt atactacgcg agctccgcga gaggcagatt caccatctcc 600agaccctcgt ccaagaacac ggtggatctt caaatgaaca gcctgagagc cgaggacacg 660gctgtgtatt actgtgcgag agactctggt tatagtgatc ctatgtgggg ccagggaacc 720ctggtcaccg tctcgagcgg cggtggaggg tccggcggtg gtggatccca gtcggtggag 780gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tacagcctct 840ggaatcgacc ttaataccta cgacatgatc tgggtccgcc aggctccagg caaggggcta 900gagtgggttg gaatcattac ttatagtggt agtagatact acgcgaactg ggcgaaaggc 960cgattcacca tctccaaaga caataccaag aacacggtgt atctgcaaat gaacagcctg 1020agagctgagg acacggctgt gtattactgt gccagagatt atatgagtgg ttcccacttg 1080tggggccagg gaaccctggt caccgtctct agtgctagca ccaagggccc atcggtcttc 1140cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 1200aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 1260gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 1320accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 1380agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 1440ccaccgtgcc cagcacctga agccgcgggg gcaccgtcag tcttcctctt ccccccaaaa 1500cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1560agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1620gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1680accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcgcggt ctccaacaaa 1740gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1800caggtgtata ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgacc 1860tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1920ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1980tatagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 2040gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 2100ggcggtggag ggtccggcgg tggtggatcc gaggtgcagc tgttggagtc tgggggaggc 2160ttggtacagc ctggggggtc cctgagactc tcctgtgcag cctctggatt caccatcagt 2220cgctaccaca tgacttgggt ccgccaggct ccagggaagg ggctggagtg gatcggacat 2280atttatgtta ataatgatga cacagactac gcgagctccg cgaaaggccg gttcaccatc 2340tccagagaca attccaagaa cacgctgtat ctgcaaatga acagcctgag agccgaggac 2400acggccacct atttctgtgc gagattggat gttggtggtg gtggtgctta tattggggac 2460atctggggcc agggaactct ggttaccgtc tcttcaggcg gtggcggtag tgggggaggc 2520ggttctggcg gcggagggtc cggcggtgga ggatcagaca tccagatgac ccagtctcca 2580tcctccctgt ctgcatctgt aggagacaga gtcaccatca cttgccagtc cagtcagagt 2640gtttataaca acaacgactt agcctggtat cagcagaaac cagggaaagt tcctaagctc 2700ctgatctatt atgcttccac tctggcatct ggggtcccat ctcggttcag tggcagtgga 2760tctgggacag atttcactct caccatcagc agcctgcagc ctgaagatgt tgcaacttat 2820tactgtgcag gcggttatga tacggatggt cttgatacgt ttgctttcgg cggagggacc 2880aaggtggaga tcaaaggcgg tggagggtcc ggcggtggtg gatccgaggt gcagctggtg 2940gagtctgggg gaggcttggt ccagcctggg gggtccctga gactctcctg tgcagcctct 3000ggattcacca tcagtaccaa tgcaatgagc tgggtccgcc aggctccagg gaaggggctg 3060gagtggatcg gagtcattac tggtcgtgat atcacatact acgcgagctg ggcgaaaggc 3120agattcacca tctccagaga caattccaag aacacgctgt atcttcaaat gaacagcctg 3180agagccgagg acacggctgt gtattactgt gcgcgcgacg gtggatcatc tgctattact 3240agtaacaaca tttggggcca aggaactctg gtcaccgttt cttcaggcgg tggcggtagt 3300gggggaggcg gttctggcgg cggagggtcc ggcggtggag gatcagacgt cgtgatgacc 3360cagtctcctt ccaccctgtc tgcatctgta ggagacagag tcaccatcaa ttgccaagcc 3420agtgagagca ttagcagttg gttagcctgg tatcagcaga aaccagggaa agcccctaag 3480ctcctgatct atgaagcatc caaactggca tctggggtcc catcaaggtt cagcggcagt 3540ggatctggga cagagttcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 3600tattactgcc aaggctattt ttattttatt agtcgtactt atgtaaattc tttcggcgga 3660gggaccaagg tggagatcaa a 3681721227PRTArtificial SequenceSynthesized 72Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr 20 25 30Leu Ser Trp Tyr Gln Gln Lys Pro

Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro65 70 75 80Gly Asp Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp 85 90 95Tyr Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly 100 105 110Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125Gly Gly Ser Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser145 150 155 160Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 165 170 175Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala Ser Ser 180 185 190Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys Asn Thr Val 195 200 205Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 210 215 220Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr225 230 235 240Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser 260 265 270Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn Thr Tyr Asp 275 280 285Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 290 295 300Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp Ala Lys Gly305 310 315 320Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val Tyr Leu Gln 325 330 335Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 340 345 350Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr Leu Val Thr 355 360 365Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 370 375 380Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val385 390 395 400Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 405 410 415Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 420 425 430Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 435 440 445Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 450 455 460Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys465 470 475 480Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu 485 490 495Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 500 505 510Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 515 520 525Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 530 535 540Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu545 550 555 560Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala 565 570 575Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 580 585 590Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 595 600 605Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 610 615 620Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln625 630 635 640Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 645 650 655Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 660 665 670Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 675 680 685His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly 690 695 700Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly705 710 715 720Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 725 730 735Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly 740 745 750Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr 755 760 765Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 770 775 780Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp785 790 795 800Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala 805 810 815Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 820 825 830Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 835 840 845Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 850 855 860Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser865 870 875 880Val Tyr Asn Asn Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 885 890 895Val Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val 900 905 910Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 915 920 925Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly 930 935 940Gly Tyr Asp Thr Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr945 950 955 960Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 965 970 975Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser 980 985 990Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Thr Asn Ala 995 1000 1005Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 1010 1015 1020Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp Ala 1025 1030 1035Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 1040 1045 1050Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 1055 1060 1065Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn 1070 1075 1080Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 1085 1090 1095Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 1100 1105 1110Gly Ser Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala 1115 1120 1125Ser Val Gly Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser 1130 1135 1140Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 1145 1150 1155Pro Lys Leu Leu Ile Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val 1160 1165 1170Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu 1175 1180 1185Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys 1190 1195 1200Gln Gly Tyr Phe Tyr Phe Ile Ser Arg Thr Tyr Val Asn Ser Phe 1205 1210 1215Gly Gly Gly Thr Lys Val Glu Ile Lys 1220 122573651DNAArtificial SequenceSynthesized 73gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300ttcggcggag ggaccaaggt ggagatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 65174217PRTArtificial SequenceSynthesized 74Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45His Ser Ala Ser Ser Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Lys Asn Asn 85 90 95Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215753687DNAArtificial SequenceSynthesized 75gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660gacacggctg tgtattactg tgcgagagac ggtggttctt ctgctattac tagtaacaac 720atttggggcc agggaaccct ggtcaccgtg tcgacaggcg gtggagggtc cggcggtggt 780ggatcccagt cggtggagga gtctggggga ggcttggtcc agcctggggg gtccctgaga 840ctctcctgta ccgcctctgg aatcgacctt aatacctacg acatgatctg ggtccgccag 900gctccaggca aggggctaga gtgggttgga atcattactt atagtggtag tagatactac 960gcgaactggg cgaaaggccg attcaccatc tccaaagaca ataccaagaa cacggtgtat 1020ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagattat 1080atgagtggtt cccacttgtg gggccaggga accctggtca ccgtctcttc agctagcacc 1140aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 1200gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 1260ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 1320tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 1380aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 1440gacaaaactc acacatgccc accgtgccca gcacctgaag ccgcgggggc accgtcagtc 1500ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1560tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1620ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1680cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1740tgcgcggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1800gggcagcccc gagaaccaca ggtgtatacc ctgcccccat cccgggatga gctgaccaag 1860aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1920tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1980gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg 2040aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 2100ctctccctgt ctccgggtgg cggtggaggg tccggcggtg gtgggtccgg agaggtgcag 2160ctgttggagt ctgggggagg cttggtacag cctggggggt ccctgagact ctcctgtgca 2220gcctctggat tcaccatcag tcgctaccac atgacttggg tccgccaggc tccagggaag 2280gggctggagt ggatcggaca tatttatgtt aataatgatg acacagacta cgcgagctcc 2340gcgaaaggcc ggttcaccat ctccagagac aattccaaga acacgctgta tctgcaaatg 2400aacagcctga gagccgagga cacggccacc tatttctgtg cgagattgga tgttggtggt 2460ggtggtgctt atattgggga catctggggc cagggaactc tggttaccgt ctcttcaggc 2520ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagac 2580atccagatga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 2640acttgccagt ccagtcagag tgtttataac aacaacgact tagcctggta tcagcagaaa 2700ccagggaaag ttcctaagct cctgatctat tatgcttcca ctctggcatc tggggtccca 2760tctcggttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 2820cctgaagatg ttgcaactta ttactgtgca ggcggttatg atacggatgg tcttgatacg 2880tttgctttcg gcggagggac caaggtggag atcaaaggcg gtggagggtc cggcggtggt 2940gggtccggac ggtcgctggt ggagtctggg ggaggcttgg tccagcctgg ggggtccctg 3000agactctcct gtactgcctc tggattcacc atcagtagct accacatgca gtgggtccgc 3060caggctccag ggaaggggct ggagtacatc ggaaccatta gtagtggtgg taatgtatac 3120tacgcaagct ccgctagagg cagattcacc atctccagac cctcgtccaa gaacacggtg 3180gatcttcaaa tgaacagcct gagagccgag gacacggctg tgtattactg tgcgagagac 3240tctggttata gtgatcctat gtggggccag ggaaccctgg tcaccgtctc ttcaggcggt 3300ggcggtagtg ggggaggcgg ttctggcggc ggagggtccg gcggtggagg atcagacgtt 3360gtgatgaccc agtctccatc ttccgtgtct gcatctgtag gagacagagt caccatcacc 3420tgtcaggcca gtcagaacat taggacttac ttatcctggt atcagcagaa accagggaaa 3480gcccctaagc tcctgatcta tgctgcagcc aatctggcat ctggggtccc atcaaggttc 3540agcggcagtg gatctgggac agatttcact ctcaccatca gcgacctgga gcctggcgat 3600gctgcaactt actattgtca gtctacctat cttggtactg attatgttgg cggtgctttc 3660ggcggaggga ccaaggtgga gatcaaa 3687761229PRTArtificial SequenceSynthesized 76Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr145 150 155 160Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala 180 185 190Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 195 200 205Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn225 230 235 240Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Gly Gly Gly Gly 245 250 255Ser Gly Gly Gly Gly Ser Gln Ser Val Glu Glu Ser Gly Gly Gly Leu 260 265 270Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile 275 280 285Asp Leu Asn Thr Tyr Asp Met Ile Trp Val Arg Gln Ala Pro Gly Lys 290 295 300Gly Leu Glu Trp Val Gly Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr305 310 315 320Ala Asn Trp Ala Lys Gly Arg

