ANTI-IL-33 ANTIBODIES, COMPOSITIONS, METHODS AND USES THEREOF

Abstract

The invention provides antibodies, and antigen-binding fragments thereof, that specifically bind to IL-33, as well as uses, and associated methods thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application 62/328,294, filed Apr. 27, 2016; and U.S. provisional application 62/483,781, filed Apr. 10, 2017. The complete content of all of the above-referenced patent applications are hereby incorporated by reference for all purposes.

REFERENCE TO SEQUENCE LISTING

[0002] This application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 29, 2017, is named PC72256A_Seq_Listing_ST25.txt and is 473,842 bytes in size.

FIELD

[0003] The present invention relates to antibodies, and antigen-binding fragments thereof, that specifically bind interleukin-33, and compositions, methods and uses thereof.

BACKGROUND

[0004] IL-33 is a critical IL-1 family member that amplifies the responses of many cell types that are involved in asthma and atopic inflammation. IL-33 binds to Interleukin-1 Receptor-Like 1 (IL1RL1; also known as suppression of tumorigenicity 2 [ST2]), with high affinity and forms a ternary complex with IL1RAcP to form the signaling complex. This signaling complex leads to a series of events that is dependent on the Myddosome, with MyD88 and IRAK family members. This signaling ultimately leads to NFKb activiation and other pathways in a cellular and cytokine environment specific context. When cells such as mast cells or basophils are stimulated by IL-33, type 2 cytokines such as IL-4, 5, and 13 are produced.

[0005] IL-33 has been shown to play a critical role in a number of preclinical models of asthma and allergic disease when its activity is blocked by either pharmacologic or genetic approaches. Blockade of the pathway has been accomplished by neutralizing antibodies to IL-33 or the receptor IL1RL1, genetic deletion of IL-33 or IL1RL1, or soluble forms of the receptor IL1RL1 coupled as a fusion protein to an Fc (Coyle et al., 1999, J. Exper. Med 190(7):895-902). In most model systems where physiologic allergens are used that contain a proteolytic allergen, such as in dust mite, cock roach or the fungus alternaria, IL-33 plays an important role in driving the inflammation and other aspects of airway remodeling (Chu et al., 2013, J. Allergy Clin. Immunol. 131:187-200). In pharmacologic models that rely on adjuvants for sensitization such as aluminum hydroxide (alum), or monosodium urate crystals, IL-33 plays an important role in the sensitization phase of the model and induction of type 2 cytokines such as IL-5 and IL13 (Hara et al., 2014, J. Immunol. 192(9):4032-4042). IL-33 has also been found to play an important role in the inflammatory response associated with viral infections in the airways. Damage of the airway epithelium by viral infections can trigger the release of IL-33 and modify the type of immune response.

[0006] Diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), and asthma are diseases where multiple cytokines are likely involved in the pathogenesis. The IL-33 receptor, ST2, is expressed on many of the cell types associated with type 2 inflammation, including mast cells, basophils, Th2-T cells, innate lymphoid cells type 2 and others (Cayrol & Girard, 2014, Current Opinion in Immunology 31:31-37; Molofsky et al. 2015, Immunity 42(6):1005-1019). The primary response of these cell types to IL-33 is the production of inflammatory cytokines, and in particular those associated with type 2 inflammation, including IL-5, IL-13, IL-4, IL-31 and IL-9 (Molofsky et al., 2015, Immunity 42(6):1005-1019; Rivellese et al, 2014, Eur. J. Immunol. 44(10):3045-3055; Suzukawa et al., 2008, J. Immunology 181(9):5981-5989; Vocca et al. Immunobiology 220(8):954-963; Maier et al., 2014, J. Immunology 193(2):645-654). Other cytokines as well as chemokines are also produced which are important in driving the recruitment of additional inflammatory cell types to the tissue site (Cayrol & Girard, 2014; Molofsky et al., 2015). The initial release of IL-33 is triggered by damage to the epithelium at the body or mucosal surfaces. Disease relevant triggers include allergens with proteolytic activity, physical damage to the epithelium, viruses as well as fungi and bacteria that are common at the body surfaces. In diseases where the tissue is rich with eosinophils and mast cells, damage to the epithelium sets off a cascade whereby IL-33 is released, acts on local target cells, and drives the production of multiple cytokines that are central to a Type 2 inflammatory response.

SUMMARY OF THE INVENTION

[0007] The invention provides antibodies (and antigen-binding fragments thereof) that specifically bind to IL-33, as well as uses, and associated methods thereof. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments (E).

E1. An isolated antibody or antigen-binding fragment thereof that specifically binds to human IL-33. E2. The antibody, or antigen-binding fragment thereof, of E1, comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of one of the group consisting of SEQ ID NO:14, 32, 90, 94, 97, 113, 118, 121, 124, 126, 129, 132, 135, 138, 141, 144, 147, 150, 152, 155, 158, 161, 163, 165, 167, 170, 173, 176, 179, 182, 184, 186, 201, 204, 210, 213, 216, 219, 222, 225, 228, 231, and 234. E3. The antibody, or antigen-binding fragment thereof, of any one of E1-E2, comprising the CDR-L1, CDR-L2, and CDR-L3 sequences of one of the group consisting of SEQ ID NO:19, 36, 81, 91, 98, 115, 189, 192, 195, 198, and 207. E4. The antibody, or antigen binding fragment thereof, as in any one of E1-E3 comprising one or more of (i)-(vi)

[0008] (i) a CDR-L1 selected from the group consisting of SEQ ID NO:20, 37, 190, 193, 257, 258, 259, and 260,

[0009] (ii) a CDR-L2 selected from the group consisting of SEQ ID NO:21, 196, 199, 261, 262, 263, and 264,

[0010] (iii) a CDR-L3 selected from the group consisting of SEQ ID NO:22, 38, 208, 265, 26, 267, and 268,

[0011] (iv) a CDR-H1 selected from the group consisting of SEQ ID NO:16, 33, 269, 270, and 271,

[0012] (v) a CDR-H2 selected from the group consisting of SEQ ID NO:17, 34, 168, 171, 174, 180, 202, 205, 211, 214, 217, 220, 223, 226, 229, 232, 235, 272, 273, 274, and 275,

[0013] (vi) a CDR-H3 selected from the group consisting of SEQ ID NO:18, 35, 114, 119, 122, 127, 130, 133, 136, 139, 142, 145, 148, 153, 156, 159, 177, 187, 276, 277, 278 and 279. E5. The antibody, or antigen binding fragment thereof, as in any one of E1-E4 comprising

[0014] (i) a CDR-L1 selected from the group consisting of SEQ ID NO:257, 258, 259, and 260,

[0015] (ii) a CDR-L2 selected from the group consisting of SEQ ID NO:261, 262, 263, and 264,

[0016] (iii) a CDR-L3 selected from the group consisting of SEQ ID NO:265, 266, 267, and 268,

[0017] (iv) a CDR-H1 selected from the group consisting of SEQ ID NO:269, 270, and 271,

[0018] (v) a CDR-H2 selected from the group consisting of SEQ ID NO:272, 273, 274, and 275,

[0019] (vi) a CDR-H3 selected from the group consisting of SEQ ID NO: 276, 277, 278, and 279. E6. The antibody, or antigen binding fragment thereof, as in any one of E1-E5 comprising

[0020] (i) a CDR-L1 comprising SEQ ID NO:257,

[0021] (ii) a CDR-L2 comprising SEQ ID NO:261,

[0022] (iii) a CDR-L3 comprising SEQ ID NO:265,

[0023] (iv) a CDR-H1 comprising SEQ ID NO:269,

[0024] (v) a CDR-H2 comprising SEQ ID NO:272,

[0025] (vi) a CDR-H3 comprising SEQ ID NO: 276. E7. The antibody, or antigen binding fragment thereof, as in any one of E1-E6 comprising

[0026] (i) a CDR-L1 comprising SEQ ID NO:258,

[0027] (ii) a CDR-L2 comprising SEQ ID NO:262,

[0028] (iii) a CDR-L3 comprising SEQ ID NO:266,

[0029] (iv) a CDR-H1 comprising SEQ ID NO:270,

[0030] (v) a CDR-H2 comprising SEQ ID NO:273,

[0031] (vi) a CDR-H3 comprising SEQ ID NO: 277. E8. The antibody, or antigen binding fragment thereof, as in any one of E1-E7 comprising

[0032] (i) a CDR-L1 comprising SEQ ID NO:259,

[0033] (ii) a CDR-L2 comprising SEQ ID NO:263,

[0034] (iii) a CDR-L3 comprising SEQ ID NO:267,

[0035] (iv) a CDR-H1 comprising SEQ ID NO:271,

[0036] (v) a CDR-H2 comprising SEQ ID NO:274,

[0037] (vi) a CDR-H3 comprising SEQ ID NO: 278. E9. The antibody, or antigen binding fragment thereof, as in any one of E1-E8 comprising

[0038] (i) a CDR-L1 comprising SEQ ID NO:260,

[0039] (ii) a CDR-L2 comprising SEQ ID NO:264,

[0040] (iii) a CDR-L3 comprising SEQ ID NO:268,

[0041] (iv) a CDR-H1 comprising SEQ ID NO:271,

[0042] (v) a CDR-H2 comprising SEQ ID NO:275,

[0043] (vi) a CDR-H3 comprising SEQ ID NO: 278. E10. The antibody, or antigen binding fragment thereof, as in any one of E1-E9 comprising

[0044] (i) a CDR-L1 comprising SEQ ID NO:20,

[0045] (ii) a CDR-L2 comprising SEQ ID NO:21,

[0046] (iii) a CDR-L3 comprising SEQ ID NO:208,

[0047] (iv) a CDR-H1 comprising SEQ ID NO:16,

[0048] (v) a CDR-H2 comprising SEQ ID NO:226,

[0049] (vi) a CDR-H3 comprising SEQ ID NO: 18. E11. The antibody, or antigen-binding fragment thereof, of any one of E1-E10, comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:225. E12. The antibody, or antigen-binding fragment thereof, of any one of E1-E11, comprising the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:207. E13. The antibody, or antigen-binding fragment thereof, of any one of E1-E12, comprising one or more of the following substitutions:

[0050] (i) 1, 2, 3, 4, 5, or 6 substitutions in CDR L1 to the corresponding residue of a human germline VL sequence,

[0051] (ii) 1, 2, 3, 4, or 5 substitutions in CDR L2 to the corresponding residue of a human VL germline sequence,

[0052] (iii) 1, 2, 3, 4, 5, or 6 substitutions in CDR L3 to the corresponding residue of a human germline VL sequence,

[0053] (iv) 1 substitution in CDR H1 to the corresponding residue of a human germline VH sequence,

[0054] (v) 1, 2, 3, 4, 5, 6, 7, or 8 substitutions in CDR H2 to the corresponding residue of a human germline VH sequence,

[0055] wherein the human germline VL sequence is selected from the group consisting of DPK9, DPK12, DPK18, DPK24, HK102_V1, DPK1, DPK8, DPK3, DPK21, Vg_38K, DPK22, DPK15, DPL16, DPL8, V1-22, V.lamda. consensus, V.lamda.1 consensus, V.lamda.3 consensus, V.kappa. consensus, V.kappa.1 consensus, V.kappa.2 consensus, and V.kappa.3, and the human germline VH is selected from the group consisting of DP54, DP47, DP50, DP31, DP46, DP71, DP75, DP10, DP7, DP49, DP51, DP38, DP79, DP78, DP73, VH3, VH5, VH1, and VH4. E14. The antibody, or antigen-binding fragment thereof, of any one of E1-E13, comprising a VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP54, DP47, DP50, DP31, DP46, DP71, DP75, DP10, DP7, DP49, DP51, DP38, DP79, DP78, DP73, VH3, VH5, VH1, and VH4. E15. The antibody, or antigen-binding fragment thereof, of any one of E1-E14, comprising a framework VH sequence derived from a human VH3 germline sequence. E16. The antibody, or antigen-binding fragment thereof, of any one of E1-E15, comprising a framework VH sequence derived from a human germline VH sequence selected from the group consisting of DP54, DP47, DP50, DP31, DP46, DP49, and DP51. E17. The antibody, or antigen-binding fragment thereof, of any one of E1-E16, comprising a framework VH sequence derived from a human germline VH sequence selected from the group consisting of DP54, DP47, DP50, and DP31. E18. The antibody, or antigen-binding fragment thereof, of any one of E1-E17, comprising a VH framework sequence derived from a human germline DP54 sequence. E19. The antibody, or antigen-binding fragment thereof, of any one of E1-E18, comprising a VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK9, DPK12, DPK18, DPK24, HK102_V1, DPK1, DPK8, DPK3, DPK21, Vg_38K, DPK22, DPK15, DPL16, DPL8, V1-22, V.lamda. consensus, V.lamda.1 consensus, V.lamda.3 consensus, V.kappa. consensus, V.kappa.1 consensus, V.kappa.2 consensus, and V.kappa.3. E20. The antibody, or antigen-binding fragment thereof, of any one of E1-E19, comprising a VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK9, DPK12, DPK18, DPK24, HK102_V1, DPK1, DPK8, DPK3, DPK21, Vg_38K, DPK22, DPK15, V.kappa. consensus, V.kappa.1 consensus, V.kappa.2 consensus, and V.kappa.3. E21. The antibody, or antigen-binding fragment thereof, of any one of E1-E20, comprising a VL framework sequence derived from a human germline V.kappa.1 sequence. E22. The antibody, or antigen-binding fragment thereof, of any one of E1-E21, comprising a VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK9, HK102_V1, DPK1, and DPK8. E23. The antibody, or antigen-binding fragment thereof, of any one of E1-E22, comprising a VL framework sequence derived from a human germline DPK9 sequence. E24. The antibody, or antigen-binding fragment thereof, of any one of E1-E23, comprising a VL framework sequence and a VH framework sequence, and wherein one or both of the VL framework sequence or VH framework sequence is at least 90% identical to the human germline sequence from which it was derived. E25. The antibody, or antigen-binding fragment thereof, of any one of E1-E24, comprising a VL framework sequence and a VH framework sequence, and wherein one or both of the VL framework sequence or VH framework sequence is at least 66%, 76%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the human germline sequence from which it was derived. E26. The antibody, or antigen-binding fragment thereof, of any one of E1-E25, comprising a VL framework sequence and a VH framework sequence, and wherein one or both of the VL framework sequence or VH framework sequence is identical to the human germline sequence from which it was derived. E27. The antibody, or antigen-binding fragment thereof, of any one of E1-E26, comprising a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:225. E28. The antibody, or antigen-binding fragment thereof, of any one of E1-E27, comprising a VH comprising an amino acid sequence at least 92% identical to SEQ ID NO:225. E29. The antibody, or antigen-binding fragment thereof, of any one of E1-E28, comprising a VH comprising the amino acid sequence of SEQ ID NO:225. E30. The antibody, or antigen-binding fragment thereof, of any one of E1-E29, comprising a VL comprising an amino acid sequence at least 66% identical to SEQ ID NO:207. E31. The antibody, or antigen-binding fragment thereof, of any one of E1-E30, comprising a VL comprising an amino acid sequence at least 66%, 76%, 80%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:207. E32. The antibody, or antigen-binding fragment thereof, of any one of E1-E31, comprising a VL comprising the amino acid sequence of SEQ ID NO:207. E33. The antibody, or antigen-binding fragment thereof, of any one of E1-E32, comprising an Fc domain. E34. The antibody, or antigen-binding fragment thereof, of E33, wherein the Fc domain is the Fc domain of an IgA (for example IgA.sub.1 or IgA.sub.2), IgD, IgE, IgM, or IgG (for example IgG.sub.1, IgG.sub.2, IgG.sub.3, or IgG.sub.4). E35. The antibody, or antigen-binding fragment thereof, of E34 wherein the Fc domain is the Fc domain of an IgG. E36. The antibody, or antigen-binding fragment thereof, of E35, wherein the IgG is selected from the group consisting of IgG.sub.1, IgG.sub.2, IgG.sub.3, or IgG.sub.4. E37. The antibody, or antigen-binding fragment thereof, of E36, wherein the IgG is IgG.sub.1. E38. The antibody, or antigen-binding fragment thereof, of any one of E1-E37, comprising a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:244. E39. The antibody, or antigen-binding fragment thereof, of any one of E1-E38, comprising a heavy chain comprising an amino acid sequence at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:244 E40. The antibody, or antigen-binding fragment thereof, of any one of E1-E39, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:244. E41. The antibody, or antigen-binding fragment thereof, of any one of E1-E40, comprising a LC comprising an amino acid sequence at least 90% identical to SEQ ID NO:209. E42. The antibody, or antigen-binding fragment thereof, of any one of E1-E41, comprising a LC comprising an amino acid sequence at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:209. E43. The antibody, or antigen-binding fragment thereof, of any one of E1-E42, comprising a LC comprising the amino acid sequence of SEQ ID NO:209. E44. The antibody, or antigen-binding fragment thereof, of any one of E1-E43, comprising the VH sequence encoded by the plasmid deposited at the ATCC and having ATCC Accession No. PTA-122724. E45. The antibody, or antigen-binding fragment thereof, of any one of E1-E44, comprising the VL sequence encoded by the plasmid deposited at the ATCC and having ATCC Accession No. PTA-122725. E46. An antibody, or antigen-binding fragment thereof, that competes for binding to human IL-33 with an antibody or antigen-binding fragment thereof of any one of E1-E45. E47. An antibody, or antigen-binding fragment thereof, that competes for binding to human IL-33 with one or more of 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS. E48. An antibody, or antigen-binding fragment thereof, that competes for binding to human IL-33 with IL33-158LS, or an antigen-binding fragment of IL33-158LS. E49. The antibody, or antigen-binding fragment thereof, of any one of E1-E48, wherein the antibody or antigen-binding fragment is an Fc fusion protein, a monobody, a maxibody, a bifunctional antibody, an scFab, an scFv, a peptibody. E50. The antibody, or antigen-binding fragment thereof, of E1-E49, wherein the antibody, or antigen binding fragment thereof, binds human IL-33 with a K.sub.D about or less than a value selected from the group consisting of about 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, and 1 pM. E51. The antibody, or antigen-binding fragment thereof, of E1-E50, wherein the antibody, or antigen binding fragment thereof, binds cynomologus monkey IL-33 with a K.sub.D about or less than a value selected from the group consisting of about 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 13 pM, 10 pM, 5 pM, and 1 pM. E52. The antibody, or antigen-binding fragment thereof, of E1-E51, wherein the binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 is within 1 order of magnitude of the binding K.sub.D of the antibody, or antigen binding fragment thereof, to human IL-33. E53. The antibody, or antigen-binding fragment thereof, of E1-E52, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to human IL-33 compared with the binding to cynomologous IL-33 is between 5:1 and 1:5. E54. The antibody, or antigen-binding fragment thereof, of E1-E53, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to human IL-33 compared with the binding to cynomologous IL-33 is between 2:1 and 1:2.