Phe Thr Ile Ser Lys Asp Asn Thr Lys 325 330 335Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 340 345 350Val Tyr Tyr Cys Ala Arg Asp Tyr Met Ser Gly Ser His Leu Trp Gly 355 360 365Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 370 375 380Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala385 390 395 400Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 405 410 415Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 420 425 430Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 435 440 445Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 450 455 460Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys465 470 475 480Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 485 490 495Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 500 505 510Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 515 520 525Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 530 535 540His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr545 550 555 560Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 565 570 575Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 580 585 590Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 595 600 605Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 610 615 620Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu625 630 635 640Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 645 650 655Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 660 665 670Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 675 680 685His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 690 695 700Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Glu Val Gln705 710 715 720Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg 725 730 735Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Arg Tyr His Met Thr 740 745 750Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile 755 760 765Tyr Val Asn Asn Asp Asp Thr Asp Tyr Ala Ser Ser Ala Lys Gly Arg 770 775 780Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met785 790 795 800Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Leu 805 810 815Asp Val Gly Gly Gly Gly Ala Tyr Ile Gly Asp Ile Trp Gly Gln Gly 820 825 830Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 835 840 845Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 850 855 860Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile865 870 875 880Thr Cys Gln Ser Ser Gln Ser Val Tyr Asn Asn Asn Asp Leu Ala Trp 885 890 895Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Tyr Ala 900 905 910Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 915 920 925Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val 930 935 940Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr Asp Gly Leu Asp Thr945 950 955 960Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly 965 970 975Ser Gly Gly Gly Gly Ser Gly Arg Ser Leu Val Glu Ser Gly Gly Gly 980 985 990Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly 995 1000 1005Phe Thr Ile Ser Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro 1010 1015 1020Gly Lys Gly Leu Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn 1025 1030 1035Val Tyr Tyr Ala Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser Arg 1040 1045 1050Pro Ser Ser Lys Asn Thr Val Asp Leu Gln Met Asn Ser Leu Arg 1055 1060 1065Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly Tyr 1070 1075 1080Ser Asp Pro Met Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1085 1090 1095Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1100 1105 1110Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Ser Ser 1115 1120 1125Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 1130 1135 1140Ser Gln Asn Ile Arg Thr Tyr Leu Ser Trp Tyr Gln Gln Lys Pro 1145 1150 1155Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ala Asn Leu Ala 1160 1165 1170Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 1175 1180 1185Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly Asp Ala Ala Thr 1190 1195 1200Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr Val Gly Gly 1205 1210 1215Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1220 122577651DNAArtificial SequenceSynthesized 77gcctatgata tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60atcaagtgtc aggccagtga ggacatttat agcttcttgg cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatccattct gcatcctctc tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtcaacag ggttatggta aaaataatgt tgataatgct 300ttcggcggag ggaccaaggt ggagatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 65178217PRTArtificial SequenceSynthesized 78Ala Tyr Asp Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Lys Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45His Ser Ala Ser Ser Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Lys Asn Asn 85 90 95Val Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215793675DNAArtificial SequenceSynthesized 79gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660gacacggctg tgtattactg tgcgagagac ggtggttctt ctgctattac tagtaacaac 720atttggggcc agggaaccct ggtcaccgtg tcgacaggcg gtggagggtc cggcggtggt 780ggatccgagg tgcagctgtt ggagtctggg ggaggcttgg tacagcctgg ggggtccctg 840agactctcct gtgcagcctc tggattcacc atcagtcgct accacatgac ttgggtccgc 900caggctccag ggaaggggct ggagtggatc ggacatattt atgttaataa tgatgacaca 960gactacgcga gctccgcgaa aggccggttc accatctcca gagacaattc caagaacacg 1020ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccacctattt ctgtgcgaga 1080ttggatgttg gtggtggtgg tgcttatatt ggggacatct ggggccaggg aaccctggtc 1140accgtctcga gcgctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 1200agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1260gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1320ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 1380ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1440agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 1500gccgcggggg caccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1560tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1620aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1680gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1740ctgaatggca aggagtacaa gtgcgcggtc tccaacaaag ccctcccagc ccccatcgag 1800aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtatac cctgccccca 1860tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1920cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1980acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 2040aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 2100aaccactaca cgcagaagag cctctccctg tctccgggtg gcggtggagg gtccggcggt 2160ggtggatccc agtcggtgga ggagtctggg ggaggcttgg tccagcctgg ggggtccctg 2220agactctcct gtaccgcctc tggaatcgac cttaatacct acgacatgat ctgggtccgc 2280caggctccag gcaaggggct agagtgggtt ggaatcatta cttatagtgg tagtagatac 2340tacgcgaact gggcgaaagg ccgattcacc atctccaaag acaataccaa gaacacggtg 2400tatctgcaaa tgaacagcct gagagctgag gacacggctg tgtattactg tgcgagagat 2460tatatgagtg gttcccactt gtggggccag ggaaccctgg tcaccgtctc ttccggtgga 2520ggcggttcag gcggaggtgg aagtggtggt ggcggctctg gaggcggcgg atctgcctat 2580gatatgaccc agtctccatc ttccgtgtct gcatctgtag gagacagagt caccatcaag 2640tgtcaggcca gtgaggacat ttatagcttc ttggcctggt atcagcagaa accagggaaa 2700gcccctaagc tcctgatcca ttctgcatcc tctctggcat ctggggtccc atcaaggttc 2760agcggcagtg gatctgggac agatttcact ctcaccatca gcagcctgca gcctgaagat 2820tttgcaactt actattgtca acagggttat ggtaaaaata atgttgataa tgctttcggc 2880ggagggacca aggtggagat caaaggcggt ggagggtccg gcggtggtgg gtccggacgg 2940tcgctggtgg agtctggggg aggcttggtc cagcctgggg ggtccctgag actctcctgt 3000actgcctctg gattcaccat cagtagctac cacatgcagt gggtccgcca ggctccaggg 3060aaggggctgg agtacatcgg aaccattagt agtggtggta atgtatacta cgcaagctcc 3120gctagaggca gattcaccat ctccagaccc tcgtccaaga acacggtgga tcttcaaatg 3180aacagcctga gagccgagga cacggctgtg tattactgtg cgagagactc tggttatagt 3240gatcctatgt ggggccaggg aaccctggtc accgtctctt caggcggtgg cggtagtggg 3300ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagacgttgt gatgacccag 3360tctccatctt ccgtgtctgc atctgtagga gacagagtca ccatcacctg tcaggccagt 3420cagaacatta ggacttactt atcctggtat cagcagaaac cagggaaagc ccctaagctc 3480ctgatctatg ctgcagccaa tctggcatct ggggtcccat caaggttcag cggcagtgga 3540tctgggacag atttcactct caccatcagc gacctggagc ctggcgatgc tgcaacttac 3600tattgtcagt ctacctatct tggtactgat tatgttggcg gtgctttcgg cggagggacc 3660aaggtggaga tcaaa 3675801225PRTArtificial SequenceSynthesized 80Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr145 150 155 160Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala 180 185 190Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 195 200 205Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn225 230 235 240Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Gly Gly Gly Gly 245 250 255Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly 260 265 270Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 275 280 285Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly 290 295 300Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr305 310 315 320Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 325 330 335Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 340 345 350Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala 355 360 365Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 370 375 380Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys385 390 395 400Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 405 410 415Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 420 425 430Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 435 440 445Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 450 455 460Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys465 470 475 480Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 485 490 495Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro 500 505 510Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 515 520 525Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 530 535 540Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu545 550 555 560Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 565 570 575His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn 580 585 590Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 595 600

605Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 610 615 620Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr625 630 635 640Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 645 650 655Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 660 665 670Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 675 680 685Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 690 695 700Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly705 710 715 720Gly Gly Ser Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro 725 730 735Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ile Asp Leu Asn 740 745 750Thr Tyr Asp Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 755 760 765Trp Val Gly Ile Ile Thr Tyr Ser Gly Ser Arg Tyr Tyr Ala Asn Trp 770 775 780Ala Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Val785 790 795 800Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 805 810 815Cys Ala Arg Asp Tyr Met Ser Gly Ser His Leu Trp Gly Gln Gly Thr 820 825 830Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 835 840 845Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Tyr Asp Met Thr Gln 850 855 860Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Lys865 870 875 880Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe Leu Ala Trp Tyr Gln Gln 885 890 895Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile His Ser Ala Ser Ser Leu 900 905 910Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 915 920 925Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 930 935 940Tyr Cys Gln Gln Gly Tyr Gly Lys Asn Asn Val Asp Asn Ala Phe Gly945 950 955 960Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly 965 970 975Gly Ser Gly Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 980 985 990Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser 995 1000 1005Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 1010 1015 1020Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala 1025 1030 1035Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys 1040 1045 1050Asn Thr Val Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 1055 1060 1065Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met 1070 1075 1080Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 1085 1090 1095Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1100 1105 1110Ser Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser 1115 1120 1125Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile 1130 1135 1140Arg Thr Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 1145 1150 1155Lys Leu Leu Ile Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro 1160 1165 1170Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 1175 1180 1185Ile Ser Asp Leu Glu Pro Gly Asp Ala Ala Thr Tyr Tyr Cys Gln 1190 1195 1200Ser Thr Tyr Leu Gly Thr Asp Tyr Val Gly Gly Ala Phe Gly Gly 1205 1210 1215Gly Thr Lys Val Glu Ile Lys 1220 122581660DNAArtificial SequenceSynthesized 81gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc agtccagtca gagtgtttat aacaacaacg acttagcctg gtatcagcag 120aaaccaggga aagttcctaa gctcctgatc tattatgcat ccactctggc atctggggtc 180ccatctcggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240cagcctgaag atgttgcaac ttattactgt gcaggcggtt atgatacgga tggtcttgat 300acgtttgctt tcggcggagg gaccaaggtg gagatcaaac gtacggtggc tgcaccatct 360gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 66082220PRTArtificial SequenceSynthesized 82Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Asn Asn 20 25 30Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu 35 40 45Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu65 70 75 80Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr 85 90 95Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220833696DNAArtificial SequenceSynthesized 83gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa tttactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660gacacggctg tgtattactg tgcgagagac ggtggttctt ctgctattac tagtaacaac 720atttggggcc agggaaccct ggtcaccgtg tcgacaggcg gtggagggtc cggcggtggt 780ggatcagagg tgcagctgtt ggagtctggg ggaggcttgg tacagcctgg ggggtccctg 840agactctcct gtgcagcctc tggattcacc atcagtcgct accacatgac ttgggtccgc 900caggctccag ggaaggggct ggagtggatc ggacatattt atgttaataa tgatgacaca 960gactacgcga gctccgcgaa aggccggttc accatctcca gagacaattc caagaacacg 1020ctgtatctgc aaatgaacag cctgagagcc gaggacacgg ccacctattt ctgtgcgaga 1080ttggatgttg gtggtggtgg tgcttatatt ggggacatct ggggccaggg aactctggtt 1140accgtctctt cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 1200agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 1260gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 1320ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 1380ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1440agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 1500gccgcggggg caccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1560tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1620aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1680gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1740ctgaatggca aggagtacaa gtgcgcggtc tccaacaaag ccctcccagc ccccatcgag 1800aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1860tcccgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1920cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1980acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 2040aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 2100aaccactaca cgcagaagag cctctccctg tctccgggtg gcggtggagg gtccggcggt 2160ggtggatccg aggtgcagct gttggagtct gggggaggct tggtacagcc tggggggtcc 2220ctgagactct cctgtgcagc ctctggattc tccttcagta gcgggtacga catgtgctgg 2280gtccgccagg ctccagggaa ggggctggag tggatcgcat gcattgctgc tggtagtgct 2340ggtatcactt acgacgcgaa ctgggcgaaa ggccggttca ccatctccag agacaattcc 2400aagaacacgc tgtatctgca aatgaacagc ctgagagccg aggacacggc cgtatattac 2460tgtgcgagat cggcgttttc gttcgactac gccatggacc tctggggcca gggaaccctg 2520gtcaccgtct cgagcggtgg aggcggatct ggcggaggtg gttccggcgg tggcggctcc 2580ggtggaggcg gctctgacat ccagatgacc cagtctcctt ccaccctgtc tgcatctgta 2640ggagacagag tcaccatcac ttgccaggcc agtcagagca ttagttccca cttaaactgg 2700tatcagcaga aaccagggaa agcccctaag ctcctgatct ataaggcatc cactctggca 2760tctggggtcc catcaaggtt cagcggcagt ggatctggga cagaatttac tctcaccatc 2820agcagcctgc agcctgatga ttttgcaact tattactgcc aacagggtta tagttggggt 2880aatgttgata atgttttcgg cggagggacc aaggtggaga tcaaaggcgg tggagggtcc 2940ggcggtggtg gctccggacg gtcgctggtg gagtctgggg gaggcttggt ccagcctggg 3000gggtccctga gactctcctg tactgcctct ggattcacca tcagtagcta ccacatgcag 3060tgggtccgcc aggctccagg gaaggggctg gagtacatcg gaaccattag tagtggtggt 3120aatgtatact acgcaagctc cgctagaggc agattcacca tctccagacc ctcgtccaag 3180aacacggtgg atcttcaaat gaacagcctg agagccgagg acacggctgt gtattactgt 3240gcgagagact ctggttatag tgatcctatg tggggccagg gaaccctggt caccgtctct 3300tcaggcggtg gcggtagtgg gggaggcggt tctggcggcg gagggtccgg cggtggagga 3360tcagacgttg tgatgaccca gtctccatct tccgtgtctg catctgtagg agacagagtc 3420accatcacct gtcaggccag tcagaacatt aggacttact tatcctggta tcagcagaaa 3480ccagggaaag cccctaagct cctgatctat gctgcagcca atctggcatc tggggtccca 3540tcaaggttca gcggcagtgg atctgggaca gatttcactc tcaccatcag cgacctggag 3600cctggcgatg ctgcaactta ctattgtcag tctacctatc ttggtactga ttatgttggc 3660ggtgctttcg gcggagggac caaggtggag atcaaa 3696841232PRTArtificial SequenceSynthesized 84Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr145 150 155 160Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala 180 185 190Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 195 200 205Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn225 230 235 240Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Thr Gly Gly Gly Gly 245 250 255Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly 260 265 270Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 275 280 285Phe Thr Ile Ser Arg Tyr His Met Thr Trp Val Arg Gln Ala Pro Gly 290 295 300Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Val Asn Asn Asp Asp Thr305 310 315 320Asp Tyr Ala Ser Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 325 330 335Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 340 345 350Thr Ala Thr Tyr Phe Cys Ala Arg Leu Asp Val Gly Gly Gly Gly Ala 355 360 365Tyr Ile Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 370 375 380Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys385 390 395 400Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 405 410 415Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 420 425 430Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 435 440 445Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 450 455 460Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys465 470 475 480Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 485 490 495Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro 500 505 510Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 515 520 525Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 530 535 540Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu545 550 555 560Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 565 570 575His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn 580 585 590Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 595 600 605Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 610 615 620Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr625 630 635 640Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 645 650 655Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 660 665 670Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 675 680 685Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 690 695 700Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly705 710 715 720Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln 725 730 735Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe 740 745 750Ser Ser Gly Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly 755 760 765Leu Glu Trp Ile Ala Cys Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr 770 775 780Asp Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser785 790 795 800Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 805 810 815Ala Val Tyr Tyr Cys Ala Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met 820 825 830Asp Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 835 840 845Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 850 855 860Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val865 870 875 880Gly Asp Arg Val Thr Ile Thr Cys Gln Ala