E55. The antibody, or antigen-binding fragment thereof, of E1-E54, wherein the antibody, or antigen binding fragment thereof, binds active IL-33 with a lower K.sub.D than the K.sub.D with which it binds inactive IL-33. E56. The antibody, or antigen-binding fragment thereof, of E1-E55, wherein the K.sub.D of the antibody, or antigen binding fragment thereof, binding to active IL-33 is at least 10, times lesser than the K.sub.D of the antibody, or antigen binding fragment thereof, binding to inactive IL-33. E57. The antibody, or antigen-binding fragment thereof, of E1-E56, wherein the K.sub.D of the antibody, or antigen binding fragment thereof, binding to active IL-33 is at least 10, 100, 1.times.10.sup.3, 1.times.10.sup.4, 1.times.10.sup.5, 1.times.10.sup.6, 1.times.10.sup.7 times lesser than the K.sub.D of the antibody, or antigen binding fragment thereof, binding to an inactive form of IL-33. E58. The antibody, or antigen-binding fragment thereof, of E1-E57, wherein the antibody, or antigen binding fragment thereof, binds active IL-33, but does not bind inactive IL-33. E59. The antibody, or antigen-binding fragment thereof, of E55-E58, wherein the measurement of K.sub.D of active IL-33 is made using an IL-33 variant, wherein cysteine amino acid residue at position 208 (C208), according to the numbering of SEQ ID NO:396, is substituted with a non-cysteine amino acid residue. E60. The antibody, or antigen-binding fragment thereof, of E55-E59, wherein the measurement of K.sub.D of active IL-33 is made using an IL-33 variant, wherein C208 and C232, according to the numbering of SEQ ID NO:396, are substituted with a non-cysteine amino acid residue. E61. The antibody, or antigen-binding fragment thereof, of E55-E60, wherein the measurement of K.sub.D of active IL-33 is made using a reduced form of wild-type IL-33. E62. The antibody, or antigen-binding fragment thereof, of E55-E61, wherein the measurement of K.sub.D of inactive IL-33 is made using a non-reduced form of wild-type IL-33. E63. The antibody, or antigen-binding fragment thereof, of E55-E62, wherein the IL-33 is human IL-33. E64. The antibody, or antigen-binding fragment thereof, of E55-E62, wherein the IL-33 is cynomologus monkey IL-33. E65. The antibody, or antigen-binding fragment thereof, of E1-E64, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 compared with the binding to human IL-33 is within a range whose lower value is selected from the group consisting of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, and 6.2, and whose upper value is selected from the group consisting of 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 6.2, 9, 9.2, and 10. E66. The antibody, or antigen-binding fragment thereof, of E1-E55, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 compared with the binding to human IL-33 is between about 0.5 and about 3.0. E67. The antibody, or antigen-binding fragment thereof, of E1-E56, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 compared with the binding to human IL-33 is between about 1.2 and about 2.4. E68. The antibody, or antigen-binding fragment thereof, of E1-E57, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 compared with the binding to human IL-33 is between about 1 and about 2. E69. The antibody, or antigen-binding fragment thereof, of E1-58 wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 compared with the binding to human IL-33 is between about 1.3 and about 2.3. E70. The antibody, or antigen-binding fragment thereof, of E1-E59, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 compared with the binding to human IL-33 is between about 1.3 and about 1.8. E71. The antibody, or antigen-binding fragment thereof, of E1-E70, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:5 compared with the binding to human IL-33 of SEQ ID NO:3 is between about 1.0 and about 2.3. E72. The antibody, or antigen-binding fragment thereof, of E1-E71, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:5 compared with the binding to human IL-33 of SEQ ID NO:3 is between about 1.0 and about 2.0. E73. The antibody, or antigen-binding fragment thereof, of E1-E72, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:5 compared with the binding to human IL-33 of SEQ ID NO:3 is between about 1.3 and about 1.8. E74. The antibody, or antigen-binding fragment thereof, of E1-E73, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:5 compared with the binding to human IL-33 of SEQ ID NO:3 is measured by comparing the results of a HEK293 ST2 NF.kappa.B reporter assay for neutralization of cynomologous and human IL-33. E75. The antibody, or antigen-binding fragment thereof, of E1-74, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:397 compared with the binding to human IL-33 of SEQ ID NO:1 is between about 4 and about 10. E76. The antibody, or antigen-binding fragment thereof, of E1-E75, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:397 compared with the binding to human IL-33 of SEQ ID NO:1 is between about 4.2 and about 9.2. E77. The antibody, or antigen-binding fragment thereof, of E1-E76, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:397 compared with the binding to human IL-33 of SEQ ID NO:1 is about 4.2. E78. The antibody, or antigen-binding fragment thereof, of E1-E77, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:397 compared with the binding to human IL-33 of SEQ ID NO:1 is about 6.2. E79. The antibody, or antigen-binding fragment thereof, of E1-E78, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:397 compared with the binding to human IL-33 of SEQ ID NO:1 is about 9.2. E80. The antibody, or antigen-binding fragment thereof, of E1-E79, wherein the ratio of binding K.sub.D of the antibody or antigen binding fragment to cynomologous IL-33 of SEQ ID NO:397 compared with the binding to human IL-33 of SEQ ID NO:1 is measured by comparing the results of a HEK293 ST2 NF.kappa.B reporter assay for neutralization of cynomologous and human IL-33. E81. The antibody, or antigen-binding fragment thereof, of any one of E50-E80, wherein the K.sub.D value is measured by surface plasmon resonance (SPR). E82. The antibody, or antigen-binding fragment thereof, of any one of E50-E81, wherein the K.sub.D value is measured by surface plasmon resonance (SPR), and the IL-33 is immobilized. E83. The antibody, or antigen-binding fragment thereof, of any one of E1-E82, wherein the terminal half life in cynomologous monkeys is at least about 15 days. E84. The antibody, or antigen-binding fragment thereof, of any one of E1-E83, wherein the terminal half life in cynomologous monkeys is at least about 16 days. E85. The antibody, or antigen-binding fragment thereof, of any one of E1-E84, wherein the terminal half life in cynomologous monkeys is at least about 18 days. E86. The antibody, or antigen-binding fragment thereof, of any one of E1-E85, wherein the terminal half life in humans is at least about 30 days. E87. The antibody, or antigen-binding fragment thereof, of any one of E1-E86, wherein the terminal half life in humans is at least about 50 days. E88. The antibody, or antigen-binding fragment thereof, of any one of E1-E87, wherein the terminal half life in humans is at least about 55 days. E89. The antibody, or antigen-binding fragment thereof, of any one of E1-E88, wherein the terminal half life in humans is at least about 60 days E90. The antibody, or antigen-binding fragment thereof, of any one of E1-E89, wherein the terminal half life in humans is at least about 65 days. E91. The antibody, or antigen-binding fragment thereof, of any one of E1-E90, wherein the terminal half life in humans is at least about 70 days. E92. The antibody, or antigen-binding fragment thereof, of any one of E1-E91, wherein the terminal half life in humans is at least about 75 days. E93. The antibody, or antigen-binding fragment thereof, of any one of E1-E92, wherein the terminal half life in humans is at least about 80 days. E94. The antibody, or antigen-binding fragment thereof, of any one of E1-E93, wherein the terminal half life in humans is at least about 85 days. E95. The antibody, or antigen-binding fragment thereof, of any one of E1-E94, wherein the terminal half life in humans is at least about 90 days. E96. The antibody, or antigen-binding fragment thereof, of any one of E1-E95, wherein the antibody has a wavelength of maximum absorbance relative to blank of less than 15 nm in an affinity-capture self-interaction nanoparticle spectroscopy assay. E97. The antibody, or antigen-binding fragment thereof, of any one of E1-E96, wherein the antibody has a wavelength of maximum absorbance relative to blank of less than 10 nm in an affinity-capture self-interaction nanoparticle spectroscopy assay. E98. The antibody, or antigen-binding fragment thereof, of any one of E1-E97, wherein the antibody has a wavelength of maximum absorbance relative to blank of less than 5 nm in an affinity-capture self-interaction nanoparticle spectroscopy assay. E99. The antibody, or antigen-binding fragment thereof, of any one of E1-E98, wherein the antibody has a wavelength of maximum absorbance relative to blank of less than 1 nm in an affinity-capture self-interaction nanoparticle spectroscopy assay. E100. The antibody, or antigen-binding fragment thereof, of any one of E1-E99, wherein the antibody has a DNA binding score normalized to blank of less than 19. E101. The antibody, or antigen-binding fragment thereof, of any one of E1-E100, wherein the antibody has a DNA binding score normalized to blank of less than 15. E102. The antibody, or antigen-binding fragment thereof, of any one of E1-E101, wherein the antibody has a DNA binding score normalized to blank of less than 10. E103. The antibody, or antigen-binding fragment thereof, of any one of E1-E102, wherein the antibody has a DNA binding score normalized to blank of less than 7.55. E104. An antibody, or antigen binding fragment thereof, that competes for binding with the antibody, or antigen-binding fragment thereof, of any one of E1-E103 E105. An antibody, or antigen binding fragment thereof, that binds the same epitope as The antibody, or antigen-binding fragment thereof, of any one of E1-E104. E106. An antibody, or antigen binding fragment thereof, comprising the CDRs of an antibody selected from the group consisting of 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS. E107. An antibody, or antigen binding fragment thereof, comprising the VL and VH of an antibody selected from the group consisting of 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS. E108. An antibody, or antigen binding fragment thereof, selected from the group consisting of 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS. E109. An isolated nucleic acid molecule, comprising one or more nucleotide sequences encoding the antibody, or antigen-binding fragment thereof, of any one of E1-E108. E110. An isolated nucleic acid molecule comprising the nucleic acid sequence as set forth as one or more of SEQ ID NOs: 398, 399, 400, and 401. E111. An isolated nucleic acid molecule comprising the nucleic acid sequence as set forth as SEQ ID NO:398. E112. An isolated nucleic acid molecule comprising the nucleic acid sequence isolated nucleic acid molecule comprising the the nucleic acid sequence as set forth as one or more of SEQ ID NOs: 398, 399, 400, and 401 as set forth as SEQ ID NO:399. E113. An isolated nucleic acid molecule comprising the nucleic acid sequence as set forth as SEQ ID NO:400. E114. An isolated nucleic acid molecule comprising the nucleic acid sequence as set forth as SEQ ID NO:401. E115. An isolated nucleic acid molecule comprising the coding sequence of the nucleic acid molecule deposited with the ATCC and having Accession No. PTA-122724. E116. An isolated nucleic acid molecule comprising the coding sequence of the nucleic acid molecule deposited with the ATCC and having Accession No. PTA-122725. E117. A vector comprising the nucleic acid molecule of any one of E109-E116. E118. A host cell comprising the nucleic acid molecule of any one of E109-E116, or the vector of E117. E119. The host cell of E118, wherein said cell is a mammalian cell. E120. The host cell of E119, wherein said host cell is a CHO cell, a HEK-293 cell, or an Sp2.0 cell. E121. A method of making an antibody or antigen-binding fragment thereof, comprising culturing the host cell of any one of E119-E120, under a condition wherein said antibody or antigen-binding fragment is expressed by said host cell. E122. The method of E121, further comprising isolating said antibody or antigen-binding fragment thereof. E123. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of any one of E1-E108, and a pharmaceutically acceptable carrier or excipient. E124. A method of reducing the activity of IL-33, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody, or antigen-binding fragment thereof, of any one of embodiments E1-E108, or the pharmaceutical composition of E123. E125. A method of treating an inflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody, or antigen-binding fragment thereof, of any one of E1-E108, or the pharmaceutical composition of E123. E126. A method of treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody, or antigen-binding fragment thereof, of any one of E1-E108, or the pharmaceutical composition of E123. E127. A method of treating inflammatory bowel disease, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody, or antigen-binding fragment thereof, of any one of any one of E1-E108, or the pharmaceutical composition of E123. E128. The method of any one of E121-E127, wherein said subject is a human. E129. The method of any one of E121-E128, comprising administering said antibody or antigen-binding fragment thereof, or pharmaceutical composition, intravenously. E130. The method of any one of E121-E128, comprising administering said antibody or antigen-binding fragment thereof, or pharmaceutical composition, subcutaneously. E131. The method of any one of E121-E130, wherein said antibody or antigen-binding fragment thereof, or pharmaceutical composition, is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months. E132. The antibody, or antigen-binding fragment thereof, of any one of E1-E108, or the pharmaceutical composition of E123, for use as a

medicament. E133. The antibody, or antigen-binding fragment thereof, of any one of E1-108, or the pharmaceutical composition of E123, for use in reducing the activity of IL-33 in a subject. E134. The antibody, or antigen-binding fragment thereof, of any one of E1-E108, or the pharmaceutical composition of E123, for use in treating an inflammatory disease in a subject. E135. The antibody, or antigen-binding fragment thereof, of any one of E1-E108, or the pharmaceutical composition of E123, for use in treating atopic dermatitis in a subject. E136. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody, or antigen-binding fragment thereof, of any one of E1-E108, or the pharmaceutical composition of E123. E137. The method of E136, wherein the condition is selected from the group consisting of inflammatory bowel disease, allergies, allergic rhinitis, allergic conjunctivitis, vernal keratoconjunctivitis, a seasonal allergy, pet allergy, asthma, food allergy, peanut allergy, atopic dermatitis, chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis, bronchitis, chronic obstructive pulmonary disease (COPD), viral exacerbations of respiratory disease, viral infection in children and adults, (respiratory syncytial virus (RSV), rhinovirus, influenza), urticarias, eosinophilic esophagitis, chronic fibrosis, liver fibrosis, non-alcoholic steatohepatitis (NASH), chronic kidney disease, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis, acute kidney injury, sepsis, pancreatitis, type 1 diabetes, graft-versus-host disease (GVHD), tissue transplant, Alzheimer's, rheumatoid arthritis, irritable bowel syndrome (IBS), Crohns disease, ulcerative colitis, multiple sclerosis, psoriasis, celiac disease and Raynaud's disease or phenomenon.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIGS. 1A-1C are panels showing surface plasmon resonance traces of IL-33 binding to captured rat 7E8 Fab. FIG. 1A shows binding of rat 7E8 Fab to immobilized human IL-33 (mm2). FIG. 1B shows binding of rat 7E8 Fab to immobilized human IL-33 (WT) in the absence of reducing agent. FIG. 1C shows binding of rat 7E8 Fab to immobilized human IL-33 (WT) in the presence of reducing agent (DTT).

[0057] FIGS. 2A-2B are panels showing sequence alignment of anti-IL-33 optimized variable regions to human DP-54/DPK9 germlines. FIG. 2A. shows alignment of VH (SEQ ID NO:225) and VL (SEQ ID NO:207) of IL33-158-152/IL33-158LS with human germline sequences DP-54/JH4 (SEQ ID NO:7) and DPK9/JK4 (SEQ ID NO:11). FIG. 2B shows alignment of VH (SEQ ID NO:210) and VL (SEQ ID NO:91) of IL33-167-153/IL33-167LS with human germline sequences DP-54/JH4 (SEQ ID NO:7) and DPK9/JK4 (SEQ ID NO:11)

[0058] FIGS. 3A-3B are panels showing binding of cytokines to antibodies on the invention immobilized on a chip. FIG. 3A shows binding of cytokines to immobilized IL33-158LS Fab. FIG. 3B shows binding of cytokines to immobilized 7E8 Fab.

DETAILED DESCRIPTION OF THE INVENTION

Antibodies

[0059] An "antigen-binding fragment" of an antibody refers to a fragment of a full-length antibody that retains the ability to specifically bind to an antigen (preferably with substantially the same binding affinity). Examples of an antigen-binding fragment includes (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR), disulfide-linked Fvs (dsFv), and anti-idiotypic (anti-Id) antibodies and intrabodies. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)); see e.g., Bird et al. Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al, 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994, Structure 2:1121-1123).

[0060] An antibody "variable domain" refers to the variable region of the antibody light chain (VL) or the variable region of the antibody heavy chain (VH), either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs), and contribute to the formation of the antigen-binding site of antibodies.

[0061] "Complementarity Determining Regions" (CDRs) can be identified according to the definitions of the Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and/or conformational definitions or any method of CDR determination well known in the art. See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The identity of the amino acid residues in a particular antibody that make up a CDR can be determined using methods well known in the art. AbM definition of CDRs is a compromise between Kabat and Chothia and uses Oxford Molecular's AbM antibody modeling software (Accelrys.RTM.). The "contact" definition of CDRs is based on observed antigen contacts, set forth in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The "conformational" definition of CDRs is based on residues that make enthalpic contributions to antigen binding (see, e.g., Makabe et al., 2008, J. Biol. Chem., 283:1156-1166). North has identified canonical CDR conformations using a different preferred set of CDR definitions (North et al., 2011, J. Mol. Biol. 406: 228-256). In another approach, referred to herein as the "conformational definition" of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding (Makabe et al., 2008, J Biol. Chem. 283:1156-1166). Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs (or other residue of the antibody) may be defined in accordance with any of Kabat, Chothia, North, extended, AbM, contact, and/or conformational definitions.

[0062] Residues in a variable domain are numbered according Kabat, which is a numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies. See, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard" Kabat numbered sequence. Various algorithms for assigning Kabat numbering are available. The algorithm implemented in the version 2.3.3 release of Abysis (www.abysis.org) is used herein to assign Kabat numbering to variable regions CDR-L1, CDR-L2, CDR-L3, CDR-H2, and CDR-H3. AbM definition is used for CDR-H1.

[0063] Specific amino acid residue positions in an antibody may also be numbered according to Kabat.

[0064] "Framework" (FR) residues are antibody variable domain residues other than the CDR residues. A VH or VL domain framework comprises four framework sub-regions, FR1, FR2, FR3 and FR4, interspersed with CDRs in the following structure: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0065] An "epitope" refers to the area or region of an antigen to which an antibody specifically binds, e.g., an area or region comprising residues that interacts with the antibody. Epitopes can be linear or conformational.

[0066] An antibody that "preferentially binds" or "specifically binds" (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a IL-33 epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other IL-33 epitopes or non-IL-33 epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) which specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding. "Specific binding" or "preferential binding" includes a compound, e.g., a protein, a nucleic acid, an antibody, and the like, which recognizes and binds to a specific molecule, but does not substantially recognize or bind other molecules in a sample. For instance, an antibody or a peptide receptor which recognizes and binds to a cognate ligand or binding partner (e.g., an anti-human tumor antigen antibody that binds a tumor antigen) in a sample, but does not substantially recognize or bind other molecules in the sample, specifically binds to that cognate ligand or binding partner. Thus, under designated assay conditions, the specified binding moiety (e.g., an antibody or an antigen-binding portion thereof or a receptor or a ligand binding portion thereof) binds preferentially to a particular target molecule and does not bind in a significant amount to other components present in a test sample.

[0067] A variety of assay formats may be used to select an antibody or peptide that specifically binds a molecule of interest. For example, solid-phase ELISA immunoassay, immunoprecipitation, BIAcore.TM. (GE Healthcare, Piscataway, N.J.), fluorescence-activated cell sorting (FACS), Octet.TM. (ForteBio, Inc., Menlo Park, Calif.) and Western blot analysis are among many assays that may be used to identify an antibody that specifically reacts with an antigen or a receptor, or ligand binding portion thereof, that specifically binds with a cognate ligand or binding partner. Typically, a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times background, even more specifically, an antibody is said to "specifically bind" an antigen when the equilibrium dissociation constant (K.sub.D) is .ltoreq.1 .mu.M, preferably .ltoreq.100 nM, more preferably .ltoreq.10 nM, even more preferably, .ltoreq.100 pM, yet more preferably, .ltoreq.10 pM, and even more preferably, .ltoreq.1 pM.

[0068] The term "compete", as used herein with regard to an antibody, means that binding of a first antibody, or an antigen-binding portion thereof, to an antigen reduces the subsequent binding of the same antigen by a second antibody or an antigen-binding portion thereof. In general, the binding a first antibody creates steric hindrance, conformational change, or binding to a common epitope (or portion thereof), such that the binding of the second antibody to the same antigen is reduced. Standard competition assays may be used to determine whether two antibodies compete with each other. One suitable assay for antibody competition involves the use of the Biacore technology, which can measure the extent of interactions using surface plasmon resonance (SPR) technology, typically using a biosensor system (such as a BIACORE.RTM. system). For example, SPR can be used in an in vitro competitive binding inhibition assay to determine the ability of one antibody to inhibit the binding of a second antibody. Another assay for measuring antibody competition uses an ELISA-based approach.

[0069] Furthermore, a high throughput process for "binning" antibodies based upon their competition is described in International Patent Application No. WO2003/48731. Competition is present if one antibody (or fragment) reduces the binding of another antibody (or fragment) to IL-33. For example, a sequential binding competition assay may be used, with different antibodies being added sequentially. The first antibody may be added to reach binding that is close to saturation. Then, the second antibody is added. If the binding of second antibody to IL-33 is not detected, or is significantly reduced (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% reduction) as compared to a parallel assay in the absence of the first antibody (which value can be set as 100%), the two antibodies are considered as competing with each other. An exemplary antibody competition assay (and overlapping epitope analysis) by SPR is provided in Example 4.

[0070] An "Fc fusion" protein is a protein wherein one or more polypeptides are operably linked to an Fc polypeptide. An Fc fusion combines the Fc region of an immunoglobulin with a fusion partner.

[0071] The term "treatment" includes prophylactic and/or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease, or shortening the length of the disease.

Binding Affinity

[0072] The binding affinity of an antibody can be expressed as K.sub.D value, which refers to the dissociation rate of a particular antigen-antibody interaction. K.sub.D is the ratio of the rate of dissociation, also called the "off-rate (K.sub.off)", to the association rate, or "on-rate (k.sub.on)". Thus, K.sub.D equals k.sub.off/k.sub.on and is expressed as a molar concentration (M), and the smaller the K.sub.D, the stronger the affinity of binding. K.sub.D values for antibodies can be determined using methods well established in the art. One exemplary method for measuring Kd is surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE.RTM. system. BIAcore kinetic analysis comprises analyzing the binding and dissociation of an antigen from chips with immobilized molecules (e.g. molecules comprising epitope binding domains), on their surface. Another method for determining the Kd of an antibody is by using Bio-Layer Interferometry, typically using OCTET.RTM. technology (Octet QKe system, ForteBio). Alternatively or in addition, a KinExA.RTM. (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Id.) can also be used.

[0073] In some aspects, the K.sub.D value is measured by surface plasmon resonance (SPR). The IL-33 may be immobilized. The IL-33 may be immobilized to a solid surface. The IL-33 may be immobilized to a chip, for example by covalent coupling (such as amine coupling). The chip may be a CM5 sensor chip.

[0074] As the analyte binds to the ligand the accumulation of protein on the sensor surface causes an increase in refractive index. This refractive index change is measured in real time (sampling in a kinetic analysis experiment is taken every 0.1 s), and the result plotted as response units (RU) versus time (termed a sensorgram). Importantly, a response (background response) will also be generated if there is a difference in the refractive indices of the running and sample buffers. This background response must be subtracted from the sensorgram to obtain the actual binding response. The background response is recorded by injecting the analyte through a control or reference flow cell, which has no ligand or an irrelevant ligand immobilized to the sensor surface. The real time measurement of association and dissociation of a binding interaction allows for the calculation of association and dissociation rate constants and the corresponding affinity constants. One RU represents the binding of 1 pg of protein per square mm. More than 50 pg per square mm of analyte binding is generally needed in practice to generate good reproducible responses. Between 85 and 370 RU of IL-33 may be immobilized. Between 85 and 225 RU of IL-33 may be immobilized.

[0075] Dissociation of the antibody from the IL-33 may be monitored for about 3600 seconds. The SPR analysis may be conducted, and the data collected at between about 15.degree. C. and about 37.degree. C. The SPR analysis may be conducted, and the data collected at between about 25.degree. C. and 37.degree. C. The SPR analysis may be conducted, and the data collected at about 37.degree. C. The SPR analysis may be conducted, and the data collected at 37.degree. C. The K.sub.D value may be measured by SPR using a BIAcore T200 instrument. The SPR rates and affinities may be determined by fitting resulting sensorgram data to a 1:1 model in BIAcore T200 Evaluation software version 1.0. The collection rate may be about 1 Hz.

[0076] The term "IL-33 molecule" refers to molecules that demonstrate a greater sequence identity to wild type IL-33 than to another member of the IL-1 family of cytokines, (such comparisons being made within the same species). The term IL-33 molecule includes mutants, variants, truncations, fragments, splice variants, species variants, and IL-33 like portions of fusion proteins.

[0077] IL-33 is produced as precursor with an N-terminal domain that is responsible for translocation to the nucleus and binding to chromatin, and a C-terminal 12-stranded beta-trefoil domain that interacts with the ST2 receptor and is responsible for the biological activity of IL-33. The full length form of human IL-33 as represented by UniProtKB/Swiss-Prot accession number 095760.1 is herein provided as SEQ ID NO:396.

[0078] Upon release of IL-33 from cells, the N-terminal domain is cleaved, leading to the release of a C-terminal domain with greater activity than that of the full-length protein. A number of different proteases, both endogenous to the cellular source of IL-33, such as calpains, as well as exogenous proteases derived from inflammatory cells, such as mast cells and neutrophils, can cleave the IL-33 precursor molecule. The precise cleavage site of IL-33 will vary depending on the proteases that are present. A recombinant form of IL-33 C terminal domain from amino acids 112-270 of SEQ ID NO:396 is representative of the active C-terminal forms of IL-33, and is given as SEQ ID NO:1.

[0079] The structure of IL-33 suggests it is a .beta.-trefoil protein with four free cysteine residues (C208, C232, C227 and C259, according to the numbering of SEQ ID NO:396). Evidence suggest that IL-33 exists in an active form, with these four cysteines reduced, and an inactive form, with disulfide bonds between pairs of cysteine residues, (including diusulfide bonds between the pairs C208-C259 and C227-C232), which likely coincide with a substantial conformational change, including disruption to the high-affinity ST2 binding site, thus providing a potential structural explanation for the loss of ST2 binding (Cohen et al., 2015, Nature Communications 6:8327; doi: 10.1038/ncomms9327). Mutational evidence further suggests that cysteine residues C208 and C232 may also form a disulfide bond that leads to inactivation of IL-33 (Cohen et al., 2015).