Ser Gln Ser Ile Ser Ser 885 890 895His Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu 900 905 910Ile Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 915 920 925Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln 930 935 940Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly945 950 955 960Asn Val Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly 965 970 975Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Arg Ser Leu Val Glu Ser 980 985 990Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr 995 1000 1005Ala Ser Gly Phe Thr Ile Ser Ser Tyr His Met Gln Trp Val Arg 1010 1015 1020Gln Ala Pro Gly Lys Gly Leu Glu Tyr Ile Gly Thr Ile Ser Ser 1025 1030 1035Gly Gly Asn Val Tyr Tyr Ala Ser Ser Ala Arg Gly Arg Phe Thr 1040 1045 1050Ile Ser Arg Pro Ser Ser Lys Asn Thr Val Asp Leu Gln Met Asn 1055 1060 1065Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp 1070 1075 1080Ser Gly Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr Leu Val Thr 1085 1090 1095Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 1100 1105 1110Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser 1115 1120 1125Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 1130 1135 1140Cys Gln Ala Ser Gln Asn Ile Arg Thr Tyr Leu Ser Trp Tyr Gln 1145 1150 1155Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ala 1160 1165 1170Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 1175 1180 1185Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly Asp 1190 1195 1200Ala Ala Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr 1205 1210 1215Val Gly Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1220 1225 123085660DNAArtificial SequenceSynthesized 85gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc agtccagtca gagtgtttat aacaacaacg acttagcctg gtatcagcag 120aaaccaggga aagttcctaa gctcctgatc tattatgcat ccactctggc atctggggtc 180ccatctcggt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240cagcctgaag atgttgcaac ttattactgt gcaggcggtt atgatacgga tggtcttgat 300acgtttgctt tcggcggagg gaccaaggtg gagatcaaac gtacggtggc tgcaccatct 360gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 66086220PRTArtificial SequenceSynthesized 86Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ser Ser Gln Ser Val Tyr Asn Asn 20 25 30Asn Asp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu 35 40 45Leu Ile Tyr Tyr Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu65 70 75 80Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Ala Gly Gly Tyr Asp Thr 85 90 95Asp Gly Leu Asp Thr Phe Ala Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220873690DNAArtificial SequenceSynthesized 87gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaaggcg gtggcggtag tgggggaggc 360ggttctggcg gcggagggtc cggcggtgga ggatcagagg tgcagctggt ggagtctggg 420ggaggcttgg tccagcctgg ggggtccctg agactctcct gtgcagcctc tggattcacc 480atcagtacca atgcaatgag ctgggtccgc caggctccag ggaaggggct ggagtggatc 540ggagtcatta ctggtcgtga tatcacatac tacgcgagct gggcgaaagg cagattcacc 600atctccagag acaattccaa gaacacgctg tatcttcaaa tgaacagcct gagagccgag 660gacacggctg tgtattactg tgcgcgcgac ggtggatcat ctgctattac tagtaacaac 720atttggggcc aaggaactct ggtcaccgtt tcttcaggcg gtggagggtc cggcggtggt 780ggatccgagg tgcagctggt gcagtctgga gcagaggtga agaaaccagg agagtctctg 840aagatctcct gtaagggttc tggatacagc tttagcagtt catggatcgg ctgggtgcgc 900caggcacctg ggaaaggcct ggaatggatg gggatcatct atcctgatga ctctgatacc 960agatacagtc catccttcca aggccaggtc accatctcag ccgacaagtc catcaggact 1020gcctacctgc agtggagtag cctgaaggcc tcggacaccg ctatgtatta ctgtgcgaga 1080catgttacta tgatttgggg agttattatt gacttctggg gccagggaac cctggtcacc 1140gtctcctcag ctagcaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 1200acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 1260acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 1320cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 1380acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 1440gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaagcc 1500gcgggggcac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 1560cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1620ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1680cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1740aatggcaagg agtacaagtg cgcggtctcc aacaaagccc tcccagcccc catcgagaaa 1800accatctcca aagccaaagg gcagccccga gaaccacagg tgtataccct gcccccatcc 1860cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1920agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1980cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 2040agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 2100cactacacgc agaagagcct ctccctgtct ccgggtggcg gtggagggtc cggcggtggt 2160ggatccgagg tgcagctgtt ggagtctggg ggaggcttgg tacagcctgg ggggtccctg 2220agactctcct gtgcagcctc tggattctcc ttcagtagcg ggtacgacat gtgctgggtc 2280cgccaggctc cagggaaggg gctggagtgg atcgcatgca ttgctgctgg tagtgctggt 2340atcacttacg acgcgaactg ggcgaaaggc cggttcacca tctccagaga caattccaag 2400aacacgctgt atctgcaaat gaacagcctg agagccgagg acacggccgt atattactgt 2460gcgagatcgg cgttttcgtt cgactacgcc atggacctct ggggccaggg aaccctggtc 2520accgtctcga gcggtggagg cggatctggc ggaggtggtt ccggcggtgg cggctccggt 2580ggaggcggct ctgacatcca gatgacccag tctccttcca ccctgtctgc atctgtagga 2640gacagagtca ccatcacttg ccaggccagt cagagcatta gttcccactt aaactggtat 2700cagcagaaac cagggaaagc ccctaagctc ctgatctata aggcatccac tctggcatct 2760ggggtcccat caaggttcag cggcagtgga tctgggacag aatttactct caccatcagc 2820agcctgcagc ctgatgattt tgcaacttat tactgccaac agggttatag ttggggtaat 2880gttgataatg ttttcggcgg agggaccaag gtggagatca aaggcggtgg agggtccggc 2940ggtggtggat cccggtcgct ggtggagtct gggggaggct tggtccagcc tggggggtcc 3000ctgagactct cctgtacagc ctctggattc accatcagta gctaccacat gcagtgggtc 3060cgccaggctc cagggaaggg gctggagtac atcggaacca ttagtagtgg tggtaatgta 3120tactacgcga gctccgcgag aggcagattc accatctcca gaccctcgtc caagaacacg 3180gtggatcttc aaatgaacag cctgagagcc gaggacacgg ctgtgtatta ctgtgcgaga 3240gactctggtt atagtgatcc tatgtggggc cagggaaccc tggtcaccgt ctcgagcggc 3300ggtggcggta gtgggggagg cggttctggc ggcggagggt ccggcggtgg aggatcagac 3360gttgtgatga cccagtctcc atcttccgtg tctgcatctg taggagacag agtcaccatc 3420acctgtcagg ccagtcagaa cattaggact tacttatcct ggtatcagca gaaaccaggg 3480aaagccccta agctcctgat ctatgctgca gccaatctgg catctggggt cccatcaagg 3540ttcagcggca gtggatctgg gacagatttc actctcacca tcagcgacct ggagcctggc 3600gatgctgcaa cttactattg tcagtctacc tatcttggta ctgattatgt tggcggtgct 3660ttcggcggag ggaccaaggt ggagatcaaa 3690881230PRTArtificial SequenceSynthesized 88Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser 85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr145 150 155 160Ile Ser Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175Leu Glu Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala 180 185 190Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 195 200 205Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 210 215 220Tyr Tyr Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn225 230 235 240Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 245 250 255Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu 260 265 270Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly 275 280 285Tyr Ser Phe Ser Ser Ser Trp Ile Gly Trp Val Arg Gln Ala Pro Gly 290 295 300Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr305 310 315 320Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys 325 330 335Ser Ile Arg Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp 340 345 350Thr Ala Met Tyr Tyr Cys Ala Arg His Val Thr Met Ile Trp Gly Val 355 360 365Ile Ile Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 370 375 380Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser385 390 395 400Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 405 410 415Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 420 425 430Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 435 440 445Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 450 455 460Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg465 470 475 480Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 485 490 495Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys 500 505 510Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 515 520 525Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 530 535 540Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu545 550 555 560Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 565 570 575Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys 580 585 590Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 595 600 605Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 610 615 620Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro625 630 635 640Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 645 650 655Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 660 665 670Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 675 680 685Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 690 695 700Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly705 710 715 720Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 725 730 735Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser 740 745 750Ser Gly Tyr Asp Met Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 755 760 765Glu Trp Ile Ala Cys Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp 770 775 780Ala Asn Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys785 790 795 800Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 805 810 815Val Tyr Tyr Cys Ala Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp 820 825 830Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 835 840 845Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 850 855 860Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly865 870 875 880Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His 885 890 895Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 900 905 910Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 915 920 925Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 930 935 940Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn945 950 955 960Val Asp Asn Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly 965 970 975Gly Gly Ser Gly Gly Gly Gly Ser Arg Ser Leu Val Glu Ser Gly Gly 980 985 990Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser 995 1000 1005Gly Phe Thr Ile Ser Ser Tyr His Met Gln Trp Val Arg Gln Ala 1010 1015 1020Pro Gly Lys Gly Leu Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly 1025 1030 1035Asn Val Tyr Tyr Ala Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser 1040 1045 1050Arg Pro Ser Ser Lys Asn Thr Val Asp Leu Gln Met Asn Ser Leu 1055 1060 1065Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly 1070 1075 1080Tyr Ser Asp Pro Met Trp Gly Gln Gly Thr Leu Val Thr Val Ser 1085 1090 1095Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1100 1105 1110Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Ser 1115 1120 1125Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln 1130 1135 1140Ala Ser Gln Asn Ile Arg Thr Tyr Leu Ser Trp Tyr Gln Gln Lys 1145