[0080] A constitutively active form of IL-33 may be generated by mutating one or more of the cysteine residues to a non-cysteine residue. Residue C208 has been found to be particulary important for the inactivation process, with mutation of residue C232 also appearing to confer resistance to inactivation. Evidence also suggests that possible disulfide bonds between C208-C259 and C227-C232 are not the entire source of inactivation, as mutations in C227 and C259 do not confer similar levels of resistance to inactivity; thus there may be several pattens of disulfide bond formation for IL-33. (Cohen 2015).

[0081] "Active IL-33" may be defined as an IL-33 molecule able to bind ST2. Active IL-33 may be defined as an IL-33 molecule lacking one or two intramolecular covalent bonds between pairs of residues at positions 208, 227, 232, and 259 (according to the numbering of SEQ ID NO:396). Active IL-33 may be defined as an IL-33 molecule lacking two intramolecular covalent bonds between pairs of residues at positions 208, 227, 232, and 259 (according to the numbering of SEQ ID NO:396). In some aspects, active IL-33 is an IL-33 molecule lacking a covalent bond between residues 208 and 259. In some aspects, active IL-33 is an IL-33 molecule lacking a covalent bond between residues 227 and 232. In some aspects, active IL-33 is an IL-33 molecule lacking a covalent bond between residues 208 and 227. In some aspects, active IL-33 is an IL-33 molecule lacking a covalent bond between residues 208 and 232. In some aspects, active IL-33 is an IL-33 molecule lacking a covalent bond between residue pairs 208/259 and 227/232, or between residue pairs 208/232 and 227/259. Active IL-33 therefore includes reduced forms of wild type IL-33, and mutant forms of IL-33, wherein at least one, two, three or four residues at position numbers 208, 227, 232, and 259, are not cysteine. In some aspects, at least one of residue 208 and 232 is not cysteine. In some aspects, at least residue 208 is not cysteine. In some aspects, at least residues 208 and 232 are not cysteine. In some aspects, each of residues 208, 227, 232 and 259 are not cysteine. In some aspects, one or more of residues 208, 227, 232 and 259 are serine. The covalent bond may be a disulfide bond. The foregoing residue numbering is according to the numbering of SEQ ID NO:1. In some aspects, active IL-33 comprises a fully reduced molecule comprising SEQ ID NO:1. In some aspects, active IL-33 comprises a fully reduced molecule comprising SEQ ID NO:4. In some aspects, active IL-33 comprises a molecule comprising SEQ ID NO:3. In some aspects, active IL-33 comprises a molecule comprising SEQ ID NO:5.

[0082] Inactive IL-33 may be defined as an IL-33 molecule that binds ST2 with an affinity at least 10-fold lower than active IL-33. In some aspects, inactive IL-33 binds ST2 with an affinity at least 100-fold lower than active IL-33. In some aspects, inactive IL-33 binds ST2 with an affinity at least 1000-fold lower than active IL-33. In some aspects, inactive IL-33 binds ST2 with an affinity at least 4 orders of magnitude lower than active IL-33. In some aspects, inactive IL-33 binds ST2 with an affinity at least 5 orders of magnitude lower than active IL-33. In some aspects, inactive IL-33 comprises a covalent bond between one or both of residue pairs 208/259 and 227/232. In some aspects, inactive IL-33 comprises a covalent bond between one or both of residue pairs 208/232 and and 227/259. In some aspects, inactive IL-33 comprises a covalent bond between residues 208 and 232. In some aspects, inactive IL-33 comprises a covalent bond between residues 208 and 259. In some aspects, inactive IL-33 comprises a covalent bond between residues 227 and 232. In some aspects, inactive IL-33 comprises a covalent bond between both of residue pairs 208/259 and 227/232. One or more of the residues may be cysteines. One or both of the covalent bonds may be a disulfide bond. The foregoing residue numbering is according to the numbering of SEQ ID NO:396.

[0083] In some aspects, the IL-33 is human IL-33. In some aspects, the sequence of wild type IL-33 is SEQ ID NO:1. In some aspects, the IL-33 is rat IL-33. In some aspects, the IL-33 is mouse IL-33. In some aspects, the IL-33 is primate IL-33. In some aspects, the IL-33 is ape IL-33. In some aspects, the IL-33 is monkey IL-33. In some aspects, the IL-33 is cynomologus monkey IL-33.

[0084] The measurement of K.sub.D of active IL-33 may be made using an IL-33 variant, wherein at least C208 is substituted with another amino acid residue. In some aspects, the measurement of K.sub.D of active IL-33 is made using an IL-33 variant, wherein at least C232 is substituted with another residue. In some aspects, the measurement of K.sub.D of active IL-33 is made using an IL-33 variant, wherein at least C208 and C232 are substituted. In some aspects, the measurement of K.sub.D of active IL-33 is made using an IL-33 variant, wherein C208, C227, C232, and C259 are substituted. In some aspects, one or more of the cysteine residues are substituted with serine.

Antibodies to IL-33

[0085] In some aspects, the invention provides antagonistic IL-33 antibodies. A high affinity antagonist of the IL-33 pathway may be effective on multiple cell types, and multiple tissue compartments where IL-33 is thought to act on its target cells. In some aspects, antibodies of the invention may access sites where IL-33 is released from cells, particularly epithelial and endothelial cells. In some aspects, the invention provides an IL-33 antibody that can partition to the extracellular spaces within the lung and other tissues, can effectively compete with binding of IL-33 to the cell surface receptor and has a relatively long half-life so as to allow for infrequent dosing. Antibodies of the invention have the potential to modify an important pathway that drives the development and inflammation associated with asthma.

[0086] A neutralizing or "blocking" antibody, refers to an antibody whose binding to IL-33: (i) interferes with, limits, or inhibits the interaction between IL-33 or an IL-33 fragment and an IL-33 receptor component (for example, ST2, IL-1 RAcP, etc.); and/or (ii) results in inhibition of at least one biological function of IL-33. Assays to determine the neutralization by an antibody of the invention are described elsewhere herein and are well-known in the art.

[0087] The present invention provides antibodies that specifically bind to IL-33. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 50%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 60%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 70%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 80%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 90%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 95%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 96%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 97%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 98%. In some aspects, the invention provides an antibody, or antigen binding fragment thereof, that neutralizes IL-33 by at least 99%.

[0088] The antibody, or an antigen binding fragment thereof, may be selected from the group consisting of 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7, 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS, antigen binding fragments thereof, and mutants, variants, derivatives and substantially similar versions thereof.

CDR Consensus Sequences

[0089] In some aspects, the CDRs comprise SEQ ID NOs: 257, 261, 265, 269, 272, and 276. These CDR sequences incorporate the consensus based on all available data (ABS plus mutations plus rat repertoire), tested VH germlines, and mutations that were based on modeling to either retain/improve binding to IL-33 or reduce polyreactivity or sequence liabilities without disrupting binding.

[0090] CDR H1: The broad consensus sequence for CDR H1 is SEQ ID NO:269, based on the totality of information available. A further refined subset of consensus sequences for CDR H1 is SEQ ID NO:270, including the results from optimization of parental rat antibodies 7E8 and 9B3 and augmented binary substitution (ABS). The consensus CDR H1 sequence for optimized 7E8 is .sup.26GF(T/E)F(S/E)(N/S)YWMY.sup.32 (SEQ ID NO:270). Substitution of the CDR H1 from 9B3, which introduced a S31N mutation, or introduction of the mutations T28E or S30E, allowed retention of full activity. Augmented binary substitution mutagenesis showed a strong preference for Y at position 35 instead of the DP54 germline residue S. The consensus CDR H1 sequence for optimized 7E8 addressing the 9B3 sequence at position 31 and the ABS preferences at position 35 is SEQ ID NO:271.

[0091] CDR H2: The broad consensus sequence for CDR H2 is SEQ ID NO:272, based on the totality of information available. A further refined subset of consensus sequences for CDR H2 is SEQ ID NO:273, including the results from optimization of 7E8 and 9B3 and augmented binary substitution (ABS). The consensus CDR H2 sequence for optimized 7E8 is .sup.50(S/A)I(T/N)(P/N)(N/D)(G/A)(G/S/H)(N/D/E)(T/K/D/E) YY(P/V/L)(D/E) SV(K/Q)G.sup.66(SEQ ID NO:273). Introduction of the mutations 550A, G55A, G56H, N57D, N57E, T58D, T58E, D62E, or K65Q allowed retention of human IL-33 neutralization potency without substantial increases in non-specific binding. N54I, N54L, N54V, N54Y, and N54W allowed retention of human IL-33 neutralization potency but introduced increased non-specific binding. Substitution of the CDR H2 from 9B3 into 7E8, which introduced four changes (T52N, P53N, N54D, and P61L), allowed retention of potent neutralization of human IL-33 but led to a reduction in potency of cynomolgus monkey IL-33 neutralization. Augmented binary substitution mutagenesis showed a strong preference for S, T and P at positions 50, 52 and 53 instead of the DP54 germline residues N, K and Q, but incorporation of the DP54 germline mutations N54D, G56S, N57E, T58K, and P61V was tolerated. The consensus CDR H2 sequence for optimized 7E8 addressing the ABS preferences at positions 52 and 53 and the 9B3 sequences tolerated for neutralization of human IL-33 is SEQ ID NO:274. The consensus CDR H2 sequence for optimized 7E8 addressing the ABS preferences at positions 52 and 53 is SEQ ID NO:275.

[0092] CDR H3: The broad consensus sequence for CDR H3 is SEQ ID NO:276, based on the totality of information available. A further refined subset of consensus sequences for CDR H3 is SEQ ID NO:277, including the results from optimization of 7E8 and 9B3 and analysis of sequence from the antibody repertoire of a rat immunized with human IL-33. The consensus CDR H3 sequence for optimized 7E8 is .sup.99G(H/Y)Y(Y/S)(Y/H)(T/S/N)(S/A)YS(L/F)(G/S)Y.sup.110 (SEQ ID NO:278). Introduction of the mutations H100Y, Y103H, T104N, T104S, or S105A allowed retention of human IL-33 neutralization potency without substantial increases in non-specific binding. The mutations S105D and S105N led to loss of human IL-33 neutralization potency. Substitution of the CDR H3 from 9B3 into 7E8, which introduced the mutations Y102S, T104S, L108F, and G109S, allowed retention of potent neutralization of human IL-33 but led to a reduction in potency of cynomolgus monkey IL-33 neutralization. Incorporation of 7E8-related CDR H3 sequences identified from the antibody repertoire of a rat immunized with human IL-33 showed that the following amino acids are compatible with high human IL-33 neutralization potency: R100, F101, N104, I108, A109, H110, N110, S110, and F110. The consensus CDR H3 sequence for optimized 7E8 addressing the 9B3 sequences tolerated for neutralization of human IL-33 is SEQ ID NO:279.

[0093] CDR L1: The broad consensus sequence for CDR L1 is SEQ ID NO:257, based on the totality of information available. A further refined subset of consensus sequences for CDR L1 is SEQ ID NO:258, including the results from optimization of 7E8 and 9B3 and augmented binary substitution (ABS). The consensus CDR L1 sequence for optimized 7E8 is .sup.24(K/R)AS(Q/H)(N/S)I(N/S)(K/S)HLD.sup.34 (SEQ ID NO:259). Augmented binary substitution mutagenesis showed a strong preference for H and D at positions 32 and 34 instead of the DPK9 germline residues Y.sup.32 and N.sup.34 but incorporation of the DPK9 germline mutations K24R, N28S, N30S, and K31S was tolerated. Substitution of the 9B3 light chain for the 7E8 light chain (which includes the light chain sequence variation Q27H) allowed retention of IL-33 neutralization potency without introducing non-specific binding. Introduction of the mutations N30H, K31R, and H32Y allowed retention of human IL-33 neutralization but increased nonspecific binding, while the mutations N30Y, N30D, N30W, K31E, and K31D reduced potency and/or introduced higher nonspecific binding. The consensus CDR L1 sequence for optimized 7E8 addressing the ABS preferences at positions 32 and 34 without allowing for the light chain sequence variation at position 27 is SEQ ID NO:260.

[0094] CDR L2: The broad consensus sequence for CDR L2 is SEQ ID NO:261, based on the totality of information available. A further refined subset of consensus sequences for CDR L2 is SEQ ID NO:262, including the results from optimization of 7E8 and 9B3 and augmented binary substitution (ABS). The consensus CDR L2 sequence for optimized 7E8 is .sup.50F(T/A)(N/S)(N/S)LQ(T/S).sup.56 (SEQ ID NO:263). Augmented binary substitution mutagenesis showed a strong preference for F at position 50 instead of the DPK9 germline residue A, but incorporation of the DPK9 germline mutations T51A, N52S, N53S, and T56S was tolerated. Introduction of the mutations N52Y or N53R allowed retention of human IL-33 neutralization but increased nonspecific binding, while the mutations F50H, T56D, T56E, and T56Q reduced potency and/or introduced higher nonspecific binding. The consensus CDR L2 sequence for optimized 7E8 without allowing for variation at position 53 is SEQ ID NO:264.

[0095] CDR L3: The broad consensus sequence for CDR L3 is SEQ ID NO:265, based on the totality of information available. A further refined subset of consensus sequences for CDR L3 is SEQ ID NO:266, including the results from optimization of 7E8 and 9B3 and augmented binary substitution (ABS). The consensus CDR L3 sequence for optimized 7E8 is .sup.89(F/Q)QY(N/Y)(N/S/Q/R)GWT.sup.96 (SEQ ID NO:267). Introduction of the mutation N93Q allowed retention of human IL-33 neutralization potency without a substantial increase in non-specific binding, while the mutation N93R allowed retention of human IL-33 neutralization potency with minor increases in non-specific binding. The mutations N92R and G94R allowed retention of human IL-33 neutralization potency but led to increases in nonspecific binding. Substitution of the 9B3 light chain for the 7E8 light chain (which includes the light chain sequence variation N93S) allowed retention of IL-33 neutralization potency without introducing non-specific binding. Augmented binary substitution mutagenesis showed a strong preference for Y and G at positions 91 and 94 instead of the DPK9 germline residues S and T, but incorporation of the DPK9 germline mutations F89Q, N92Y, and N93S was tolerated. Retention of the rat J segment residue W95 was strongly favored over substitution of the human JK4 residue W95L. The consensus CDR L3 sequence for optimized 7E8 addressing the ABS preferences at positions 91 and 94 without allowing for incorporation of R at position 93 is SEQ ID NO:268.

[0096] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1 comprising SEQ ID NO:257, a CDR-L2 comprising SEQ ID NO:261, a CDR-L3 comprising SEQ ID NO:265, a CDR-H1 comprising SEQ ID NO:269, a CDR-H2 comprising SEQ ID NO:272, and a CDR-H3 comprising SEQ ID NO: 276

[0097] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1 comprising SEQ ID NO:258, a CDR-L2 comprising SEQ ID NO:262, a CDR-L3 comprising SEQ ID NO:266, a CDR-H1 comprising SEQ ID NO:270, a CDR-H2 comprising SEQ ID NO:273, and a CDR-H3 comprising SEQ ID NO: 277.

[0098] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1 comprising SEQ ID NO:259, a CDR-L2 comprising SEQ ID NO:263, a CDR-L3 comprising SEQ ID NO:267, a CDR-H1 comprising SEQ ID NO:271, a CDR-H2 comprising SEQ ID NO:274, and a CDR-H3 comprising SEQ ID NO: 278.

[0099] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1 comprising SEQ ID NO:260, a CDR-L2 comprising SEQ ID NO:264, a CDR-L3 comprising SEQ ID NO:268, a CDR-H1 comprising SEQ ID NO:271, a CDR-H2 comprising SEQ ID NO:275, and a CDR-H3 comprising SEQ ID NO: 279.

[0100] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1 comprising SEQ ID NO:20, a CDR-L2 comprising SEQ ID NO:21, a CDR-L3 comprising SEQ ID NO:208, a CDR-H1 comprising SEQ ID NO:16, a CDR-H2 comprising SEQ ID NO:226, and a CDR-H3 comprising SEQ ID NO: 18.

[0101] In some aspects, the antibody, or antigen binding fragment thereof, comprises the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:225.

[0102] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:207.

[0103] The antibody or antigen-binding fragment may comprise a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:225. The VH may comprise an amino acid sequence at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:225. The VH may comprise the amino acid sequence of SEQ ID NO:225.

[0104] The antibody or antigen-binding fragment may comprise a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:207. The VL may comprise an amino acid sequence at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:207. The VL may comprise the amino acid sequence of SEQ ID NO:207.

[0105] The antibody or antigen-binding fragment may comprise a HC comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:244. The HC may comprise the amino acid sequence of SEQ ID NO:244.

[0106] The antibody or antigen-binding fragment may comprise a LC comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:209. The LC may comprise the amino acid sequence of SEQ ID NO:209.

[0107] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1 comprising SEQ ID NO:20, a CDR-L2 comprising SEQ ID NO:21, a CDR-L3 comprising SEQ ID NO:22, a CDR-H1 comprising SEQ ID NO:16, a CDR-H2 comprising SEQ ID NO:211, and a CDR-H3 comprising SEQ ID NO: 18.

[0108] In some aspects, the antibody, or antigen binding fragment thereof, comprises the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:210.

[0109] In some aspects, the antibody, or antigen binding fragment thereof, comprises a CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:91.

[0110] The antibody or antigen-binding fragment may comprise a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:210. The VH may comprise an amino acid sequence at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:210. The VH may comprise the amino acid sequence of SEQ ID NO:210.

[0111] The antibody or antigen-binding fragment may comprise a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:91. The VL may comprise an amino acid sequence at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:91. The VL may comprise the amino acid sequence of SEQ ID NO:91.

[0112] The antibody or antigen-binding fragment may comprise a HC comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:245. The HC may comprise the amino acid sequence of SEQ ID NO:245.

[0113] The antibody or antigen-binding fragment may comprise a LC comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to SEQ ID NO:93. The LC may comprise the amino acid sequence of SEQ ID NO:93.

Germline Substitutions

[0114] In certain embodiments, The antibody, or antigen-binding fragment thereof, comprises the following heavy chain CDR sequences: (i) CDR-H1 comprising SEQ ID NO:16, CDR-H2 comprising SEQ ID NO:226, and CDR-H3 comprising SEQ ID NO:18; and/or (ii) the following light chain CDR sequences: CDR-L1 comprising SEQ ID NO:20, CDR-L2 comprising SEQ ID NO:21, and CDR-L3 comprising SEQ ID NO:208.

[0115] In certain embodiments, no more than 11, or no more than one 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 substitution is made in CDR-L1, relative to SEQ ID NO:20. In certain embodiments, no more than 6, no more than 5, no more than 4, no more than 3, no more than 3, no more than 2, or no more than one substitution is made in CDR-L2, relative to SEQ ID NO:21. In certain embodiments, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 3, no more than 2, or no more than one substitution is made in CDR-L3, relative to SEQ ID NO:208.1n some embodiments, no more than one 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 substitution is made in CDR-H1, relative to SEQ ID NO:16. In some embodiments, no more than no more than 17, no more than 16, no more than 15, no more than 14, no more than 13, no more than 12, no more than 11, or no more than one 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 substitution is made in CDR-H2, relative to SEQ ID NO:211. In some embodiments, no more than 12, no more than 11, or no more than one 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 substitution is made in CDR-H3, relative to SEQ ID NO:18. In certain embodiments, the substitution(s) do not change binding affinity (K.sub.D) value by more than 1000-fold, more than 100-fold, or 10-fold. In certain embodiments, the substitution is a conservative substation according to Table 1.

TABLE-US-00001 TABLE 1 Conservative Substitutions Conservative Conservative Residue substitution Residue substitution Ala Ser Leu Ile, Val Arg Lys Lys Arg, Gln Asn Gln; His Met Leu, Ile Asp Glu Phe Met, Leu, Tyr Cys Ser Ser Thr; Gly Gln Asn Thr Ser, Val Glu Asp Trp Tyr Gly Pro Tyr Trp, Phe His Asn, Gln Val Ile, Leu Ile Leu, Val Pro --

[0116] In certain embodiments, the substitution is human germline substitution in which a CDR residue is replaced with the corresponding human germline residue, to increase the human amino acid content and potentially reduce immunogenicity of the antibody. For example, if human germline DPK9 framework is used and the exemplary antibody IL-33-158LS, then the alignment of the CDR-L1 of IL33-158L5 antibody (SEQ ID NO:20) and human germline DPK9 is as follows:

TABLE-US-00002 Position 24 25 26 27 28 29 30 31 32 33 34 Human Germline R A S Q S I S S Y L N DPK9 IL33-158L5 K A S Q N I N K H L D (SEQ ID NO: 20)

[0117] For positions 25 26, 27, 29, 33, and 34, the human germline residue and the corresponding IL33-158L5 residue are the same, and a germline substitution is not possible. For positions 24, 28, 30, 31, and 32 (bold and underlined), the human germline residue and the corresponding IL33-158L5 residue are different. Residues of IL33-158L5 at these positions may be replaced with the corresponding human germline DPK9 residue to further increase the human residue content.

[0118] Methods and libraries for introducing human germline residues in antibody CDRs are described in detail in U.S. provisional application 62/162,905, and (Townsend et al., 2015, Proc. Natl. Acad. Sci. USA. 112(50):15354-15359), and both are herein incorporated by reference in their entirety.

[0119] The antibody, or antigen-binding fragment thereof, may comprise a VH framework comprising a human germline VH framework sequence. The VH framework sequence can be from a human VH3 germline, a VH1 germline, a VH5 germline, or a VH4 germline. Preferred human germline heavy chain frameworks are frameworks derived from VH1, VH3, or VH5 germlines. For example, VH frameworks from the following germlines may be used: IGHV3-23, IGHV3-7, or IGHV1-69 (germline names are based on IMGT germline definition). Preferred human germline light chain frameworks are frameworks derived from VK or V.lamda. germlines. For example, VL frameworks from the following germlines may be used: IGKV1-39 or IGKV3-20 (germline names are based on IMGT germline definition). Alternatively or in addition, the framework sequence may be a human germline consensus framework sequence, such as the framework of human V.lamda.1 consensus sequence, VK1 consensus sequence, VK2 consensus sequence, VK3 consensus sequence, VH3 germline consensus sequence, VH1 germline consensus sequence, VH5 germline consensus sequence, or VH4 germline consensus sequence. Sequences of human germline frameworks are available from various public databases, such as V-base, IMGT, NCBI, or Abysis.