1150 1155Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ala Asn Leu 1160 1165 1170Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 1175 1180 1185Asp Phe Thr Leu Thr Ile Ser Asp Leu Glu Pro Gly Asp Ala Ala 1190 1195 1200Thr Tyr Tyr Cys Gln Ser Thr Tyr Leu Gly Thr Asp Tyr Val Gly 1205 1210 1215Gly Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1220 1225 123089642DNAArtificial SequenceSynthesized 89gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300gggaccaaag tggatatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 64290214PRTArtificial SequenceSynthesized 90Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210913675DNAArtificial SequenceSynthesized 91gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag tttaatagtt acccattcac tttcggccct 300gggaccaaag tggatatcaa aggcggtggc ggtagtgggg gaggcggttc tggcggcgga 360gggtccggcg gtggaggatc agaggtgcag ctggtgcagt ctggagcaga ggtgaagaaa 420ccaggagagt ctctgaagat ctcctgtaag ggttctggat acagctttag cagttcatgg 480atcggctggg tgcgccaggc acctgggaaa ggcctggaat ggatggggat catctatcct 540gatgactctg ataccagata cagtccatcc ttccaaggcc aggtcaccat ctcagccgac 600aagtccatca ggactgccta cctgcagtgg agtagcctga aggcctcgga caccgctatg 660tattactgtg cgagacatgt tactatgatt tggggagtta ttattgactt ctggggccag 720ggaaccctgg tcaccgtctc ctcaggcggt ggagggtccg gcggtggtgg atccgaggtg 780cagctggtgg agtctggggg aggcttggtc cagcctgggg ggtccctgag actctcctgt 840gcagcctctg gattcaccat cagtaccaat gcaatgagct gggtccgcca ggctccaggg 900aaggggctgg agtggatcgg agtcattact ggtcgtgata tcacatacta cgcgagctgg 960gcgaaaggca gattcaccat ctccagagac aattccaaga acacgctgta tcttcaaatg 1020aacagcctga gagccgagga cacggctgtg tattactgtg cgcgcgacgg tggatcatct 1080gctattacta gtaacaacat ttggggccaa ggaactctgg tcaccgtttc ttcagctagc 1140accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 1200gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 1260tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 1320tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 1380tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 1440tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aagccgcggg ggcaccgtca 1500gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1560acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1620gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1680taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1740aagtgcgcgg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1800aaagggcagc cccgagaacc acaggtgtat accctgcccc catcccggga tgagctgacc 1860aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1920gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1980tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 2040gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 2100agcctctccc tgtctccggg tggcggtgga gggtccggcg gtggtggatc cgaggtgcag 2160ctgttggagt ctgggggagg cttggtacag cctggggggt ccctgagact ctcctgtgca 2220gcctctggat tctccttcag tagcgggtac gacatgtgct gggtccgcca ggctccaggg 2280aaggggctgg agtggatcgc atgcattgct gctggtagtg ctggtatcac ttacgacgcg 2340aactgggcga aaggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg 2400caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgag atcggcgttt 2460tcgttcgact acgccatgga cctctggggc cagggaaccc tggtcaccgt ctcgagcggt 2520ggaggcggat ctggcggagg tggttccggc ggtggcggct ccggtggagg cggctctgac 2580atccagatga cccagtctcc ttccaccctg tctgcatctg taggagacag agtcaccatc 2640acttgccagg ccagtcagag cattagttcc cacttaaact ggtatcagca gaaaccaggg 2700aaagccccta agctcctgat ctataaggca tccactctgg catctggggt cccatcaagg 2760ttcagcggca gtggatctgg gacagaattt actctcacca tcagcagcct gcagcctgat 2820gattttgcaa cttattactg ccaacagggt tatagttggg gtaatgttga taatgttttc 2880ggcggaggga ccaaggtgga gatcaaaggc ggtggagggt ccggcggtgg tggatcccgg 2940tcgctggtgg agtctggggg aggcttggtc cagcctgggg ggtccctgag actctcctgt 3000acagcctctg gattcaccat cagtagctac cacatgcagt gggtccgcca ggctccaggg 3060aaggggctgg agtacatcgg aaccattagt agtggtggta atgtatacta cgcgagctcc 3120gcgagaggca gattcaccat ctccagaccc tcgtccaaga acacggtgga tcttcaaatg 3180aacagcctga gagccgagga cacggctgtg tattactgtg cgagagactc tggttatagt 3240gatcctatgt ggggccaggg aaccctggtc accgtctcga gcggcggtgg cggtagtggg 3300ggaggcggtt ctggcggcgg agggtccggc ggtggaggat cagacgttgt gatgacccag 3360tctccatctt ccgtgtctgc atctgtagga gacagagtca ccatcacctg tcaggccagt 3420cagaacatta ggacttactt atcctggtat cagcagaaac cagggaaagc ccctaagctc 3480ctgatctatg ctgcagccaa tctggcatct ggggtcccat caaggttcag cggcagtgga 3540tctgggacag atttcactct caccatcagc gacctggagc ctggcgatgc tgcaacttac 3600tattgtcagt ctacctatct tggtactgat tatgttggcg gtgctttcgg cggagggacc 3660aaggtggaga tcaaa 3675921225PRTArtificial SequenceSynthesized 92Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser 100 105 110Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 115 120 125Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 130 135 140Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ser Ser Ser Trp145 150 155 160Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly 165 170 175Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln 180 185 190Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Arg Thr Ala Tyr Leu 195 200 205Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 210 215 220Arg His Val Thr Met Ile Trp Gly Val Ile Ile Asp Phe Trp Gly Gln225 230 235 240Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 245 250 255Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 260 265 270Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser 275 280 285Thr Asn Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 290 295 300Trp Ile Gly Val Ile Thr Gly Arg Asp Ile Thr Tyr Tyr Ala Ser Trp305 310 315 320Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 325 330 335Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 340 345 350Cys Ala Arg Asp Gly Gly Ser Ser Ala Ile Thr Ser Asn Asn Ile Trp 355 360 365Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 370 375 380Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr385 390 395 400Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 405 410 415Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 420 425 430Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 435 440 445Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 450 455 460His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser465 470 475 480Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 485 490 495Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 500 505 510Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 515 520 525His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 530 535 540Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr545 550 555 560Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 565 570 575Gly Lys Glu Tyr Lys Cys Ala Val Ser Asn Lys Ala Leu Pro Ala Pro 580 585 590Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 595 600 605Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 610 615 620Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val625 630 635 640Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 645 650 655Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 660 665 670Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 675 680 685Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 690 695 700Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln705 710 715 720Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg 725 730 735Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Gly Tyr Asp Met 740 745 750Cys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Ala Cys 755 760 765Ile Ala Ala Gly Ser Ala Gly Ile Thr Tyr Asp Ala Asn Trp Ala Lys 770 775 780Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu785 790 795 800Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 805 810 815Arg Ser Ala Phe Ser Phe Asp Tyr Ala Met Asp Leu Trp Gly Gln Gly 820 825 830Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 835 840 845Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 850 855 860Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile865 870 875 880Thr Cys Gln Ala Ser Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln 885 890 895Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Thr 900 905 910Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 915 920 925Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr 930 935 940Tyr Tyr Cys Gln Gln Gly Tyr Ser Trp Gly Asn Val Asp Asn Val Phe945 950 955 960Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly 965 970 975Gly Gly Ser Arg Ser Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 980 985 990Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Ile Ser 995 1000 1005Ser Tyr His Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 1010 1015 1020Glu Tyr Ile Gly Thr Ile Ser Ser Gly Gly Asn Val Tyr Tyr Ala 1025 1030 1035Ser Ser Ala Arg Gly Arg Phe Thr Ile Ser Arg Pro Ser Ser Lys 1040 1045 1050Asn Thr Val Asp Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 1055 1060 1065Ala Val Tyr Tyr Cys Ala Arg Asp Ser Gly Tyr Ser Asp Pro Met 1070 1075 1080Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 1085 1090 1095Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 1100 1105 1110Ser Asp Val Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser 1115 1120 1125Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile 1130 1135 1140Arg Thr Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 1145 1150 1155Lys Leu Leu Ile Tyr Ala Ala Ala Asn Leu Ala Ser Gly Val Pro 1160 1165 1170Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 1175 1180 1185Ile Ser Asp Leu Glu Pro Gly Asp Ala Ala Thr Tyr Tyr Cys Gln 1190 1195 1200Ser Thr Tyr Leu Gly Thr Asp Tyr Val Gly Gly Ala Phe Gly Gly 1205 1210 1215Gly Thr Lys Val Glu Ile Lys 1220 122593657DNAArtificial SequenceSynthesized 93gacgtcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcaattgcc aagccagtga gagcattagc agttggttag cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgaa gcatccaaac tggcatctgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaaggc tatttttatt ttattagtcg tacttatgta 300aattctttcg gcggagggac caaggtggag atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 65794219PRTArtificial SequenceSynthesized 94Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Tyr Phe Tyr Phe Ile Ser