[0120] The antibody, or antigen-binding fragment thereof, may comprise a VL framework comprising a human germline VL framework sequence. The VL framework may comprise one or more amino acid subsitutions, additions, or deletions, while still retaining functional and structural similarity with the germline from which it was derived. In some aspects, the VL framework is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a human germline VL framework sequence. In some aspects, the antibody, or antigen binding fragment thereof, comprises a VL framework comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VL framework sequence. In some aspects, the 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions or deletions are only in the framework regions. In some aspects, the % identity is based on similarity with VL excluding those portions herein defined as CDRs.

[0121] The human germline VL framework may be the framework of DPK9 (IMGT name: IGKV1-39). The human germline VL framework may be the framework of DPK12 (IMGT name: IGKV2D-29). The human germline VL framework may be the framework of DPK18 (IMGT name: IGKV2-30). The human germline VL framework may be the framework of DPK24 (IMGT name: IGKV4-1). The human germline VL framework may be the framework of HK102_V1 (IMGT name: IGKV1-5). The human germline VL framework may be the framework of DPK1 (IMGT name: IGKV1-33). The human germline VL framework may be the framework of DPK8 (IMGT name: IGKV1-9). The human germline VL framework may be the framework of DPK3 (IMGT name: IGKV1-6). The human germline VL framework may be the framework of DPK21 (IMGT name: IGKV3-15). The human germline VL framework may be the framework of Vg_38K (IMGT name: IGKV3-11). The human germline VL framework may be the framework of DPK22 (IMGT name: IGKV3-20). The human germline VL framework may be the framework of DPK15 (IMGT name: IGKV2-28). The human germline VL framework may be the framework of DPL16 (IMGT name: IGLV3-19). The human germline VL framework may be the framework of DPL8 (IMGT name: IGLV1-40). The human germline VL framework may be the framework of V1-22 (IMGT name: IGLV6-57). The human germline VL framework may be the framework of human V.lamda. consensus sequence. The human germline VL framework may be the framework of human V.lamda.1 consensus sequence. The human germline VL framework may be the framework of human V.lamda.3 consensus sequence. The human germline VL framework may be the framework of human VK consensus sequence. The human germline VL framework may be the framework of human VK1 consensus sequence. The human germline VL framework may be the framework of human VK2 consensus sequence. The human germline VL framework may be the framework of human VK3 consensus sequence.

[0122] In some aspects, the VL framework is DPK9. Other similar framework regions are also predicted to deliver advantageous antibodies of the invention comprising CDRs of SEQ ID NOs: 257, 261, an 265; or SEQ ID NOs: 258, 262, and 266; or SEQ ID NOs: 259, 263, and 267; or SEQ ID NOs: 260, 264, an 268; or SEQ ID NOs: 20, 21, and 208; including DPK5, DPK4, DPK1, IGKV1-5*01, DPK24, DPK21, DPK15, IGKV1-13*02, IGKV1-17*01, DPK8, IGKV3-11*01, and DPK22 which comprise 99, 97, 97, 96, 80, 76, 66, 97, 97, 96, 76, and 74% identity respectively to the FW region of DPK-9 and one or fewer amino acid differences in common structural features (Kabat Numbering) (A) residues directly underneath CDR (Vernier Zone), L2, L4, L35, L36, L46, L47, L48, L49, L64, L66, L68, L69, L71, (B) VH/VL Chain packing Residues: L36, L38, L44, L46, L87 and (C) canonical CDR Structural support residues L2, L48, L64, L71 (see Lo, "Antibody Humanization by CDR Grafting", (2004) Antibody Engineering, Vol. 248, Methods in Molecular Biology pp 135-159 and O'Brien and Jones, "Humanization of Monoclonal Antibodies by CDR Grafting", (2003) Recombinant Antibodies for Cancer Therapy, Vol. 207, Methods in Molecular Biology pp 81-100). Particularly preferred are framework regions of DPK5, DPK4, DPK1, IGKV1-5*01, DPK24, DPK21, DPK15 sharing 99, 97, 97, 96, 80, 76, 66% identity to DPK9 respectively and have no amino acid differences in these common structural features. In some aspects, the % identity is based on similarity with VL excluding those portions herein defined as CDRs.

[0123] Residues in CDR-L1, CDR-L2, and CDR-L3 of the antibodies (and fragments) of the invention may be substituted with the corresponding germline residues as shown in Table 2.

TABLE-US-00003 TABLE 2 SEQ ID Light CHain 280 DPK9 CDR-L1 RASQSISSYLN 281 DPK9 CDR-L2 AASSLQS 282 DPK9 CDR-L3 QQSYSTP 283 DPK12 CDR-L1 KSSQSLLHSDGKTYLY 284 DPK12 CDR-L2 EVSNRFS 285 DPK12 CDR-L3 MQSIQLP 286 DPK18 CDR-L1 RSSQSLVYSDGNTYLN 287 DPK18 CDR-L2 KVSNRDS 288 DPK18 CDR-L3 MQGTHWP 289 DPK24 CDR-L1 KSSQSVLYSSNNKNYLA 290 DPK24 CDR-L2 WASTRES 291 DPK24 CDR-L3 QQYYSTP 292 HK102 V1 CDR-L1 RASQSISSWLA 293 HK102 V1 CDR-L2 DASSLES 294 HK102 V1 CDR-L3 QQYNSYS 295 DPK1 CDR-L1 QASQDISNYLN 296 DPK1 CDR-L2 DASNLET 297 DPK1 CDR-L3 QQYDNLP 298 DPK8 CDR-L1 RASQGISSYLA 299 DPK8 CDR-L2 AASTLQS 300 DPK8 CDR-L3 QQLNSYP 301 DPK21 CDR-L1 RASQSVSSNLA 302 DPK21 CDR-L2 GASTRAT 303 DPK21 CDR-L3 QQYNNWP 304 Vg 38K CDR-L1 RASQSVSSYLA 305 Vg 38K CDR-L2 DASNRAT 306 Vg 38K CDR-L3 QQRSNWP 307 DPK22 CDR-L1 RASQSVSSSYLA 308 DPK22 CDR-L2 GASSRAT 309 DPK22 CDR-L3 QQYGSSP 310 DPK15 CDR-L1 RSSQSLLHSNGYNYLD 311 DPK15 CDR-L2 LGSNRAS 312 DPK15 CDR-L3 MQALQTP 313 DPL16 CDR-L1 QGDSLRSYYAS 314 DPL16 CDR-L2 GKNNRPS 315 DPL16 CDR-L3 NSRDSSGNH 316 DPL8 CDR-L1 TGSSSNIGAGYDVH 317 DPL8 CDR-L2 GNSNRPS 318 DPL8 CDR-L3 QSYDSSLSG 319 V1-22 CDR-L1 TRSSGSIASNYVQ 320 V1-22 CDR-L2 EDNQRPS 321 V1-22 CDR-L3 QSYDSSN 322 V.lamda. CDR-L1 TGSSSGGSYYVS or 323 TGSSSDVGGSYYVS 324 V.lamda. CDR-L2 ENDSNRPS or 325 EDSNR(S/D)K(Q/G)QKPS 326 V.lamda. CDR-L3 QSWDSSA(N/T) or 327 QSWDSSA(N/T)F(F/V)(G/V) 328 V.lamda.1 CDR-L1 SGSSSNIGNN(A/Y)V(N/H/S) or 329 SGSSSNIIGNN(A/Y)V(N/H/S) 330 V.lamda.1 CDR-L2 GNN(K/N/Q)RPS 331 V.lamda.1 CDR-L3 AAWDDSL(N/S)G 332 V.lamda.3 CDR-L1 CSGD(A/V)LG(K/S)KYAH 333 V.lamda.3 CDR-L2 KDSERPS 334 V.lamda.3 CDR-L3 QSWDSSG(N/D/T/A) or 335 QSWDSSG(N/D/T/A)H 336 VK CDR-L1 RASQSLLHSDGISSYLA or 337 RASQGISSYLA 338 VK CDR-L2 AASSRAS 339 VK CDR-L3 QQYNSYP 340 VK1 CDR-L1 RASQGIS (N/S) YLA 341 VK1 CDR-L2 AASSLQS 342 VK1 CDR-L3 QQYNSYP 343 VK2 CDR-L1 RSSQSLLHSDGNTYLD or 344 RSSQSLLHSDDGNTYLD 345 VK2 CDR-L2 (K/T)(V/I)SNR(A/F)S 346 VK2 CDR-L3 MQATQFP 347 VK3 CDR-L1 RASQS(S/V)(S/V)SSYLA 348 VK3 CDR-L2 GASTRAT 349 VK3 CDR-L3 QQY(S/N/G/H)NWP 350 DPK3 CDR-L1 RASQGIRNDLG 351 DPK3 CDR-L2 AASSLQS 352 DPK3 CDR-L3 LQDYNYPLT Alternative sequences are provided for the consensus sequence with and without gaps. At positions where there is no consensus, residues in ( ) are those that are tied for the most frequent residues.

[0124] The antibody, or antigen-binding fragment thereof, may comprise a VH framework comprising a human germline VH framework sequence. The VH framework may comprise one or more amino acid subsitutions, additions, or deletions, while still retaining functional and structural similarity with the germline from which it was derived. In some aspects, the VH framework is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a human germline VH framework sequence. In some aspects, the antibody, or antigen binding fragment thereof, comprises a VH framework comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VH framework sequence. In some aspects, the 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions or deletions are only in the framework regions. In some aspects, the % identity is based on similarity with VH excluding those portions herein defined as CDRs.

[0125] The human germline VH framework may be the framework of DP54 or IGHV3-7. The human germline VH framework may be the framework of DP47 or IGHV3-23. The human germline VH framework may be the framework of DP71 or IGHV4-59. The human germline VH framework may be the framework of DP75 or IGHV1-2_02. The human germline VH framework may be the framework of DP10 or IGHV1-69. The human germline VH framework may be the framework of DP7 or IGHV1-46. The human germline VH framework may be the framework of DP49 or IGHV3-30. The human germline VH framework may be the framework of DP51 or IGHV3-48. The human germline VH framework may be the framework of DP38 or IGHV3-15. The human germline VH framework may be the framework of DP79 or IGHV4-39. The human germline VH framework may be the framework of DP78 or IGHV4-30-4. The human germline VH framework may be the framework of DP73 or IGHV5-51. The human germline VH framework may be the framework of DP50 or IGHV3-33. The human germline VH framework may be the framework of DP46 or IGHV3-30-3. The human germline VH framework may be the framework of DP31 or IGHV3-9. The human germline VH framework may be the framework of human VH germline consensus sequence. The human germline VH framework may be the framework of human VH3 germline consensus sequence. The human germline VH framework may be the framework of human VH5 germline consensus sequence. The human germline VH framework may be the framework of human VH1 germline consensus sequence. The human germline VH framework may be the framework of human VH4 germline consensus sequence.

[0126] In some aspects, the VH framework is DP-54. Other similar framework regions are also predicted to deliver advantageous antibodies of the invention comprising CDRs of SEQ ID NOs: 269, 272, and 276; or SEQ ID NOs: 270, 273, and 277; or SEQ ID NOs: 271, 274, and 278; or SEQ ID NOs: 271, 275, and 278; or SEQ ID NOs: 16, 226, and 18; including DP-50, IGHV3-30*09, IGHV3-30*15, IGHV3-48*01, DP-77, DP-51, IGHV3-66*01, DP-53, DP-48, IGHV3-53*01, IGHV3-30*02, and DP-49 which comprise 93, 92, 92, 99, 97, 97, 96, 96, 94, 94, 93, 92% identity respectively to the FW region of DP-54 and one or fewer amino acid differences in common structural features (Kabat Numbering) (A) residues directly underneath CDR (Vernier Zone), H2, H47, H48, and H49, H67, H69, H71, H73, H93, H94, (B) VH/VL Chain packing Residues: H37, H39, H45, H47, H91, H93 and (C) canonical CDR Structural support residues H24, H71, H94 (see Lo 2004, and O'Brien and Jones 2003). Particularly preferred are framework regions of DP-50, IGHV3-30*09, IGHV3-30*15 sharing 93, 92 and 92% identity to DP-54 respectively and have no amino acid differences in these common structural features. In some aspects, the % identity is based on similarity with VH excluding those portions herein defined as CDRs.

[0127] Residues in CDR-H1, CDR-H2, and CDR-H3 of the antibodies (and fragments) of the invention may be substituted with the corresponding germline residues as shown in Table 3.

TABLE-US-00004 TABLE 3 SEQ ID Heavy Chain 353 DP54 CDR-H1 GFTFSSYWMS 354 DP54 CDR-H2 ANIKQDGSEKYYVDSVKG 355 DP47 CDR-H1 GFTFSSYAMS 356 DP47 CDR-H2 AISGSGGSTYYADSVKG 357 DP71 CDR-H1 GGSISSYYWS 358 DP71 CDR-H2 GYIYYSGSTNYNPSLKS 359 DP75 CDR-H1 GYTFTGYYMH 360 DP75 CDR-H2 GWINPNSGGTNYAQKFQG 361 DP10 CDR-H1 GGTFSSYAIS 362 DP10 CDR-H2 GGIIPIFGTANYAQKFQG 363 DP7 CDR-H1 GYTGTSYYMH 364 DP7 CDR-H2 GIINPSGGSTSYAQKFQG 365 DP49 CDR-H1 GFTFSSYGMH 366 DP49 CDR-H2 AVISYDGSNKYYADSVKG 367 DP51 CDR-H1 GFTFSSYSMN 368 DP51 CDR-H2 SYISSSSSTIYYADSVKG 369 DP38 CDR-H1 GFTFSNAWMS 370 DP38 CDR-H2 GRIKSKTDGGTTDYAAPVKG 371 DP79 CDR-H1 GGSISSSSYYWG 372 DP79 CDR-H2 GSIYYSGSTYYNPSLKS 373 DP78 CDR-H1 GGSISSGDYYWS 374 DP78 CDR-H2 GYIYYSGSTYYNPSLKS 375 DP73 CDR-H1 GYSFTSYWIG 376 DP73 CDR-H2 GIIYPGDSDTRYSPSFQG 377 VH consensus GFTFSSYAM(H/S) or 378 CDR-H1 GFTFSSYAM(H/S)WS 379 VH consensus GWISPNGGSTYYADSVKG or 380 CDR-H2 GWISPKANGGSTYYADSVKG 381 VH3 consensus GFTFSSYAMS CDR-H1 382 VH3 consensus SVISSDG(G/S)STYYADSVKG or 383 CDR-H2 SVISSKADG(G/S)STYYADSVKG 384 VH5 consensus GYSFTSYWI(S/G/H) CDR-H1 385 VH5 consensus G(R/I/S)IYPGDSDTRYSPSFQG CDR-H2 386 VH1 consensus GYTFTSY(A/Y)(I/M)H CDR-H1 387 VH1 consensus GWINP(G/Y)NGNTNYAQKFQ CDR-H2 388 VH4 consensus GGSISSG(N/Y)YYWS CDR-H1 389 VH4 consensus GYIYYSGSTYYNPSLKS CDR-H2 390 DPK50 CDR-L1 GFTFSSYGMH 391 DPK50 CDR-L2 VIWYDGSNKYYADSAKG 392 DPK46 CDR-L1 GFTFSSYAMH 393 DPK46 CDR-L2 VISYDGSNKYYADSVKG 394 DPK31 CDR-L1 GFTFDDYAMH 395 DPK31 CDR-L2 GISWNSGSIGYADSVKG Alternative sequences are provided for the consensus sequence with and without gaps. At positions where there is no consensus, residues in ( ) are those that are tied for the most frequent residues.

[0128] In certain embodiments, the antibody, or antigen-binding fragment thereof, described herein comprises (i) a VH comprising an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:225, and/or (ii) a VL comprising an amino acid sequence that is at least 50%, at least 60%, at least 66%, at least 70%, at least 75%, at least 76%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:207. Any combination of these VL and VH sequences is also encompassed by the invention.

[0129] In certain embodiments, the antibody, or antigen-binding fragment thereof, described herein comprises (i) a HC comprising an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:244; and/or (ii) a LC comprising an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:209. Any combination of these HC and LC sequences is also encompassed by the invention.

[0130] In certain embodiments, the antibody, or antigen-binding fragment thereof, described herein comprises an Fc domain. The Fc domain can be derived from IgA (e.g., IgA.sub.1 or IgA.sub.2), IgG, IgE, or IgG (e.g., IgG.sub.1, IgG.sub.2, IgG.sub.3, or IgG.sub.4).

[0131] In some embodiments, the antibody, or antigen-binding fragment thereof, described herein comprises (i) a VH comprising an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to one of the group consisting of SEQ ID NOs: 14, 32, 43, 54, 61, 72, 90, 94, 97, 101, 106, 111, 113, 118, 121, 124, 126, 129, 132, 135, 138, 141, 144, 147, 150, 152, 155, 158, 161, 163, 165, 167, 170, 173, 176, 179, 182, 184, 186, 201, 204, 210, 213, 216, 219, 222, 225, 228, 231, and 234, and/or (ii) a VL comprising an amino acid sequence that is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any of SEQ ID NOs:19, 36, 47, 56, 65, 76, 81, 84, 86, 88, 91, 98, 103, 108, 115, 189, 192, 195, 198, and 207. Any combination of these VL and VH sequences is also encompassed by the invention. In some aspects, the VH is not one or more selected from the group consisting of SEQ ID NOs:43, 54, and 101. In some aspects, the VL is not one or more selected from the group consisting of SEQ ID NOs:47, 56, and 103.

[0132] Also provided by the invention is an antibody, or antigen-binding fragment thereof, that competes for binding to human IL-33 with any of the antibody, or antigen-binding fragment thereof, described herein, such as any one of the antibodies provided herein (or antigen-binding fragment thereof). For example, if the binding of an antibody, or an antigen-binding portion thereof, to human IL-33 hinders the subsequent binding to human IL-33 by IL33-158LS, the antibody or an antigen-binding portion thereof competes with IL33-158LS for human IL-33 binding.

[0133] Also provided by the invention is an antibody, or antigen-binding fragment thereof, that binds to the same human IL-33 epitope as any of the antibody, or antigen-binding fragment thereof, described herein, such as any one of the antibodies provided herein or antigen-binding fragment thereof. For example, antibody competition assay (and overlapping epitope analysis) can be assessed by SPR, as described in detail herein.

[0134] The antibodies and antigen-binding fragments provided by the invention include monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab').sub.2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion, domain antibodies (dAbs), humanized antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies and antigen-binding fragments may be murine, rat, human, or any other origin (including chimeric or humanized antibodies). In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric, humanized or human antibody. In certain embodiments, the antibody is a human antibody. In certain embodiments, the antibody is a humanized antibody.

Biological Deposit

[0135] Representative materials of the present invention were deposited in the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209, USA, on 23.sup.rd December 2015. Vector VH-IL33-158LS having ATCC Accession No. PTA-122724 comprises a DNA insert encoding the heavy chain variable region of antibody IL33-158LS, and vector VL-IL33-158LS having ATCC Accession No. PTA-122725 comprises a DNA insert encoding the light chain variable region of antibody IL33-158LS. The deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and Regulations thereunder (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. The deposit will be made available by ATCC under the terms of the Budapest Treaty, and subject to an agreement between Pfizer Inc. and ATCC, which assures permanent and unrestricted availability of the progeny of the culture of the deposit to the public upon issuance of the pertinent U.S. patent or upon laying open to the public of any U.S. or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks to be entitled thereto according to 35 U.S.C. Section 122 and the Commissioner's rules pursuant thereto (including 37 C.F.R. Section 1.14 with particular reference to 886 OG 638).

[0136] The assignee of the present application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.

Nucleic Acids

[0137] The invention also provides polynucleotides encoding any of the antibodies, including antibody portions and modified antibodies described herein. The invention also provides a method of making any of the polynucleotides described herein. Polynucleotides can be made and expressed by procedures known in the art.

[0138] The sequence of a desired antibody, defined antibody fragment, or antigen-binding fragment thereof, and nucleic acid encoding such antibody, or fragment thereof, can be determined using standard sequencing techniques. A nucleic acid sequence encoding a desired antibody, defined antibody fragment, or antigen-binding fragment thereof, may be inserted into various vectors (such as cloning and expression vectors) for recombinant production and characterization. A nucleic acid encoding the heavy chain, defined antibody fragment, or an antigen-binding fragment of the heavy chain, and a nucleic acid encoding the light chain, defined antibody fragment, or an antigen-binding fragment of the light chain, can be cloned into the same vector, or different vectors.

[0139] In one aspect, the invention provides polynucleotides encoding the amino acid sequences of any of the following IL-33 antibodies and antigen-binding portions thereof: 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS.

[0140] The invention provides polynucleotides encoding the amino acid sequences an antibody, or antigen-binding fragment thereof, that binds substantial the same epitope as an antibody selected from the group consisting of: 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9 B3_31V2, 9B3_36, 9 B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS.

[0141] The invention provides polynucleotides encoding the amino acid sequences of an antibody, or antigen-binding fragment thereof, that competes for binding to IL-33 with an antibody selected from the group consisting of: 7E8_chimera, 9B3_chimera, 9B3_chimera_huJseg, 7E8 CDR graft, IL33-10, 9B3 CDR graft, 9B3_1, 9B3_2A, 9B3_2B, 9B3_3, 9B3_5, 9B3_7 9B3_13, 9B3_15, 9B3_17, 9B3_22, 9B3_31V2, 9B3_36, 9B3_79, 9B3_124, 9B3_162, 7E8H/9B3K, 9B3_563, IL33-11, IL33-12, IL33-13, IL33-45, IL33-55, IL33-56, IL33-57, IL33-58, IL33-61, IL33-62, IL33-68, IL33-74, IL33-75, IL33-80, IL33-81, IL33-103, IL33-117, IL33-136, IL33-153, IL33-154, IL33-155, IL33-156, IL33-157, IL33-158, IL33-167, IL33-168, IL33-169, IL33-170, IL33-171, IL33-172, IL33-175, IL33-186, IL33-187, IL33-188, IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS.

[0142] The invention provides polynucleotides encoding one or more proteins comprising the amino acid sequence selected from the group consisting of: (i) SEQ ID NOs:1-279.

[0143] The invention provides polynucleotides comprising the nucleic acid sequence as set forth as one or more of SEQ ID NOs: 398, 399, 400, and 401. The invention provides a polynucleotide comprising the nucleic acid sequence as set forth as SEQ ID NO:398. The invention provides a polynucleotide comprising the nucleic acid sequence as set forth as SEQ ID NO:399. The invention provides a polynucleotide comprising the nucleic acid sequence as set forth as SEQ ID NO:400. The invention provides a polynucleotide comprising the nucleic acid sequence as set forth as SEQ ID NO:401.

[0144] The invention provides a polynucleotide comprising one or both of the coding sequence of the DNA insert of the nucleic acid molecule deposited with the ATCC and having Accession No. PTA-122724, and Accession No. PTA-122725. The invention provides a polynucleotide comprising the nucleic acid molecule deposited with the ATCC and having Accession No. PTA-122724. The invention provides a polynucleotide comprising the nucleic acid molecule deposited with the ATCC and having Accession No. PTA-122725.

[0145] The invention provides cells comprising one or more nucleic acid molecules as set forth in one or more of SEQ ID NOs: 398, 399, 400, and 401. The invention provides cells comprising one or more nucleic acid molecules as set forth in SEQ ID NOs:398 and 399. The invention provides cells comprising one or more nucleic acid molecules as set forth in SEQ ID NOs:400 and 401.

[0146] In another aspect, the invention provides polynucleotides and variants thereof encoding an anti-IL-33 antibody, wherein such variant polynucleotides share at least 70%, at least 75%, at least 80%, at least 85%, at least 87%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to any of the specific nucleic acid sequences disclosed herein. These amounts are not meant to be limiting, and increments between the recited percentages are specifically envisioned as part of the disclosure.

[0147] The invention provides polypeptides encoded by the nucleic acid molecules described herein.

[0148] In one embodiment, the VH and VL domains, or antigen-binding portion thereof, or full length HC or LC, are encoded by separate polynucleotides. Alternatively, both VH and VL, or antigen-binding portion thereof, or HC and LC, are encoded by a single polynucleotide.

[0149] Polynucleotides complementary to any such sequences are also encompassed by the present disclosure. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present disclosure, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.

[0150] Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes an antibody or a portion thereof) or may comprise a variant of such a sequence. Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not diminished, relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide may generally be assessed as described herein. In some embodiments, variants exhibit at least about 70% identity, in some embodiments, at least about 80% identity, in some embodiments, at least about 90% identity, and in some embodiments, at least about 95% identity to a polynucleotide sequence that encodes a native antibody or a portion thereof. These amounts are not meant to be limiting, and increments between the recited percentages are specifically envisioned as part of the disclosure.

[0151] Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, or 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0152] Optimal alignment of sequences for comparison may be conducted using the MegAlign.RTM. program in the Lasergene.RTM. suite of bioinformatics software (DNASTAR.RTM., Inc., Madison, Wis.), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M. O., 1978, A model of evolutionary change in proteins--Matrices for detecting distant relationships. In Dayhoff, M. O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington D.C. Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, Calif.; Higgins, D. G. and Sharp, P. M., 1989, CABIOS 5:151-153; Myers, E. W. and Muller W., 1988, CABIOS 4:11-17; Robinson, E. D., 1971, Comb. Theor. 11:105; Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425; Sneath, P. H. A. and Sokal, R. R., 1973, Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, Calif.; Wilbur, W. J. and Lipman, D. J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730.

[0153] In some embodiments, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0154] Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementary sequence).

[0155] Suitable "moderately stringent conditions" include prewashing in a solution of 5.times.SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50.degree. C.-65.degree. C., 5.times.SSC, overnight; followed by washing twice at 65.degree. C. for 20 minutes with each of 2.times., 0.5.times. and 0.2.times.SSC containing 0.1% SDS.

[0156] As used herein, "highly stringent conditions" or "high stringency conditions" are those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50.degree. C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide, 5.times.SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5.times.Denhardt's solution, sonicated salmon sperm DNA (50 .mu.g/mL), 0.1% SDS, and 10% dextran sulfate at 42.degree. C., with washes at 42.degree. C. in 0.2.times.SSC (sodium chloride/sodium citrate) and 50% formamide at 55.degree. C., followed by a high-stringency wash consisting of 0.1.times.SSC containing EDTA at 55.degree. C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

[0157] It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present disclosure. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present disclosure. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).

[0158] The polynucleotides of this disclosure can be obtained using chemical synthesis, recombinant methods, or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of skill in the art can use the sequences provided herein and a commercial DNA synthesizer to produce a desired DNA sequence.

[0159] For preparing polynucleotides using recombinant methods, a polynucleotide comprising a desired sequence can be inserted into a suitable vector, and the vector in turn can be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides may be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The polynucleotide so amplified can be isolated from the host cell by methods well known within the art. See, e.g., Sambrook et al., 1989.

[0160] Alternatively, PCR allows reproduction of DNA sequences. PCR technology is well known in the art and is described in U.S. Pat. Nos. 4,683,195, 4,800,159, 4,754,065 and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

[0161] RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those of skill in the art, as set forth in Sambrook et al., 1989, for example.

[0162] Suitable cloning and expression vectors can include a variety of components, such as promoter, enhancer, and other transcriptional regulatory sequences. The vector may also be constructed to allow for subsequent cloning of an antibody variable domain into different vectors. Suitable cloning vectors may be constructed according to standard techniques, or may be selected from a large number of cloning vectors available in the art. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones containing the vector. Suitable examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial vendors such as BioRad, Strategene, and Invitrogen. Expression vectors are further provided. Expression vectors generally are replicable polynucleotide constructs that contain a polynucleotide according to the disclosure. It is implied that an expression vector must be replicable in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO 87/04462. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional controlling elements (such as promoters, enhancers and terminator). For expression (i.e., translation), one or more translational controlling elements are also usually required, such as ribosome binding sites, translation initiation sites, and stop codons.

[0163] The vectors containing the polynucleotides of interest and/or the polynucleotides themselves, can be introduced into the host cell by any of a number of appropriate means, including electroporation, transfection employing calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipofection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of introducing vectors or polynucleotides will often depend on features of the host cell.

[0164] The antibody, or antigen-binding fragment thereof, may be made recombinantly using a suitable host cell. A nucleic acid encoding the antibody or antigen-binding fragment thereof can be cloned into an expression vector, which can then be introduced into a host cell, such as E. coli cell, a yeast cell, an insect cell, a simian COS cell, a Chinese hamster ovary (CHO) cell, or a myeloma cell where the cell does not otherwise produce an immunoglobulin protein, to obtain the synthesis of an antibody in the recombinant host cell. Preferred host cells include a CHO cell, a Human embryonic kidney (HEK) 293 cell, or an Sp2.0 cell, among many cells well-known in the art. An antibody fragment can be produced by proteolytic or other degradation of a full-length antibody, by recombinant methods, or by chemical synthesis. A polypeptide fragment of an antibody, especially shorter polypeptides up to about 50 amino acids, can be conveniently made by chemical synthesis. Methods of chemical synthesis for proteins and peptides are known in the art and are commercially available.

[0165] The antibody, or antigen-binding fragment thereof, of the invention may be affinity matured. For example, an affinity matured antibody can be produced by procedures known in the art (Marks et al., 1992, Bio/Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci, USA 91:3809-3813; Schier et al., 1995, Gene, 169:147-155; Yelton et al., 1995, J. Immunol., 155:1994-2004; Jackson et al., 1995, J. Immunol., 154(7):3310-9; Hawkins et al., 1992, J. Mol. Biol., 226:889-896; and WO2004/058184).

Uses and Medical Therapies

[0166] In some aspects, the invention provides for therapeutic methods for inhibiting IL-33 activity using an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the therapeutic methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof. The disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of IL-33 activity or signaling.

[0167] In some aspects, the disorder is an inflammatory disease or disorder, or a condition with at least one symptom associated with the inflammatory disease or disorder. The inflammatory disease or disorder or symptom may be alleviated, or reduced in severity, duration or frequency of occurrence.

[0168] Allergic as well as other diseases at mucosal or body surfaces where antibodies and antigen binding fragments thereof of the invention may be effective include: allergies, allergic rhinitis, allergic conjunctivitis, vernal keratoconjunctivitis, seasonal allergies, pet allergy, asthma, food allergies, peanut allergy, atopic dermatitis, chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis, bronchitis, chronic obstructive pulmonary disease (COPD), viral exacerbations of respiratory disease, viral infections in children and adults, (respiratory syncytial virus (RSV), rhinovirus, influenza), urticarias, and eosinophilic esophagitis. Diseases involing chronic fibrosis may also be treated by antibodies and antigen binding fragments thereof of the invention. These include: liver fibrosis, non-alcoholic steatohepatitis (NASH), chronic kidney disease, idiopathic pulmonary fibrosis (IPF), scleroderma, systemic sclerosis. Disease involving acute tissue injury may also be treated by antibodies and antigen binding fragments thereof of the invention, including: Acute kidney injury, sepsis, pancreatitis, type 1 Diabetes, graft-versus-host disease (GVHD), tissue transplant. Other chronic degenerative or chronic inflammatory diseases that may be treated with antibodies and antigen binding fragments thereof of the invention, include: Alzheimer's, rheumatoid arthritis, inflammatory bowel diseases: irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis. Further diseases that may be treated with antibodies and antigen binding fragments thereof of the invention include multiple sclerosis, psoriasis, celiac disease and Raynaud's disease.

[0169] The antibodies and antibody fragments thereof may be administered in combination with one or more additional therapeutically active compounds. The additional therapeutically active compounds include antagonists to one or more of IL-la, IL-1b, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, IL-18, IL-21, IL-23, IL-25, IL-26, IL-31, IL36 IFN.alpha., IFN.gamma., or antagonists of their respective receptors, NSAIDs, steroids, and corticosteroids.

[0170] The anti-IL-33 antibodies of the present invention may also be used to detect and/or measure IL-33, or IL-33-expressing cells in a sample, e.g., for diagnostic purposes. For example, an anti-IL-33 antibody, or fragment thereof, may be used to diagnose a condition or disease characterized by aberrant expression (e.g., over-expression, under-expression, lack of expression, etc.) of IL-33. Exemplary diagnostic assays for IL-33 may comprise, e.g., contacting a sample, obtained from a patient, with an anti-IL-33 antibody of the invention, wherein the anti-IL-33 antibody is labeled with a detectable label or reporter molecule.

[0171] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990; and Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing, 2000).

Compositions

[0172] The antibody, or antigen-binding fragment thereof, of the invention can be formulated as a pharmaceutical composition. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, and/or stabilizer (Remington: The Science and practice of Pharmacy 20th Ed., 2000, Lippincott Williams and Wilkins, Ed. K. E. Hoover), in the form of lyophilized formulation or aqueous solution. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG). Pharmaceutically acceptable excipients are further described herein.

Dosage

[0173] As used herein, an "effective dosage", "effective amount", or "therapeutically effective amount" of drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing inflammation or one or more symptoms resulting from high expression of active IL-33, decreasing the dose of other medications required to treat the disease, enhancing the effect of another medication, and/or delaying the progression of the disease of patients. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0174] An "individual" or a "subject" is a mammal, more preferably, a human. Mammals also include, but are not limited to, farm animals, sport animals, pets, primates, horses, dogs, cats, mice and rats.

[0175] In some embodiments, the method or use comprises administering an initial dose of about 0.025 mg/kg to about 20 mg/kg of an antibody, or antigen binding fragment thereof, or a pharmaceutical composition of the invention. The initial dose may be followed by one or more subsequent doses. In some embodiments, one or more subsequent dose may be administered at least any of weekly, every other week, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks.

[0176] In some embodiments, the method or use comprises administering a fixed dose of about 0.25 mg to about 2000 mg of an antibody, or antigen binding fragment thereof, of the invention. In some embodiments, the antibody, or antigen binding fragment thereof, is administered weekly, every other week, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks.

Kits

[0177] The invention also provides kits or an article of manufacture comprising an antibody, or antigen binding fragment thereof, of the invention, and instructions for use. Accordingly, in some embodiments, provided is a kit or an article of manufacture, comprising a container, a composition within the container comprising an anti-IL-33 antagonist antibody, and a package insert containing instructions to administer a therapeutically effective amount of the anti-IL-33 antagonist antibody for treatment of a patient in need thereof.

[0178] In certain embodiments, the kit can contain both a first container having a dried protein and a second container having an aqueous formulation. In certain embodiments, kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.

[0179] The instructions relating to the use of antibodies or antigen binding fragments thereof of the invention generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0180] The kits of this invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump. A kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may further comprise a second pharmaceutically active agent.

[0181] Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.

Definitions

[0182] "About" or "approximately," when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g. within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater. Numeric ranges are inclusive of the numbers defining the range.

[0183] As used herein, "vector" means a construct, which is capable of delivering, and, preferably, expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[0184] The term "identity," as known in the art, refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or nucleic acid molecule sequences, as the case may be, as determined by the match between strings of nucleotide or amino acid sequences. "Identity" measures the percent of identical matches between two or more sequences with gap alignments addressed by a particular mathematical model of computer programs (i. e. "algorithms").

[0185] The term "similarity" is a related concept, but in contrast to "identity", refers to a measure of similarity which includes both identical matches and conservative substitution matches. Since conservative substitutions apply to polypeptides and not nucleic acid molecules, similarity only deals with polypeptide sequence comparisons. If two polypeptide sequences have, for example, 10 out of 20 identical amino acids, and the remainder are all nonconservative substitutions, then the percent identity and similarity would both be 50%. If in the same example, there are 5 more positions where there are conservative substitutions, then the percent identity remains 50%, but the percent similarity would be 75% (15 out of 20). Therefore, in cases where there are conservative substitutions, the degree of similarity between two polypeptide sequences will be higher than the percent identity between those two sequences.

EXAMPLES

[0186] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. The materials, methods, and examples are illustrative only and not intended to be limiting.

Example 1 Isolation of Rat Monoclonal Antibodies that Bind to Human IL-33

[0187] Sprague-Dawley rats were immunized with multiple subcutaneous injections with recombinant human IL-33 (SEQ ID NO:1), amino acids 5112-T270, R&D Systems, Minneapolis, Minn.; Cat. No. 3625-IL/OF) in alum adjuvant. Sera that showed binding activity to biotinylated human IL-33 immobilized on a streptavidin-coated ELISA plate were also screened for blockade of the binding of 10 ng/ml biotinylated human IL-33 to human ST2-Fc (SEQ ID NO:2) that had been captured by anti-human Fc immobilized on an ELISA plate. For assays, cytokine activity was maintained by reduction of wild-type IL-33 with dithiothreitol (DTT) or by using a human IL-33 variant, mm2 (SEQ ID NO:3), in which all four cysteine residues were mutated to serine. From the rat with the highest titer, hybridomas and cultured B cells enriched on IL-33-coated beads were screened for antibodies with human IL-33 binding, blockade of human IL-33/ST2-Fc binding, and neutralization of human IL-33 activity on HEK-293 cells stably expressing ST2 and a plasmid expressing secreated alkaline phosphatase under an NFkB-responsive promoter. Two-hundred twenty-seven IL-33 binding antibodies were identified, of which 6 antibodies (30A1, 30B11, 7E8, 9B3, 12F9, and 14D8) also neutralized IL33-ST2 binding and reporter cell activity and were chosen for molecular cloning and subsequent analysis.

Example 2 Cloning of Rat Anti-IL-33 Antibody Heavy and Light Chain Variable Regions

[0188] Heavy chain and light chain variable regions of the neutralizing anti-IL-33 antibodies were cloned using the SMART.RTM. cDNA synthesis system (Clontech Laboratories Inc. of Mountain View, Calif.) followed by PCR amplification. The cDNA was synthesized from 1 .mu.g total RNA isolated from approximately 500,000 cloned B cells (14D8, 12F9) or 7E8, 9B3, 30A1, 30B11 hybridoma cells, using the RNEasy kit (Qiagen) and the SMART.RTM. IIA oligo (Clontech Laboratories Inc.) with SuperscriptII.TM. reverse transcriptase (Clontech Laboratories Inc.). The cDNA was then amplified by PCR using a primer that anneals to the SMART.RTM. IIA oligo sequence and rat constant region specific primer (rat Kappa for the light chain and rat IgG1 for the heavy chain) with GoTaq Green polymerase master mix (Promega). Heavy and light chain PCR products were subcloned into the pCR4-TOPO vector (Invitrogen) and the nucleic acid sequence was determined. This method is advantageous in that no prior knowledge of the DNA sequence is required. In addition, the resultant DNA sequence is not altered by use of degenerate PCR primers.

[0189] The variable heavy regions were then cloned into the pSMED2 mammalian expression vector containing the human IgG1 constant region (SEQ ID NO:9) that was mutated to abolish effector function (Leu234Ala, Leu235Ala and Gly237Ala, EU numbering; U.S. Pat. No. 5,624,821), producing chimeric heavy chains. Variable light regions were cloned into the pSMEN3 mammalian expression vectors containing the constant region of human kappa (SEQ ID NO:30) to produce chimeric light chains. In the cases of antibodies 9B3, 14D8, 30A1, and 30B11, the closest human kappa chain J segments (SEQ ID NOs:12, 82) were also used to replace the rat kappa chain J segments in order to improve expression of the chimeric antibodies.

Example 3 IL-33 Neutralization by Anti-Human IL-33 Antibodies

[0190] The six chimeric antibodies were shown to bind human IL-33 and to neutralize its activity in the HEK293 ST2 NFkB cell-based reporter assay described in Example 1, as shown in Table 4.

TABLE-US-00005 TABLE 4 Inhibition of IL-33 (mm2) activity in the HEK293 ST2 NFkB reporter cell assay by parental rat anti-IL-33 antibodies and rat/human chimeras thereof HEK293 ST2 NFkB HC SEQ LC SEQ human Antibody NO NO IL-33(mm2) IC.sub.50 (nM) replicates 7E8 hybridoma 0.018 3 9B3 hybridoma 0.076 3 30A1 hybridoma 0.665 3 30B11 hybridoma 0.056 3 7E8 chimera 28 31 0.049 3 9B3 chimera/hu J 40 83 0.056 3 30A1 chimera 69 71 0.270 3 30B11 chimera/hu J 78 89 0.028 3 12F9 chimera 51 53 2.71 3 14D8 chimera/hu J 59 85 2.03 3 Enzo ALX-804-728 mAb (IL33026B) 32.8% @ 952 nM 3 Enzo ALX-804-840 Nessy1 mAb 238.74 3 Abcam ab-72844 clone [4E9] mAb 10.6% @ 952 nM 3

[0191] The chimeric antibodies were also tested to determine their capacity to neutralize cynomolgus monkey IL33, using the HEK293 ST2 NFkB assay with a variant of cynomolgus monkey IL-33 in which its three cysteine residues were mutated to serine (SEQ ID NO:5). 7E8, 30A1, and 30B11 were able to neutralize cynomolgus monkey IL-33 at 0.21, 2.95, and 0.20 nM IC.sub.50, respectively, while 12F8 and 14B8 were not, and 9B3 showed only weak neutralization (Table 5).

TABLE-US-00006 TABLE 5 Inhibition of cynomolgus monkey IL-33 activity in the ST2- NFkB reporter cell assay by anti-IL-33 antibodies. Antibodies were titrated against 0.1 ng/ml cynomolgus monkey IL33. HEK293 ST2 NFkB HC SEQ LC SEQ cynomolgus monkey Antibody NO NO IL-33 IC.sub.50 (nM) replicates Rat 7E8 0.21 3 Rat 9B3 23% @20 nM 3 Rat 30A1 2.95 3 Rat 30B11 0.20 3 9B3_chimera 40 42 35% @20 nM 3 12F9_chimera 51 53 3.6% @20 nM 3 30B11 chimera/hu J 78 89 0.11 3 14D8 chimera/hu J 59 85 11% @20 nM 3 human ST2-Fc 2 0.045 3

Example 4 Epitope Grouping of Anti-IL-33 Antibodies

[0192] The six neutralizing antibodies were grouped into epitope bins based on a competition assay using an Octet biosensor. Streptavidin-coated Octet tips were loaded with 10 ug/ml biotin-hIL-33 (mm2) for 150 sec., transferred to blocking buffer (1% BSA in PBS) for 50 sec, then transferred to a well containing one of the six antibodies for 290 sec to allow the first antibody to bind to IL-33. Tips were then transferred to a second well containing a second antibody for 290 sec. Antibodies were scored as non-competing if the second antibody showed an increase in the biosensor signal above that produced by the first antibody, and they were scored as competing if the second antibody did not produce an additional increase in signal (Table 6). Based on these competition data, antibodies 7E8, 9B3, 30A1, and 30B11 defined one epitope group, and 12F9 and 14D8 defined a second, non-overlapping epitope.

TABLE-US-00007 TABLE 6 Epitope grouping of anti-IL-33 antibodies by Octet biosensor 1.sup.st Ab (rows), 2.sup.nd Ab (columns) 7E8 9B3 30A1 30B11 12F9 14D8 7E8 - - - - + + 9B3 - - - - + + 30A1 - - - - + + 30B11 - - - - + + 12F9 + + + + - - 14D8 + + + + - - Table 6. Antibodies were bound sequentially to IL-33-saturated Octet tips. A "+" indicates that the second antibody (indicated by the column heading) bound in the presence of the first antibody (indicated by row headings). A "-" indicates that no increase in signal was observed upon addition of the second antibody.

Example 5 Humanization of Rat Anti-IL-33 Antibodies

[0193] Humanized versions of neutralizing rat antibodies 7E8, 9B3, 12F9, and 30B11 were generated by complementarity determining region (CDR) grafting (referred to hereafter as "CDR-grafted"). Heavy chain CDRs were grafted onto a human DP-54 framework region (VH3 sub-group; SEQ ID NO:7) with a JH4 segment (SEQ ID NO:8), while light chain CDRs were grafted onto a human DPK9 framework (VKI sub-group; SEQ ID NO:11) with a JK4 segment (SEQ ID NO:12). The humanized V.sub.H regions were joined to the effector-function mutated human IgG1 constant region (SEQ ID NO:9) and then sub-cloned into a proprietary expression vector to generate the CDR-grafted heavy chains SEQ ID NO:92 (7E8 CDR graft), 99 (9B3 CDR graft), 104 (12F9 CDR graft), and 109 (30B11 CDR graft). A second version of CDR-grafted 30B11 incorporated the rat residue (valine) at position 71 in the heavy chain instead of the germline arginine residue, with the resulting heavy chain designated SEQ ID NO:112. The humanized V.sub.L regions were fused to the human kappa constant region (SEQ ID NO:13) and then sub-cloned into a proprietary expression vector to create the CDR-grafted light chains SEQ ID NO:93 (7E8 CDR graft), 100 (9B3 CDR graft), 105 (12F8 CDR graft), and 110 (30B11 CDR graft). 7E8 was also grafted onto other VH3 germline frameworks (DP47, accession CAA78217.1; DP31, accession CAA78203.1; DP50, accession CAA78220.1) and had similar cell-based activity and nonspecific binding to that of CDR-grafted 7E8 (SEQ ID NO:92, 93).