85 90 95Arg Thr Tyr Val Asn Ser Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215

Claims

1. A method for generating a therapeutic composition, comprising providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell, wherein the first GNC protein comprising a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell through the binding with the first cytotoxic cell receptor, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor, and wherein the first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the binding interaction with the first cytotoxic cell receptor, and formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic composition is substantially free of exogenous viral and non-viral DNA or RNA.

2. The method of claim 1, wherein the incubating step is repeated by incubating a second GNC protein with the activated cell composition, wherein the second GNC protein comprising a second cytotoxic binding moiety and a second cancer targeting moiety, wherein the second cytotoxic binding moiety has a specificity to a second cytotoxic cell receptor, and wherein the second cancer targeting moiety has a specificity to a second cancer cell receptor, wherein the activated cell composition further comprises a second therapeutic cell, and wherein the second therapeutic cell comprises the second GNC protein bound to the cytotoxic cell or the first therapeutic cell through the binding interaction with the second cytotoxic cell receptor.

3. The method of claim 2, wherein the second GNC protein is the same as the first GNC protein.

4. The method of claim 2, wherein the second GNC protein is different from the first GNC protein.

5. The method of claim 1, wherein the first or the second cancer targeting moiety has the specificity against B cell, and wherein the therapeutic composition is substantially free of B cell.

6. The method of claim 1, wherein the cytotoxic cell receptor comprises a T-cell receptor, a NK cell receptor, a macrophage receptor, a dendritic cell receptor, or a combination thereof.

7. The method of claim 1, wherein the molar to cell ratio between the first GNC protein and the cytotoxic cell is at least 30 to 1 when incubating the cell material with the first GNC protein.

8. The method of claim 1, wherein the therapeutic composition comprises at least 10.sup.6 cells per ml.

9. The method of claim 1, wherein the therapeutic composition comprises the first therapeutic cell, the first GNC protein, the cytotoxic cell, or a combination thereof.

10. The method of claim 2, wherein the therapeutic composition comprises the second therapeutic cell, the second GNC protein, comprises the first therapeutic cell, the first GNC protein, the cytotoxic cell, or a combination thereof.

11. The method of claim 1, wherein the cell material comprises PBMC.

12. The method of claim 1, wherein the first and the second cancer-targeting moiety independently has a specificity for CD19, PDL1, or a combination thereof.

13. The method of claim 1, wherein the first and the second cytotoxic binding moiety independently has a specificity for CD3, PDL1, 41BB, or a combination thereof.

14. A method of treating a subject having a cancer, comprising providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell, wherein the first GNC protein comprising a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell through the binding with the first cytotoxic cell receptor, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor, and wherein the first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the binding interaction with the first cytotoxic cell receptor, and formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic composition is substantially free of exogenous viral and non-viral DNA or RNA, and administering the therapeutic composition to the subject.

15. The method of claim 14, wherein the incubating step is repeated by incubating a second GNC protein with the activated cell composition, wherein the second GNC protein comprising a second cytotoxic binding moiety and a second cancer targeting moiety, wherein the second cytotoxic binding moiety has a specificity to a second cytotoxic cell receptor, and wherein the second cancer targeting moiety has a specificity to a second cancer cell receptor, wherein the activated cell composition further comprises a second therapeutic cell, and wherein the second therapeutic cell comprises the second GNC protein bound to the cytotoxic cell or the first therapeutic cell through the binding interaction with the second cytotoxic cell receptor.

16. The method of claim 14, wherein the second GNC protein is the same as the first GNC protein.

17. The method of claim 14, wherein the second GNC protein is different from the first GNC protein.

18. The method of claim 14, wherein the first or the second cancer targeting moiety has the specificity against B cell, and wherein the therapeutic composition is substantially free of B cell.

19. The method of claim 14, further comprising isolating the cytotoxic cell from peripheral blood mononuclear cells (PBMC) before providing the cell material.

20. The method of claim 19, further comprising isolating the peripheral blood mononuclear cells (PBMC) from a blood.

21-22. (canceled)

23. The method of claim 14, further comprising administering an additional GNC protein to the subject after the administering the therapeutic composition to the subject.

24. The method of claim 14, wherein the cytotoxic cell comprises T cell, NK cell, or a combination thereof.

25. The method of claim 19, wherein the isolating the cytotoxic cell comprising isolating at least one subpopulation of cytotoxic cell to provide therapeutic T cells, wherein the subpopulation of cytotoxic cell comprises CD3+ cells, CD4+ cells, CD8+ cells, CD56+ cells, CD28+ cells, CD69+ cells, CD107a+ cells, CD45RA+ cells, CD45RO+ cells, .gamma..delta. TCR+ cells, .alpha..beta. TCR+ cells, CD25+ cells, CD127.sup.lo/- cells, CCR7+ cells, PD-1+ cells or a combination thereof.

26. (canceled)

27. The method of claim 14, further comprising evaluating therapeutic efficacy after the administering step, wherein the evaluating therapeutic efficacy comprises checking one or more biomarkers of the cancer, monitoring the life span of the therapeutic cells, or a combination thereof.

28-29. (canceled)

30. The method of claim 14, wherein the subject is a human.

31. The method of claim 14, wherein the cancer comprises cells expressing ROR1, CEA, HER2, EGFR, EGFR VIII, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, BCMA, CD19, CD20, CD33, CD123, CD22, CD30, or a combination thereof.

32. (canceled)

33. The method of claim 14, wherein the cancer is CD19 positive.

34. The method of claim 14, further comprising administering an effective amount of a therapeutic agent after the administering the therapeutic composition to the subject.

35. The method of claim 34, wherein the therapeutic agent comprises a monoclonal antibody, a multi-specific antibody, a chemotherapy agent, an enzyme, a protein, a co-stimulator, an apoptosis sensitizer, a tumor vascular disruptor, or a combination thereof, wherein the co-stimulator is configured to increase the amount of cytotoxic T cells in the subject.

36-39. (canceled)