Example 6 Neutralization of Recombinant and Native Human IL-33 and Recombinant Cynomolgus Monkey IL-33 by Humanized IL-33 Antibodies

[0194] CDR-grafted 7E8, 9B3, 12F9, and 30B11 were shown to neutralize the activity of human IL-33 in the HEK293 ST2 NFkB reporter assay described in Example 1. In particular, CDR-grafted 7E8 exhibited an IC.sub.50 of 0.019 nM, nearly identical to the 0.024 nM 10.sub.50 exhibited by the 7E8 hybridoma (Table 7). CDR-grafted 12F9 showed only partial inhibition at high concentration (Table 7) rather than the full inhibition with a 2.71 nM IC.sub.50 observed for chimeric 12F9 (Table 4). CDR-grafted 9B3 and 30B11 had IC.sub.50 values of 0.520 and 0.368 nM, respectively (Table 7), approximately 10-fold reduced activity relative to the chimeric versions of these antibodies (Table 4). A second version of CDR-grafted 30B11 containing the heavy-chain framework back-mutation R71V showed a similar reduction in potency compared with the chimera, 0.278 nM vs 0.028 nM IC.sub.50 (Table 7, Table 4).

TABLE-US-00008 TABLE 7 Neutralization of human IL-33 (mm2) activity by CDR-grafted IL-33 antibodies in HEK293 ST2 NFkB reporter assay HC SEQ LC SEQ Antibody NO NO IC.sub.50 (nM) replicates 7E8 CDR-grafted 92 93 0.019 3 9B3 CDR-grafted 99 100 0.520 3 12F9 CDR-grafted 104 105 34% @ 125 nM 3 30B11 CDR-grafted 109 110 0.368 3 30B11 CDR-grafted R71V 112 110 0.278 3 human ST2-Fc 2 0.043 3 Rat 7E8 0.024 3

[0195] CDR-grafted 7E8 and the 7E8 hybridoma were further shown to have similar neutralizing potency in the ST2-NFkB reporter assay with cynomolgus monkey IL-33 (0.069 nM and 0.032 nM, respectively; Table 8), similar to their activity in the ST2-NFkB reporter assay with human IL-33 (mm2) (0.043 nM IC.sub.50 for both CDR-grafted 7E8 and 7E8 hybridoma; Table 8). CDR-grafted 7E8 and the soluble human IL-33 receptor ST2-Fc showed similar neutralizing potency on human IL-33 (mm2) (0.043 nM and 0.056 nM, respectively) and on human IL-33 that retained the wild-type cysteine residues (3.21 nM and 1.89 nM, respectively; Table 8).

TABLE-US-00009 TABLE 8 Inhibition of IL-33 neutralization in the HEK293 ST2 NFkB assay by hybridoma-derived antibodies and CDR-grafted 7E8. IC.sub.50 HEK293 IC.sub.50 HEK293 IC.sub.50 HEK293 HC SEQ LC SEQ ST2 NFkB human ST2 NFkB cyno ST2 NFkB human Antibody NO NO IL-33 (mm2)(nM) IL-33 (nM) IL-33 (R&D)(nM) 7E8 0.043 0.032 ND 9B3 0.17 2.72 ND 30A1 0.47 0.14 ND 30B11 0.038 0.084 ND 7E8 CDR-grafted 92 93 0.043 0.069 3.21 human ST2-Fc 2 0.056 0.005 1.89 Table 8: Inhibition of IL-33 neutralization in the HEK293 ST2 NFkB assay by rat parental hybridoma-derived antibodies and humanized CDR-grafted 7E8. Dilution series of antibodies were tested against 0.1 ng/ml IL-33 (mm2), 0.1 ng/ml cynomolgus monkey IL-33, and 2 ng/ml human IL-33 (R&D). Assays were run in triplicate with a dose range of 0.0018-30 nM IL-33 (R&D). ND, not determined.

Example 7 Neutralization of the Activity of Native IL-33 from Human Cell Extracts by IL-33 Antibodies

[0196] CDR-grafted 7E8 was further shown to neutralize the activity of native human IL-33 produced by cultured human lung fibroblasts. Early passages of the human lung fibroblast line HFL-1 (ATCC) were grown in DMEM+10% heat-inactivated fetal bovine serum (FBS)+L-glutamine/penicillin/streptomycin+1/100 HEPES. When cells reached 95-100% confluence, the medium was removed and replaced with the same medium without serum and incubated for 24 hr. Medium was then removed, replaced with 20 ng/ml TNF-.alpha., and incubated for an additional 14 hr. Cells were harvested by trypsinization, pelleted, and frozen in serum-free medium. Lysates were prepared by five freeze-thaw cycles at -20.degree. C., brought to 10 mM DTT, and samples were centrifuged and diluted for assessment of IL-33 activity. HFL-1 cell lysates were shown to activate the NFkB reporter gene in the HEK293 ST2 NFkB reporter assay, and this activity could be partially blocked by soluble human ST2-Fc (SEQ ID NO:2) and a polyclonal anti-IL-33 neutralizing antibody. Activity was fully blocked by rat antibodies 7E8, 9B3, 30A11, and 30B11 and chimeras and by chimeric 14D8, indicating that these antibodies can recognize and neutralize endogenous IL-33 produced in human primary cells.

TABLE-US-00010 TABLE 9 Inhibition of native human IL-33 from human lung fibroblast lysate by anti-IL-33 antibodies % HC LC % % inhibition SEQ SEQ inhibition inhibition 0.1 nM repli- Antibody NO NO 10 nM Ab 1 nM Ab Ab cates 7E8 112.9 110.5 112.1 3 9B3 107.7 99.2 55.1 3 30A1 107.9 77.3 35.4 3 30B11 112.7 108.4 93.5 3 9B3 chimera 40 42 111.3 96.0 52.5 3 12F9 chimera 51 53 104.0 82.6 44.3 3 30A1 chimera/ 69 87 107.2 98.5 63.8 3 hu J 30611 chimera/ 78 89 109.8 109.3 101.7 3 huJ 14D8 chimera/ 59 60 107.2 99.6 61.1 3 huJ Human ST2-Fc 2 53.9 43.4 30.6 3 R&D polyclonal 84.6 -2.4 -0.9 3 anti-IL-33 Ab (AF3625) Rat IgG1 -8.2 2.5 1.9 3 isotype control Human Fc -11.3 -6.9 -3.5 3 control Table 9. Human lung fibroblast (HFL-1) lysate at a 64-fold dilution was incubated with 0.1, 1, or 10 nM antibodies in the HEK293 ST2 NFkB assay. Lysate alone produced a 3.9-fold increase of signal over medium alone. Percent inhibition is calculated as 100 .times. (1 - (test sample - medium alone)/(lysate alone - medium alone)).

Example 8 Anti-IL-33 Antibodies Neutralize IL-33 with High Potency

[0197] In order to measure the affinity for the binding of the antibody to IL-33 in an assay that is not affected by the concentration of ligand, experiments were designed with the HEK293 ST2 NFkB reporter assay system in which a Schild analysis could be performed to calculate an assay- and ligand concentration-independent measure of the affinity of 7E8 for IL-33 (Arunlakshana and Schild, 1959). The EC.sub.50 of IL-33 was determined at multiple concentrations of 7E8 CDR graft (SEQ ID NOs:92, 93) in the NFkB ST2 reporter assay, and a kB of 6.01 pM was calculated (Table 10) for IL-33 (mm2) and 83.45 pM for wild-type IL-33 (R&D).

[0198] IL-33 is also a potent costimulator of IFN.gamma. production from natural killer cells in the blood, when the costimulus is IL-12. Human peripheral blood mononuclear cells (PBMCs) were purified from fresh heparinized human blood by Ficoll and then treated with IL-12 for 2 hr., followed by treatment with a mixture of IL-33 at 5 pM and a dose titration of anti-IL-33 antibodies. The culture supernatant was collected 20 hrs after the addition of IL-33, and the levels of IFN.gamma. measured by a MSD plate reader (Meso Scale Diagnostics, Rockville, Md.). In human PBMCs, similar to the observations made in the HEK293 ST2 NFkB reporter assay, 7E8 inhibition of IL-33 (mm2) produced a calculated kB of 1.04 and 6.64 pM in two donors. Thus, the apparent affinity of 7E8 CDR graft for IL-33 (mm2) is very high, in the single-digit picomolar range, and below 100 pM for wild-type IL-33.

TABLE-US-00011 TABLE 10 Schild analysis of 7E8 CDR graft inhibition of IL-33 activity in HEK293 ST2 NFkB reporter cells and human PBMCs IL-33 (mm2) IL-33 (R&D Systems) HEK293 ST2 NFkB HEK293 ST2 NFkB IL-33 (mm2) human PBMC reporter cells reporter cells EC.sub.50 (pM) treatment EC.sub.50 (pM) EC.sub.50 (pM) donor 149 donor 172 IL-33 alone 1.0 8.4 1.0 19.7 IL-33 + 20 nM 7E8 2826.5 653.4 ND ND IL-33 + 2 nM 7E8 262.4 102.7 2826.5 1216.1 IL-33 + 200 pM 7E8 29.1 25.8 262.4 399.6 IL-33 + 20 pM 7E8 2.6 10.2 29.1 154.4 IL-33 + 2 pM 7E8 ND 8.0 2.6 23.2 IL-33 + 0.2 pM 7E8 ND ND 0.9 15.1 Calculated K.sub.B (pM) 6.01 83.45 1.04 6.64 Table 10: 0.028 pM-55.5 nM (n = 3 replicates). ND, not determined. Schild analysis of 7E8-CDR graft neutralization of IL-33 (mm2) or wild-type IL-33 (R&D Systems) at specified concentrations on HEK293 ST2 NFkB reporter cells or human PBMCs. A plot of log([A']/[A]) - 1) vs - log[B], where A' is the EC.sub.50 of IL-33 in the presence of antibody, A is the EC.sub.50 of IL-33 in the absence of antibody, and B is the concentration of antibody, produces an X intercept equal to kB, an approximation of the equilibrium constant for antibody binding to IL-33.

Example 9 Binding Affinity of IL-33 Antibodies to Human and Cynomolgus Monkey IL-33

[0199] Binding to human and cynomolgus monkey IL-33 was measured by surface plasmon resonance using a BIAcore T200 instrument. An anti-human Fc antibody was immobilized on a CM5 chip, and anti-IL-33 antibodies were captured. Human IL-33 (mm2) or cynomolgus monkey IL-33 was flowed over the chip at 50 .mu.l/min for 45 sec. over the concentration range 3.9-125 nM and allowed to dissociate for 240-1500 sec. Affinity values were determined as shown in Table 11 below. All antibodies bound to human IL-33, with affinity ranging from 171-540 pM. Captured chimeric 12F9 and chimeric 14D8 did not bind to 125 nM cynomolgus monkey IL-33 in solution, while CDR-grafted 7E8, chimeric 9B3, chimeric 30A1, and chimeric 30B11 bound to solution-phase human and cynomolgus monkey IL-33.

TABLE-US-00012 TABLE 11 Affinity of anti-IL-33 IgG binding to human and cynomolgus monkey IL-33 measured by surface plasmon resonance in IgG capture format HC SEQ LC SEQ human cynomolgus monkey Antibody NO NO IL-33 (mm2) KD (pM) IL-33 KD (pM) 7E8 CDR graft 92 93 .sup. 171 .+-. 21.8 142.4 .+-. 4.6 9B3 chimera 40 42 456.96 .+-. 56.75 835.9 .+-. 42.3 12F9 chimera 51 53 408.15 .+-. 46.75 no binding (125 nM IL-33) 14D8 huJseg 59 85 394.45 .+-. 30.45 no binding (125 nM IL-33) 30A1 hu Jseg 69 87 540.3 .+-. 52.2 196.5 .+-. 7.8 30B11 hu Jseq 78 89 366.7 .+-. 5 148.25 .+-. 15.95

Example 10 Kinetic Evaluation of 7E8 Using Surface Plasmon Resonance and KinExA.TM. Methodologies

[0200] Because the apparent affinity of antibodies measured as captured IgG was significantly lower than their potency in IL-33 neutralization in solution phase (Example 11), two alternative approaches to affinity determination were undertaken. To remove the influence of bivalent presentation of the two binding arms of the IgG molecule, monovalent anti-IL-33 antibody Fab fragments were prepared by papain cleavage of CDR-grafted 7E8 (SEQ ID NO:92, 93). Fab fragment affinity was measured by two methods, surface plasmon resonance using a BIAcore instrument, with either Fab or IL-33 captured on the chip, and solution equilibrium affinity measurements using a KinExA instrument, with both Fab and IL-33 in solution.

[0201] Surface plasmon resonance experiments were conducted in two formats. When 7E8 Fab was captured by an anti-human Fab capture kit (GE Healthcare Cat. No. 28958325), affinity (Table 12) was measured at 249.5 pM for IL-33 (mm2) and 290 pM for IL-33 (R&D), similar to the results obtained with IgG captured in a similar format (Table 11). However, when biotinylated hIL-33 (mm2) was captured on a streptavidin-coated BIAcore biosensor and a titration series of 7E8 Fab was injected over the sensor surface, the affinity of 7E8 Fab to IL-33 (mm2) was measured to be 3.06 pM (Table 12). Without wishing to be bound by any particular theory, the difference in results between the two formats may arise from matrix effects, e.g., at pH 7.4, attraction of the positively-charged Fab (pl 8.52) in solution to the negatively-charged CM5 sensor chip is expected, as is repulsion of the negatively-charged IL-33 in solution (pl 5.2 for IL-33 mm2, 4.45 for IL-33 VVT, and 5.48 for biotinylated IL-33 mm2) to the negatively-charged CM5 sensor chip (Drake et al. 2012, Anal. Biochem. 429(1):58-69). An orthogonal approach to affinity measurement is described in Example 10 below.

[0202] In order to assess the binding of 7E8 to wild-type IL33, recombinant IL-33 protein with wild-type cysteine residues (SEQ ID NO:4) was covalently coupled to a CM5 sensor chip (catalogue number BR100530, GE Healthcare) using an amine coupling kit (catalogue number BR100050, GE Healthcare) according to the manufacturer's protocol. Parallel studies were performed with non-reduced IL-33 and with IL-33 samples that had been reduced with 3 mM DTT for 3 hr. at room temperature prior to immobilization. Similar levels of IL-33 were immobilized (293 and 370 resonance units, respectively, for non-reduced and reduced IL-33). Flow cell 1 was activated and blocked for use as a reference flow cell. A titration series of the parental rat Fab 7E8 was performed, using 10 mM HEPES pH 7.4, 0.15M NaCl, 3 mM EDTA, 0.05% P-20 (HBS-EP+) as running and sample buffer, with a flow rate of 50 ul per min. Dissociation was monitored for 3600 seconds. Biacore kinetic assays were conducted at 37.degree. C. at a collection rate of 1 Hz on a Biacore T200 instrument (GE Healthcare). Rate constants and affinities were determined by fitting the resulting sensorgram data to a 1:1 model in Biacore T200 Evaluation software version 1.0 (GE Healthcare). The affinity of rat 7E8 Fab to wild-type human IL-33 that had been pre-treated with DTT was measured to be 44.23 pM (Table 12), while 7E8 Fab did not bind to non-reduced IL-33 (FIG. 1). This observation indicates that 7E8 selectively binds active IL-33 and not IL-33 that has been inactivated by oxidation and suggests that in a therapeutic setting, the presence of inactivated IL-33 would not interfere with the ability of a 7E8-derived antibody to bind active IL-33.

TABLE-US-00013 TABLE 12 Affinity of 7E8 Fab binding to human IL-33 measured by surface plasmon resonance in Fab capture format and with immobilized IL-33 Captured Fab, IL-33 in solution Immobilized IL-33; Fab in solution ka (1/Ms) .+-. kd (1/s) .+-. KD (pM) .+-. KD (pM) .+-. Ligand SEM SEM SEM (n) ka (1/Ms) kd (1/s) SEM (n) Hu IL-33 1.38E+06 .+-. 3.01E-04 .+-. 249.5 .+-. 5.47E+06 .+-. 1.68E-05 .+-. 3.06 .+-. mm2 7.00E+05 6.50E-06 120.5 (2) 7.95E+05 3.20E-06 0.14 (2) Hu IL-33 2.06E+06 .+-. 3.77E-04 .+-. 290 .+-. 2.55E+06 .+-. 1.16E-04 .+-. 44.23 .+-. WT 1.12E+06 3.20E-05 143 (2) 2.22E+05 1.18E-05 5.25 (3) Reduced Hu IL-33 ND no binding WT Non- reduced Table 12. Binding affinity of 7E8 Fab to human IL33 measured by surface plasmon resonance. Solution phase Fab was tested at 0.78-12.5 nM, and solution-phase IL-33 was tested at 0.78-25 nM.

[0203] In order to address the format-dependent differences in affinity measured by surface plasmon resonance in different reagent orientations, an orthogonal method was used to assess the affinity of 7E8 Fab for IL-33, with both binding partners in solution. A Kinetics Exclusion Assay (KinExA) instrument (model 3200, Sapidyne) was used to determine the binding affinity of 7E8 Fab to huIL-33 (mm2) (SEQ ID NO:3) and huIL33 wt (SEQ ID NO:4). HuIL33 wt was reduced in 3 mM DTT for a minimum of two hrs prior to use. Affinity determinations were made at room temperature using the fixed antigen assay format. Equilibrium binding was achieved by incubation at 25.degree. C. for 72 hrs. Data analysis was performed with the KinExA Pro software version 3.6.5 (Sapidyne). The "affinity standard" model was used to analyze the data and determine the apparent KDs and apparent active concentrations of huIL33 mm2 and reduced huIL33 wt. The "drift correction" was used when appropriate. Multiple curves were obtained, both receptor and KD controlled, in independent experiments and analyzed using the "n-curve analysis" tool to obtain global best fit values for the KD and active concentration. The software reports each best fit value along with a 95% confidence interval. KinExA analysis showed that 7E8 Fab binds human IL-33 with very high affinity, with KD measured at 0.35 pM for the mm2 form of hIL-33 and 4.04 pM for the reduced WT form (Table 13). These results are consistent with the results of cell-based assays analyzed by Schild analysis (Example 8), which showed that under solution equilibrium conditions, 7E8 CDR graft binds with low picomolar affinity to IL-33 in solution.

TABLE-US-00014 TABLE 13 Affinity of 7E8 Fab to human IL-33 (mm2) and human IL-33 (WT) measured by KinExA IL-33 form kD (pM) Percent error huIL-33 (mm2) 0.351 (0.202-0.526) 1.36 hu IL-33 (WT + DTT) 4.04 (2.60-5.76) 0.90 Table 13. Affinity determinations were made using the fixed-antigen assay format. 7E8 Fab was titrated from 15 fM to 0.25 nM into fixed concentrations of 4 pM and 100 pM huIL-33 (mm2), and it was titrated from 244 fM to 2 nM into fixed concentrations of 100 pM and 500 pM hu IL-33 (WT). The 95% confidence interval, shown in parentheses with the kD, and percent error are calculated by KinExA software based on a least-squares fit of the theoretical binding equation to the measured signals.

Example 11 Paratope Determination of Anti-IL-33 Antibodies by Augmented Binary Substitution

[0204] Three methods were used to identify amino acids critical for function of antibody 7E8. First, a systematic examination of the CDR residues that differ between the rat mAb CDR sequences and the human germline CDR sequences was carried out to determine which positions require the original rat sequence and which tolerate change. This method addressed sequences in CDR-H1 and CDR-H2 in the heavy chain and light chain CDR-L1, CDR-L2, and CDR-L3. A second method (Example 12) addressed tolerance for sequence variation in CDR-H3, which is not encoded in the germline. Sequence variation present in splenic B cells of the immunized rat from which parental 7E8 was derived was determined by next-generation sequencing (NGS), and the frequency of variation at each position of CDR-H3 was determined. Function of a subset of variant CDR sequences was tested to determine the impact of observed sequence changes. A third method that examined functional CDR residues was the examination of specific engineered amino acid variants in the course of antibody engineering (see Examples 14-16).

[0205] A method for determining critical CDR residues has been described, by which functional antibody variants are selected from a library containing either the human germline residue or the corresponding rodent residue at each CDR position except for CDR-H3 (Townsend et al., 2015). A phage scFv library was constructed in which all CDR positions of 7E8 that differed from the human germline (DP54/DPK9) were randomized such that approximately 50% of the clones encoded the rat 7E8 amino acid and approximately 50% encoded the human germline amino acid at that position (Table 14). Libraries were prepared and subjected to 3-4 rounds of selection on human IL-33 (mm2). Clones that retained binding to IL-33 were recovered and their sequences determined. From this experiment, positions at which the human sequence was observed in less than approximately 20% of the binding clones were defined as essential rat residues. Rat residues were preferentially retained at 11 positions (heavy chain residues Y35, S50, T52, and P53; light chain residues H32, D34, F50, N53, Y91, G94, and W95) indicating that replacement of these residues by human germline residues was strongly disfavored. Replacement of F50 in the light chain with A was not observed, indicating that F is the strongly preferred amino acid at this position. Rat and human residues were found with similar frequency at heavy chain residues 54 (N/D), 56, (G/S), 57 (N/E), 58 (T/K), and 61 (P/V) and light chain residues 24 (K/R), 28 (N/S), 30 (N/S), 31 (K/S), 52 (N/S), 56 (T/S), 89 (F/Q), 92 (N/Y), and 93 (N/S), indicating that the rat sequence at these positions is not critical. Position 51 in the light chain encoded a threonine residue in the rat 7E8 clone, but the alanine encoded in the human DPK9 germline sequence was favored, being incorporated in 86% of the binding clones (Table 14). While the starting frequency of alanine codons at position 51 in the library was 68%, higher than most but similar to several other residues, other positions with similar starting bias (e.g., 65% arginine codons at position L24 and 63% serine codons at postion L30 in the starting library) had a nearly-equal distribution of amino acids in the selected clones. This observation suggests that alanine is strongly favored at position 51.

TABLE-US-00015 TABLE 14 Frequency of incorporation of human amino acids in 7E8 CDR positions tested by augmented binary substitution 7E8 human starting binding rat germline library clones Site AA AA % human % human H35 Y S 52 5.88 H50 S N 37 7.84 H52 T K 51 2.6 H53 P Q 48 5.22 H54 N D 56 43.13 H56 G S 40 49.0 H57 N E 54 48.36 H58 T K 53 51.63 H61 P V 47 48.36 L24 K R 65 48.36 L28 N S 52 42.48 L30 N S 63 49.67 L31 K S 36 33.98 L32 H Y 42 16.99 L34 D N 41 13.72 L50 F A 55 0 L51 T A 68 86.27 L52 N S 47 48.36 L53 N S 46 20.26 L56 T S 45 59.48 L89 F Q 56 54.25 L91 Y S 43 16.33 L92 N Y 52 54.9 L93 N S 65 49.01 L94 G T 56 20.26 L95 W L 36 7.10 Table 14. Sites are numbered as heavy chain (H) or light chain (L) variable regions based on SEQ ID NO: 94 and SEQ ID NO: 91, respectively.

Example 12 Tolerated Variations in Anti-IL-33 Antibody CDR-H3 Sequences in Rats Immunized with Human IL33

[0206] Tolerance of CDR H3 sequence variation by antibodies related to the IL-33 neutralizing antibodies described in Example 1 was examined by sequencing of the immune repertoire of the same animal from which the antibodies were derived. RNA was isolated from spleen tissue from the immunized rat, prepared by reverse transcription-RACE PCR as described in Example 2, and subjected to next-generation sequencing on a Roche FLX+ instrument. From 62,484 sequence reads, sets of VH genes with CDR3 sequences related to those of the neutralizing antibodies in Example 1 were identified. Within the set of unique CDR3 sequences, the frequencies with which amino acids diverged from the neutralizing antibody sequences at each position were calculated, without adjustment for the frequency of each CDR3 sequence in the population (Table 15). Strongly-conserved sequences in CDR3 from both 7E8 and 9B3 (<15% variation in unweighted sample) were G99, H100, Y101, Y103, S105, Y106, and S107. Variations in Y106 were not observed among the 72 sequence variants identified in the rat repertoire, and variations from Y103, S105, and S107 were observed in fewer than 3 percent of sequences.

TABLE-US-00016 TABLE 15 Frequency of amino acid differences from 7E8 and 9B3 CDR-H3 found among variants present in immunized rat immune repertoire 7E8 CDR H3 G99 H100 Y101 Y102 Y103 T104 S105 Y106 S107 L108 G109 Y110 Frequency of 4.2 6.9 8.3 27. 8 1.4 73.6 1.4 0 2.8 87.5 65.3 30.6 differences from 7E8 9B3 CDR H3 G99 H100 Y101 S102 Y103 S104 S105 Y106 S107 F108 S109 Y110 Frequency of 4.2 6.9 8.3 73.6 1.4 31.9 1.4 0 2.8 25 97.2 30.6 differences from 9B3 Table 15. Numbers represent the frequencies of amino acid changes observed at each position of CDR H3 within the set of unique 7E8- and 9B3-related CDR H3 sequences identified in the repertoire of the immunized rat from which these antibodies were obtained. The frequency with which a given CDR H3 sequence was observed in the repertoire was not taken into account in this calculation.

[0207] A subset of CDRH3 sequences related to 9B3 and 7E8, shown in Table 16, were cloned into the framework of the chimeric 9B3 heavy chain, generating heavy chains designated by SEQ ID NOs: 116, 120, 123, 125, 128, 131, 134, 137, 140, 143, 146, 149, 151, 154, 157, and 160. These heavy chains were cotransfected with the chimeric 9B3 light chain (SEQ ID NO:117) and the resulting antibodies expressed, purified and analyzed for IL-33 dissociation rate by BIAcore analysis and inhibition of IL-33 signaling in the HEK293 ST2 NFkB reporter assay. Dissociation rates were measured following binding to 125 nM IL-33 (mm2) using intact IgG captured by an immobilized anti-human Fc antibody as described in Example 9. Both assays showed that most of the CDRH3 sequence variants present in the rat repertoire conferred little or no change in dissociation rate or neutralization potency compared to that of parental 9B3, indicating that the observed sequence variations are well-tolerated changes. The dissociation rates of all 18 antibodies tested were within 2.5-fold of that of 9B3. Cell-based potency reductions up to four-fold were observed in four of the 18 antibodies. The larger changes in potency could not be attributed to specific single changes, since all four of these antibodies contained mutations observed in other variants with minimal functional effects. Substitution of two highly-conserved amino acids with chemically-similar side chains (aromatic side chain substitution Y101F in antibody 9B3-22 and the positively-charged side chain substitution H100R in antibody 9B3-7) did not lead to significant changes in antibody function in the context of additional substitutions in these antibodies. Taken together, the amino acid sequence variation observed in the immunized repertoire suggests that residues G99, H100, Y101, Y103, S105, Y106, and S107 or residues with chemically-similar side chains are favored in the CDR H3 of antibody 9B3 and its close relative 7E8.

TABLE-US-00017 TABLE 16 IL-33 neutralization activity and dissociation rates of 9B3 chimera variants containing CDR-H3s identified from immunized rat repertoire. HEK293 ST2 HC LC end FW3 NFkB assay Dissociation SEQ SEQ (lower case) + estimated IC.sub.50 rate Antibody NO NO frequency CDR H3 (nM) (kd; 1/s) 9B3-1 116 117 1 cakGHYYYSSYSLGY 0.039 5.69E-04 9B3-2A 120 117 2 cakGHYSYSSYSFGY 0.056 4.37E-04 9B3-2B 123 117 2 cvkGHYSYSSYSIDY 0.048 5.06E-04 9B3-3 125 117 3 cakGHYSYSSYSIDY 0.048 4.24E-04 9B3-5 128 117 5 cakGHYSYTSYSFGY 0.106 3.25E-04 9B3-7 131 117 7 cakGRYYYSSYSFAY 0.069 5.89E-04 9B3 chimera 40 83 8 cakGHYSYSSYSFSY 0.061 4.51E-04 huJseg 9B-13 134 117 13 carGHYYYNSYSFAH 0.175 3.26E-04 9B3015 137 117 15 cakGHYSYSSYSFAN 0.101 4.79E-04 9B3-17 140 117 17 caeGHYYYSSYSFGS 0.040 5.09E-04 9B3-22 143 117 22 cakGHFSYTSYSFAN 0.153 5.31E-04 9B3-31v2 146 117 31 cakGHYYYSSYSFAF 0.202 7.06E-04 9B3-36 149 117 36 cakGHYYYTSYSFAY 0.251 2.89E-04 9B3-79 151 117 79 carGHYYYTSYSFAY 0.063 5.43E-04 9B3-124 154 117 124 cakGHYYYTSYSLGF 0.081 3.98E-04 9B3-162 157 117 162 cakGHYYYSSYSFGY 0.067 6.42E-04 7E8H/9B3K 28 117 234 cakGHYYYTSYSLGY 0.015 3.85E-04 9B3-563 160 117 563 cakGHYYYSSYSFAY 0.177 1.09E-03 IL-33 neutralization activity and dissociation rate of 9B3 chimera variants containing CDR-H3s identified from immunized rat repertoire. Frequency refers to the number of times the CDR3 sequence was obtained in a next-generation sequencing run from the immunized rat repertoire. Sequences diverging from 9B3 are shown in bold underlined text. Sequences at C terminal end of Framework 3 are shown in lower-case text.

Example 13 Assessment of Non-Specific Binding of Anti-IL-33 Antibodies

[0208] Nonspecific binding of antibodies to molecules other than their targets has been proposed to be a mechanism of rapid clearance in vivo (Hotzel et al., 2010, MAbs 4(6):753-760). Evidence for such polyreactive non-target binding can be obtained through measurement of binding to membrane preparations (Xu et al., 2013, Protein Eng. Des. Select. 26(10):663-70), baculovirus particles (Hotzel et al., 2012, mAbs 4:753-60), or negatively-charged substrates such as DNA, insulin, and heparin (Tiller et al., 2008, J. Immunol. Methods 329(1-2):112-124).

[0209] The ELISA for DNA and insulin used a low-stringency protocol originally developed for detection of low-affinity autoantibodies from lupus patients (Tiller et al., 2008). Insulin at 5 .mu.g/ml or single-stranded or double-stranded DNA at 10 .mu.g/ml in PBS were coated onto Nunc Maxisorp ELISA plates overnight. Wells were washed 3.times. with water, then blocked with ELISA buffer (PBS/0.05% Tween/1 mM EDTA) 1 hr room temperature. Antibodies at 3-10 .mu.g/ml in ELISA buffer were incubated in the wells for 1 hr at room temperature, and the wells were washed 3.times. with water, incubated with HRP-conjugated goat anti-human IgG 1:5000 in ELISA buffer for 1 hr room temperature. Following 3 washes with water, color was developed with TMB for 5 mins and the reaction stopped with 0.1M sulfuric acid. The ELISA for binding to baculovirus (BV) particles was based on the method described in Hotzel, 2012. Antigen was immobilized in Nunc Maxisorp ELISA plates by adding a 4% BV suspension in 50 mM sodium carbonate buffer pH 9.6 to each well and allowing the particles to adsorb to the plates overnight at 4.degree. C. The wells were blocked with blocking buffer (PBS/0.5% BSA) 1 h at room temperature. After 3 washes with PBS, antibodies at 10 .mu.g/ml in blocking buffer were added to the ELISA wells and incubated for 1 h at room temperature. Plates were washed 6 times with PBS and incubated with 20 ng/ml HRP-goat anti-human antibody (Jackson ImmunoResearch Cat No. 109-035-008) for 1 h at room temperature. Plates were washed 6 times in PBS, and 25 .mu.l of TMB substrate was added to each well and allowed to develop for 15 min and then stopped by adding 1 M phosphoric acid to each well. Detergents were not added to buffers in any step. A450 signals at 10 .mu.g/ml Ab were normalized to the signal from a blank well for comparison of samples.

[0210] Chimeric and CDR-grafted 7E8 were found to have moderate binding to DNA and insulin in the low-stringency polyreactivity ELISAs, while chimeric 9B3 showed DNA and insulin binding close to that of a negative control antibody despite sequence similarity to 7E8 (Table 17). Replacement of CDR-H2 of 7E8 by its 9B3 counterpart produces a partial reduction in polyreactivity, while replacement of CDR H1 or CDR H3 had minimal effect.

[0211] The human IL-33 (mm2) blocking activity of 9B3 is lower than that of 7E8 (0.264 nM in the HEK293 ST2 NFkB assay for 9B3 vs 0.059 nM for 7E8). The difference is more pronounced in inhibition of cynomolgus monkey IL-33: 7E8 inhibits with a potency (0.131 nM) similar to its potency on human IL-33, while 9B3 is substantially weaker on cynomolgus IL-33, blocking only partially at 20 nM. Replacement of the 7E8 CDR H2 with the 9B3 CDR H2 leads to a large loss in potency against cynomolgus monkey IL-33 (0.131 nM 10.sub.50 reduced to 3.46 nM), and similarly, replacement of the 7E8 CDR H3 with the 9B3 CDR H3 leads to a loss of cynomolgus monkey IL-33 potency (7.65 nM). Thus, CDR H2 carries determinants of both specific and nonspecific activity of the 7E8/9B3 family of IL-33 neutralizing antibodies, and CDR H3 carries determinants of specific activity.

TABLE-US-00018 TABLE 17 DNA binding activity and neutralization of human and cynomolgus monkey IL-33 by CDR graft variants of 7E8 HEK293 ST2 HEK293 NFkB ST2 2.2 nM 6.7 nM 20 nM human NFkB Ab DNA Ab DNA Ab DNA IL-33 cyno binding binding binding (mm2) IL-33 normalized normalized normalized IC.sub.50 IC.sub.50 HC LC to blank .+-. to blank .+-. to blank .+-. (nM) .+-. (nM) .+-. SEQ SEQ VH VL SEM SEM SEM SEM SEM Antibody NO NO description description (n) (n) (n) (n) (n) 7E8 28 31 7E8 7E8 20.12 20.39 26.82 chimera chimera chimera 9B3 40 42 9B3 9B3 6.26 7.64 11.98 chimera chimera chimera 9B3 40 83 9B3 9B3 3.19 5.91 9.54 0.264 .+-. 71.6% chimera/hu chimera chimera/human 0.029 @ 20 J J segment (2) nM 7E8 CDR 92 93 7E8 7E8 CDR 23.54 24.68 27.19 0.059 .+-. 0.131 .+-. graft CDR graft 0.001 0.008 graft (2) (2) IL33-10 95 93 7E8 7E8 CDR 25.40 25.16 27.51 0.017 0.132 CDR graft graft IL33-11 162 93 7E8 VH 7E8 CDR 24.02 24.29 26.71 0.090 0.204 with 9B3 graft H1 IL33-12 164 93 7E8 VH 7E8 CDR 12.64 19.21 24.68 0.144 3.460 with 9B3 graft H2 IL33-13 166 93 7E8 with 7E8 CDR 23.14 22.50 25.89 0.220 7.651 9B3 H3 graft Polyreactivity 2.52 .+-. 4.49 .+-. 8.08 .+-. negative 0.11 (2) 0.81 (2) 0.46 (2) control (8.8) Polyreactivity 15.69 20.84 26.22 positive control (scFv-Fc)

Example 14 Assessment of Non-Specific Binding and Activity of CDR Variants of 7E8

[0212] Polyreactivity has been linked to imbalance of positive charge in CDRs (Datta-Mannan et al., 2015, MAbs 7(3):483-493). No charge differences exist between light chains of 7E8 and 9B3. Inspection of the CDR-H2 and CDR-H3 sequences of 7E8 and 9B3 (SEQ ID NO:17, 34, 18, and 35) showed four CDR-H2 and four CDR-H3 differences, of which only one (at position 54, N in 7E8 and D in 9B3) would lead to a difference in charge. Modification of 7E8 with the N54D mutation to generate IL33-45 (heavy chain SEQ ID NO:169) had only modest effects on polyreactivity but reduced cynomolgus monkey IL-33 neutralization significantly, in a way similar to what was observed with substitution of CDR H2 of 7E8 with that of 9B3 (Table 18). For this reason, additional sequence variants were required in order to identify sequence changes that would allow retention of 7E8 activity on both human and cynomolgus monkey IL-33 while reducing the polyreactivity of 7E8.

TABLE-US-00019 TABLE 18 DNA binding activity and neutralization of human and cynomolgus monkey IL-33 by variants of 7E8 incorporating CDR H2 sequences from 9B3 HEK293 HEK293 2.22 nM 6.67 nM 20 nM ST2 ST2 Ab DNA Ab DNA Ab DNA NFkB NFkB HC LC binding binding binding mm2 cyno IL- SEQ SEQ VH VL normalized normalized normalized IC.sub.50 33 IC.sub.50 Antibody NO NO description description to blank to blank to blank (nM) (nM) 7E8 CDR- 92 93 Parental 7E8 CDR 28.20 30.33 30.66 0.057 0.077 grafted 7E8 CDR graft graft 9B3 40 83 9B3 9B3 8.40 13.40 18.48 ND ND chimera/hu J chimera chimera/ human J segment IL33-12 164 93 7E8 VH 9B3 CDR 25.47 29.34 29.03 0.140 0.943 with 9B3 graft H2 IL33-45 169 93 N54D 7E8 CDR 17.36 24.44 29.20 0.325 0.535 graft Polyreactivity 1.95 4.41 7.17 negative control (8.8) Polyreactivity 28.09 35.44 35.43 positive control (MJ4- 2 v1.1/P33)

Example 15 Optimization of Anti-IL-33 Antibody 7E8

[0213] A series of mutations was made in 7E8 in order to identify changes that would reduce polyreactivity without loss of activity. While substitution of N54 in CDR H2 with aspartic acid slightly reduced polyreactivity but led to reduced cell-based activity, replacement of N54 with other amino acids (I, L, V, W, Y) increased nonspecific binding to baculovirus while leaving cell-based activity intact.

[0214] Replacement of the CDR H2 residue N57 with either of two negatively-charged residues, aspartic acid or gluatamic acid, led to significant reductions in polyreactivity as measured by binding to baculovirus particles, DNA, or insulin, but these mutations did not reduce neutralization activity (Table 19). Surprisingly, addition of negative charge to CDR3 of the heavy chain (S105D) led to undesirable changes in both polyreactivity and cell-based activity, and addition of negative charges to the light chain (mutations N30D, K31D, T56D, or T56E) increased polyreactivity. The N57D and N57E variants are therefore unusual in that they improve polyreactivity without impairing neutralization of human or cynomolgus monkey IL-33. These results suggest that the position of negative charges and not simply the total charge on the variable domain is significant.

TABLE-US-00020 TABLE 19 Baculovirus binding activity and neutralization of human and cynomolgus monkey IL-33 by single amino acid variants of CDR-grafted 7E8 HEK293 ST2 HEK293 NFkB ST2 Baculo- human NFkB virus IL-33 cyno HC LC binding (mm2) IL-33 SEQ SEQ VH VL normalized IC.sub.50 IC.sub.50 Antibody NO NO description description to blank (nM) (nM) 7E8 CDR graft 92 93 7E8 CDR 7E8 CDR 1.27 0.040 0.054 graft graft IL33-12 164 93 7E8 VH 7E8 CDR 0.51 with 9B3 graft H2 IL33-55 172 93 N57D 7E8 CDR 0.97 0.084 0.19 graft IL33-56 175 93 N57E 7E8 CDR 1.00 0.053 0.104 graft IL33-57 178 93 S105D 7E8 CDR 3.17 0.310 graft IL33-58 181 93 N54L 7E8 CDR 5.04 0.027 graft IL33-61 183 93 N57E 7E8 CDR 2.48 0.595 S105D graft IL33-62 185 93 N57D 7E8 CDR 2.48 0.885 S105D graft IL33-68 188 93 S105A 7E8 CDR 1.73 0.046 0.062 graft IL33-74 95 191 7E8 CDR K31D 4.02 0.174 graft IL33-75 95 194 7E8 CDR N30D 5.14 0.156 graft IL33-80 95 197 7E8 CDR T56D 3.49 0.161 graft IL33-81 95 200 7E8 CDR T56E 4.68 0.168 graft Negative 0.52 polyreactivity control (bevacizumab) Positive 5.83 polyreactivity control (MJ4-2 VH1.1/P33)

[0215] A series of additional heavy chain CDR mutations predicted to introduce negative charge, remove hydrophobic residues, or modify residues in proximity to position 57 was examined in conjunction with N57E. Polyreactivity of 7E8 with the N57E mutation remained generally low with the incorporation of individual mutations in CDR-H2 (S50A, T58D; Table 20), and in the HEK293 ST2 NFkB cell-based assay (Table 21), potency of 7E8 with the N57E mutation was largely unchanged by the incorporation of S50A or T58D. Similarly, polyreactivity of 7E8 with the N57E mutation remained generally low with the incorporation of additional individual mutations in CDR H1 (T28E), H2 (G56H, T58D, D62E, S63A, or K65Q) or H3 (H100Y, Y102H, Y103H, Y103W, T104N, or T104S). Likewise, in the HEK293 ST2 NFkB cell-based assay, potency of 7E8 with the N57E mutation was largely unchanged by the incorporation of additional individual mutations in CDR H1 (T28E), H2 (K65Q) or H3 (H100Y, T104N, or T104S).

[0216] IL-33 can stimulate the production of IFN.gamma. in human whole blood with the costimulation by IL-12 in a format nearly identical to that used for the PBMC assay described in Example 8, except that a higher concentration of IL-33 (100 pM) is required for the whole blood response, compared to 5 pM IL-33 for PBMCs. Similar to the results observed in the HEK293 ST2 NFkB assay, the whole-blood potency of 7E8 with the N57E mutation was largely unchanged by the incorporation of individual mutations 550A or T58D (Table 21). Likewise, potency of 7E8 with the N57E mutation was largely unchanged by the incorporation of additional individual mutations in CDR H1 (T28E), H2 (S63A or K65Q) or H3 (Y103H, T104N or T104S).

[0217] A mutation designed to eliminate a potential site of posttranslational modification (light chain N93Q, which removes a potential NG asparagine deamidation site (Chelius et al., 2005, Anal. Chem. 77(18):6004-6011) was combined with the heavy chain mutation N57E in antibody IL33-136 and found to lead to retention of cell-based activity (Table 21) with a partial retention of improved polyreactivity (Table 20).

TABLE-US-00021 TABLE 20 Binding to baculovirus, DNA, and insulin by CDR H2 and CDR L3 variants of CDR- grafted 7E8 DNA Insulin baculovirus binding binding binding HC LC normalized normalized normalized SEQ SEQ VH VL to blank .+-. to blank .+-. to blank .+-. Antibody NO NO description description SEM (n) SEM (n) SEM (n) IL33-10 95 93 7E8 CDR 7E8 CDR 13.22 .+-. 2.0 6 16.6 .+-. 1.77 2.32 .+-. 0.29 graft graft (4) (4) (5) IL33-12 164 93 7E8 VH with 7E8 CDR 5.76 .+-. 0.44 7.79 .+-. 0.47 1.57 .+-. 0.29 9B3 H2 graft (4) (4) (5) IL33-45 169 93 N54D 7E8 CDR 6.91 .+-. 0.7 8.6 .+-. 1.69 3.93 .+-. 0.61 graft (4) (4) (5) IL33-55 172 93 N57D 7E8 CDR 4.94 .+-. 0.67 6.96 .+-. 0.68 1.14 .+-. 0.09 graft (4) (4) (5) IL33-56 175 93 N57E 7E8 CDR 6.13 .+-. 0.96 8.81 .+-. 0.87 1.5 .+-. 0.34 graft (4) (4) (5) IL33-103 203 93 N57E S50A 7E8 CDR 6.09 .+-. 1.01 9.1 .+-. 0.64 1.44 .+-. 0.24 graft (4) (4) (5) IL33-117 206 93 N57E T58D 7E8 CDR 6.46 .+-. 0.99 8.96 .+-. 1.5 1.47 .+-. 0.18 graft (4) (4) (5) IL33-136 175 209 N57E N93Q 11.33 .+-. 2.14 13.9 .+-. 1.4 4.34 .+-. 1.59 (4) (4) (5) Negative 5.71 .+-. 1.12 7.17 .+-. 0.87 2.19 .+-. 0.21 polyreactivity (4) (4) (5) control (8.8) Positive 35.06 .+-. 4.1 39.06 .+-. 1.33 10.54 .+-. 1.68 polyreactivity (4) (4) (5) control (MJ4-2 VH1.1/P33)

TABLE-US-00022 TABLE 21 Cell-based activity of CDR H2 and CDR L3 variants of CDR-grafted 7E8 HEK293 HEK293 HEK293 ST2 ST2 ST2 NFkB NFkB NFkB cyno WT Whole HC LC mm2 IL-33 IL-33 blood SEQ SEQ VH VL IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Antibody NO NO description description (nM) (nM) (nM) (nM) IL33-10 95 93 7E8 CDR 7E8 CDR 0.031 0.059 0.117 0.121 graft graft .+-. 0.025 (4) IL33-103 203 93 N57E 7E8 CDR 0.028 0.07 0.178 0.104 S50A graft .+-. 0.008 (4) IL33-117 206 93 N57E 7E8 CDR 0.052 0.155 0.106 T58D graft .+-. 0.014 (2) IL33-136 175 209 N57E N93Q 0.037 0.098 .+-. 0.033 (4)

[0218] Combinations of these mutations and two additional heavy chain mutations (G55A, which allowed removal of a potential NG asparagine deamidation site, and D62E, which removes a potential DS aspartic acid isomerization site; (Chelius, D., et al. (2005) were examined for activity and polyreactivity, and a set of clones with cell-based activity (in the HEK293 ST2 NFkB reporter assay, human whole blood, and human PBMC assays) within approximately two-fold of the starting clone 7E8 CDR graft and polyreactivity within two-fold of the negative control antibody was identified (Table 22, Table 23).

TABLE-US-00023 TABLE 22 Binding to baculovirus, DNA, and insulin by variants of CDR-grafted 7E8 containing multiple CDR H2 and CDR L3 mutations DNA Insulin baculovirus binding binding binding HC LC normalized normalized normalized SEQ SEQ VH VL to blank .+-. to blank .+-. to blank .+-. Antibody NO NO description description SEM (n) SEM (n) SEM (n) IL33-153 212 209 G55A N57E N93Q 4.6 .+-. 0.4 6.67 .+-. 1.14 1.42 (1) T58D (2) (2) IL33-154 215 209 G55A N57E N93Q 4.94 .+-. 0 6.21 .+-. 1.65 1.25 (1) T58D D62E (2) (2) IL33-155 218 209 S50A N57E N93Q 4.05 .+-. 0.29 5.18 .+-. 0.9 1.25 (1) T58D (2) (2) IL33-156 221 209 S50A N57E N93Q 4.32 .+-. 0.04 5.75 .+-. 1.32 1.15 (1) T58D D62E (2) (2) IL33-157 224 209 S50A G55A N93Q 4.74 .+-. 0.16 5.71 .+-. 1.67 1.55 (1) N57E T58D (2) (2) IL33-158 227 209 S50A G55A N93Q 5.25 .+-. 0.09 6.42 .+-. 1.82 1.43 (1) N57E T58D (2) (2) D62E IL33-167 212 93 G55A N57E 7E8 CDR 5.71 .+-. 0.8 8.01 .+-. 2.63 1.47 (1) T58D graft (2) (2) IL33-168 215 93 G55A N57E 7E8 CDR 4.58 .+-. 0.07 6.26 .+-. 0.95 1.03 (1) T58D D62E graft (2) (2) IL33-169 218 93 S50A N57E 7E8 CDR 5.71 .+-. 1.63 6.34 .+-. 1.84 1.24 (1) T58D graft (2) (2) IL33-170 221 93 S50A N57E 7E8 CDR 5.91 .+-. 0.89 6.35 .+-. 2.29 0.96 (1) T58D D62E graft (2) (2) IL33-171 224 93 S50A G55A 7E8 CDR 5.4 .+-. 0.83 5.45 .+-. 0.99 1.15 (1) N57E T58D graft (2) (2) IL33-172 227 93 S50A G55A 7E8 CDR 5.4 .+-. 1.16 6.2 .+-. 1.4 1.51 (1) N57E T58D graft (2) (2) D62E IL33-175 230 93 S50A G55A 7E8 CDR 6.2 .+-. 0.28 8.55 .+-. 2.19 1.57 (1) N57E D62E graft (2) (2) IL33-186 233 209 S50A N57E N93Q 4.92 .+-. 0.11 7.77 .+-. 1.63 1.01 (1) D62E (2) (2) IL33-187 236 209 S50A G55A N93Q 6.43 .+-. 0.53 7.21 .+-. 1.59 0.96 (1) N57E (2) (2) IL33-188 230 209 S50A G55A N93Q 5.52 .+-. 0.04 7.28 .+-. 1.35 0.92 (1) N57E D62E (2) (2) Polyreactivity 3.42 .+-. 1.07 3.44 .+-. 0.86 1.36 (1) negative (2) (2) control (8.8) Polyreactivity 18.19 .+-. 8.12 15.37 .+-. 3.16 4.77 (1) positive (2) (2) control (MJ4-2 v1.1/P33)

TABLE-US-00024 TABLE 23 Cell-based activity of variants of CDR-grafted 7E8 containing multiple CDR H2 and CDR L3 mutations HEK293 ST2 HEK293 NFkB Whole ST2 cyno blood PBMC NFkB IL-33 mm2 mm2 IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 HC LC (nM) .+-. (nM) .+-. (nM) .+-. (nM) .+-. SEQ SEQ VH VL SEM SEM SEM SEM Antibody NO NO description description (n) (n) (n) (n) 7E8 CDR 92 93 7E8 CDR graft 7E8 CDR 0.114 .+-. 0.18 .+-. 0.009 .+-. 0.004 .+-. graft graft 0.042 0.015 0.002 0.001 (3) (2) (8) (2) IL33-153 212 209 G55A N57E T58D N93Q 0.087 0.122 0.014 .+-. (1) (1) 0.004 (4) IL33-154 215 209 G55A N57E T58D N93Q 0.188 .+-. 0.133 .+-. 0.01 .+-. 0.007 .+-. D62E 0.061 0.018 0.003 0.002 (3) (2) (6) (2) 1L33-155 218 209 S50A N57E T58D N93Q 0.171 0.239 0.025 .+-. (1) (1) 0.008 (4) 1L33-156 221 209 S50A N57E T58D N93Q 0.116 .+-. 0.087 .+-. 0.004 .+-. 0.004 .+-. D62E 0.038 0.015 0.001 0.001 (3) (2) (6) (2) 1L33-157 224 209 S50A G55A N57E N93Q 0.118 0.161 0.016 .+-. T58D (1) (1) 0.007 (4) 1L33-158 227 209 S50A G55A N57E N93Q 0.131 .+-. 0.125 .+-. 0.007 .+-. 0.004 .+-. T58D D62E 0.033 0.033 0.002 0.001 (3) (2) (6) (2) IL33-167 212 93 G55A N57E T58D 7E8 CDR 0.049 .+-. 0.062 .+-. 0.008 .+-. 0.001 .+-. graft 0.014 0.01 0.004 0 (3) (2) (6) (2) IL33-168 215 93 G55A N57E T58D 7E8 CDR 0.109 0.264 0.014 .+-. D62E graft (1) (1) 0.005 (4) 1L33-169 218 93 S50A N57E T58D 7E8 CDR 0.071 0.176 0.009 .+-. graft (1) (1) 0.003 (4) IL33-170 221 93 S50A N57E T58D 7E8 CDR 0.176 .+-. 0.218 .+-. 0.005 .+-. D62E graft 0.091 0.033 0.001 (2) (2) (4) 1L33-171 224 93 S50A G55A N57E 7E8 CDR 0.145 0.216 0.012 .+-. T58D graft (1) (1) 0.004 (4) IL33-172 227 93 S50A G55A N57E 7E8 CDR 0.201 .+-. 0.222 .+-. 0.012 .+-. T58D D62E graft 0.105 0.07 0.004 (2) (2) (4) IL33-175 230 93 S50A G55A N57E 7E8 CDR 0.059 .+-. 0.086 0.006 .+-. 0.004 .+-. D62E graft 0.011 (1) 0.002 0 (2) (6) (2) 1L33-186 233 209 S50A N57E D62E N93Q 0.109 0.144 0.012 .+-. (1) (1) 0.006 (4) IL33-187 236 209 S50A G55A N57E N93Q 0.15 0.282 0.006 .+-. (1) (1) 0.002 (3) IL33-188 230 209 S50A G55A N57E N93Q 0.147 0.351 0.017 .+-. D62E (1) (1) 0.01 (3)

Example 17 Addition of Half-Life Extension Mutations to Optimized Antibody 7E8 Variants

[0219] Two heavy-chain variant versions of antibodies IL33-158 and IL33-167 were generated, one a variant Fc (SEQ ID NO:237) containing the mutations L234A L235A and G237A in the Fc to decrease effector function (described in U.S. Pat. No. 5,624,821) and deletion of the lysine residue at the C terminus to reduce product heterogeneity, and the other (SEQ ID NO:238) containing the L234A L235A, and G237A mutations, the C terminal lysine deletion, and the double mutation M432L N438S to enhance binding to the neonatal Fc receptor FcRn at acidic pH, expected to lead to prolonged half-life in vivo (Zalevsky et al., 2010, Nature Biotechnol. 28(2):157-159). Each construct was built in the vector pRY19 and stably transfected into CHO cells. The resulting antibodies were IL33-158-152 (SEQ ID NO:241, SEQ NO: 209), IL33-167-153 (SEQ ID NO:242, SEQ ID NO:93), IL33-158LS (SEQ ID NO:244 SEQ ID NO:209), and IL33-167L5 (SEQ ID NO:245, SEQ ID NO:93). Sequence alignments of the variable regions of the optimized antibodies with the corresponding human germline sequences are shown in FIG. 2.

Example 18 Polyreactivity Reduction in Optimized Molecules

[0220] The antibodies L33-158LS (SEQ ID NO:244 SEQ ID NO:209) and IL33-167L5 (SEQ ID NO:245, SEQ ID NO:93) produced from stably-transfected CHO cells showed polyreactivity levels comparable to those of the negative control monoclonal antibody bevacizumab (Table 24). These levels are comparable to those of IL33-158 (SEQ ID NO:227, SEQ ID NO:209) and IL33-167 (SEQ ID NO:212, SEQ ID NO:93), shown in Table 22, indicating that the addition of the constant region mutations L234A L235A, G237A, M432L and N438S mutations and deletion of the C terminal lysine did not substantially alter the polyreactivity of the resulting molecule.

TABLE-US-00025 TABLE 24 Binding to DNA and insulin by optimized variants of CDR-grafted 7E8 DNA Insulin binding binding HC LC normalized normalized SEQ SEQ VH VL to blank .+-. to blank .+-. Antibody NO NO description description SEM (n) SEM (n) 1L33-158L5 244 209 S50A G55A N57E N93Q 7.45 .+-. 0.10 8.08 .+-. 0.48 T58D D62E (8) (8) IL33-167L5 245 93 G55A N57E T58D 7E8 CDR 6.23 .+-. 0.31 5.33 .+-. 1.05 graft (8) (8) 7E8 CDR graft 92 93 7E8 CDR graft 7E8 CDR 25.42 .+-. 0.36 14.58 .+-. 1.93 graft (8) (8) IL33-10 95 93 7E8 CDR graft 7E8 CDR 26.92 .+-. 0.77 12.26 .+-. 0.38 graft (8) (8) Polyreactivity 39.62 .+-. 0.24 42.20 .+-. 0.34 positive control (8) (8) (MJ4-2 v1.1/P33) Polyreactivity negative control 7.66 .+-. 0.36 9.87 .+-. 0.27 (bevacizumab) (8) (8) Polyreactivity negative control 1.50 .+-. 0.06 4.47 .+-. 0.09 (8.8) (6) (6)

Example 19 Human and Cynomolgus Monkey IL-33 Neutralization Activity of Optimized Anti-IL-33 Antibodies in Cell-Based Assays

[0221] The antibodies IL33-158-152 (SEQ ID NO:241, SEQ ID NO:209), IL33-167-153 (SEQ ID NO:242, SEQ ID NO: 93), IL33-158LS (SEQ ID NO:244 SEQ ID NO:209), and IL33-167LS (SEQ ID NO:245, SEQ ID NO:93) produced from stably-transfected CHO cells showed neutralization of IL-33 in the HEK293 ST2 NFkB reporter assay similar to that of the parental antibody 7E8 CDR graft (SEQ ID NO:92, SEQ ID NO:93) for human IL-33 (mm2), human IL-33 (WT) and cynomolgus monkey IL-33 (cys mut).

TABLE-US-00026 TABLE 25 Neutralization activity of optimized variants of CDR- grafted 7E8 in HEK293 ST2 NFkB reporter cell assay HEK293 ST2 NFkB HEK293 ST2 NFkB HEK293 ST2 NFkB cynomolgus monkey HC SEQ LC SEQ hIL-33 (mm2) hIL-33 (R&D) IL-33 (cys mut) Antibody NO NO IC.sub.50 (nM) .+-. SEM (n) IC.sub.50 (nM) .+-. SEM (n) IC.sub.50 (nM) .+-. SEM (n) IL33-158LS 244 209 0.162 .+-. 0.058 (3) 0.983 .+-. 0.149 (2) 0.198 .+-. 0.068 (3) IL33-167LS 245 93 0.13 .+-. 0.035 (3) 0.685 .+-. 0.089 (2) 0.162 .+-. 0.071 (3) IL33-158-152 241 209 0.095 .+-. 0.032 (3) 0.62 .+-. 0.103 (2) IL33-167-153 242 93 0.129 .+-. 0.042 (3) 0.749 .+-. 0.227 (2) 7E8 CDR graft 92 93 0.093 .+-. 0.029 (3) 0.322 .+-. 0.011 (2) 0.184 .+-. 0.056 (3)

Example 20 IL-33 Neutralization Activity of Optimized Anti-IL-33 Antibodies in PBMCs and Whole Blood

[0222] The antibodies IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) and IL33-167LS (SEQ ID NO:245, SEQ ID NO:93) produced from stably-transfected CHO cells showed neutralization of IL-33 (mm2) in human PBMCs similar to that of the parental antibody 7E8 CDR graft (SEQ ID NO:92, SEQ ID NO:93).

TABLE-US-00027 TABLE 26 Neutralization activity of optimized variants of CDR-grafted 7E8 in human PBMC HC SEQ LC SEQ Antibody NO NO IC.sub.50 (nM) .+-. SEM (n) IL33-158LS 244 209 0.0014 .+-. 0.0001 (4) IL33-167LS 245 93 0.0011 .+-. 0.0002 (4) 7E8 CDR graft 92 93 0.0014 .+-. 0.0004 (4) Table 26: Neutralization of IFN-.gamma. production in PBMC. Human PBMC were primed with 16.67 pM IL-12, then treated with 5 pM human IL-33 (mm2).

[0223] The antibodies IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) and IL33-167LS (SEQ ID NO:245, SEQ ID NO:93) produced from stably-transfected CHO cells showed neutralization of IL-33-stimulated INF.gamma. production in human in human whole blood similar to that of the parental antibody 7E8 CDR graft (SEQ ID NO:92, SEQ ID NO:93) for human IL-33 (mm2) and human IL-33 (WT).

TABLE-US-00028 TABLE 27 Neutralization activity of optimized variants of CDR-grafted 7E8 in human whole blood HC SEQ LC SEQ human IL-33 (mm2) human IL-33 (R&D) Antibody NO NO IC.sub.50 (nM) .+-. SEM (n) IC.sub.50 (nM) .+-. SEM (n) IL33-158LS 244 209 0.021 .+-. 0.003 (6) 0.868 .+-. 0.235 (2) IL33-167LS 245 93 0.013 .+-. 0.001 (6) 0.451 .+-. 0.154 (2) 7E8 CDR graft 92 93 0.014 .+-. 0.002 (6) 0.387 .+-. 0.216 (2) Table 27: Whole blood was stimulated with IL-12, followed by 125 nM human IL-33 (mm2 or R&D).

[0224] The antibody IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) produced from stably-transfected CHO cells showed neutralization of human IL-33 (mm2) and human IL33 (R&D), while the commercially-available Nessy-1 did not show significant neutralization. The commercially-available monoclonal antibody 19G8 showed weaker neutralization of human IL-33 (mm2) than IL33-158LS and comparable neutralization of human IL-33 (R&D) (Table 28). Thus the strongly selective neutralization of the active form of human IL-33 represented by IL-33 (mm2) is a characteristic property of IL33-158LS.

TABLE-US-00029 TABLE 28 Neutralization activity of IL33-158LS in HEK293 ST2 NFkB assay compared to that of commercial anti-IL-33 antibodies HC SEQ LC SEQ IL-33 (mm2) IL-33 (R&D) Antibody NO NO IC.sub.50 (nM) .+-. SEM (n) IC.sub.50 (nM) .+-. SEM (n) IL33-158LS 244 209 0.079 .+-. 0.029 (2) 2.658 .+-. 1.243 (2) ALX-804-840-C100 no neutralization (1) no neutralization (1) (Nessy-1) mabg-hIL-33 (19G8) 0.283 .+-. 0.001 (2) 1.952 .+-. 0.94 (2)

Conclusions:

[0225] Humanized, optimized anti-human IL-33 antibodies IL33-158-152, IL33-167-153, IL33-158LS, and IL33-167LS are potent neutralizers of IL-33 bioactivity, in a range of bioassays, utilizing cell lines, primary human monocytes, and human whole blood.

Example 21 Kinetic Evaluation of Optimized Anti-IL-33 Antibodies Using Surface Plasmon Resonance

[0226] Biacore kinetic assays were conducted at 37.degree. C. at a collection rate of 1 Hz on a Biacore T200 instrument (GE Healthcare). Human IL33 (mm2), cynomolgus monkey IL-33, and reduced huIL33 wt were covalently coupled to a CM5 sensor chip (catalogue number BR100530, GE Healthcare) using an amine coupling kit (catalogue number BR100050, GE Healthcare) according to the manufacturer's protocol. Immobilization levels were 260 RU of human IL-33 (mm2), 85 RU of cynomolgus monkey IL-33, and 108-225 RU of reduced human IL-33 (WT), Flow cell 1 was activated and blocked for use as a reference flow cell. Titration series of the lead anti-IL-33 Fabs 158LS, 167LS and parental Fab 7E8 were injected at a flow rate of 50 ul per min and the dissociation was monitored for 3600 seconds. The dilution and running buffer was HBS-EP+(10 mM HEPES pH 7.4, 0.15M NaCl, 3 mM EDTA, 0.05% P-20). Rate constants and affinities were determined by fitting the resulting sensorgram data to a 1:1 model in Biacore T200 Evaluation software version 1.0 (GE Healthcare).

[0227] The affinity of Fab fragments of the optimized antibodies IL33-158LS and IL33-167LS were measured by surface plasmon resonance as described in Example 10, with IL-33 immobilized on the sensor chip and Fab fragments in solution phase. Both optimized antibodies showed binding affinities to human IL-33 (mm2), human IL33 (WT), and cynomolgus monkey IL-33 comparable to the affinities exhibited by the parental CDR grafted-7E8 Fab (Table 29).

TABLE-US-00030 TABLE 29 Kinetic parameters of Fab fragments of 7E8 CDR graft, IL33-158LS, and IL33-167LS binding to human and cynomolgus monkey IL-33 measured by surface plasmon resonance Fab IL-33 form ka (1/Ms) .+-. SEM kd (1/s) .+-. SEM kD (pM) .+-. SEM (n) 7E8 CDR graft huIL-33 (mm2) 2.74E+06 .+-. 1.15E+05 4.17E-05 .+-. 3.82E-06 15.48 .+-. 2.10 (4) 7E8 CDR graft hu IL-33 (WT + DTT) 3.05E+06 .+-. 2.15E+05 5.79E-05 .+-. 5.10E-06 19.05 .+-. 0.35 (2) 7E8 CDR graft cyno IL-33 (cys mut) 2.81E+06 .+-. 2.50E+04 4.07E-05 .+-. 5.25E-06 14.45 .+-. 1.75 (2) IL33-158LS huIL-33 (mm2) 2.42E+06 .+-. 3.75E+05 3.09E-05 .+-. 2.20E-06 13.00 .+-. 1.10 (2) IL33-158LS hu IL-33 (WT + DTT) 1.86E+06 .+-. 2.65E+04 1.29E-04 .+-. 2.73E-06 69.57 .+-. 2.46 (3) IL33-158LS cyno IL-33 (cys mut) 1.64E+06 .+-. 4.50E+04 1.71E-05 .+-. 7.00E-07 10.45 .+-. 0.15 (2) IL33-167LS huIL-33 (mm2) 4.75E+06 .+-. 3.00E+04 4.80E-05 .+-. 7.90E-06 10.11 .+-. 1.59 (2) IL33-167LS hu IL-33 (WT + DTT) 1.45E+06 .+-. 3.00E+04 6.56E-05 .+-. 2.50E-07 45.25 .+-. 0.85 (2) IL33-167LS cyno IL-33 (cys mut) 1.57E+06 .+-. 6.00E+04 2.09E-05 .+-. 1.00E-07 13.35 .+-. 0.45 (2)

Example 22 Cytokine Specificity of Anti-IL-33

[0228] To evaluate the cytokine specificity of anti-IL-33 antibodies 7E8 and IL33-158LS, a panel of non-target cytokines was evaluated for binding to these antibodies by surface plasmon resonance with a BIAcore T-200. The panel of cytokines included IL-la, IL-113, IL-18, IL-36.alpha., and IL-36.gamma.. Results (Table 30, FIG. 3) showed that there was no binding of the unrelated cytokines at 100 nM, while anti-IL-33 antibodies 7E8 and IL33-158LS bind IL-33 mm2 and reduced IL-33 WT at very similar % Rmax values. No binding was observed to IL-33 in the absence of reduction.

TABLE-US-00031 TABLE 30 Cytokine selectivity of 7E8 and IL33-158LS % Rmax % Rmax Cytokine 7E8 Fab IL33-158LS Fab IL-33 mm2 61 65 IL-33 WT NB NB IL-33 WT + DTT 52 52 IL-1.alpha. NB NB IL-1.beta. NB NB IL-18 NB NB IL-36 .alpha. NB NB IL-36.gamma. NB NB Table 30. Binding of the indicated Fab to 100 nM cytokine was measured by suface plasmon resonance. The Fabs were captured using the Human Fab Capture Kit (GE Healthcare) and each cytokine was injected over the captured Fab at 100 nM. Binding is indicated by the % Rmax value. % Rmax is the ratio of experimentally-observed Rmax to theoretical Rmax (assuming 100% binding), expressed as a percentage, and theoretical Rmax is the Resonance Units of captured Fab multiplied by the ratio of the molecular weights of the cytokine and the Fab. NB, no binding.

Example 23 Competition with Human ST2 for Binding to IL33

[0229] The ability of IL33-158LS to block the binding of the ST2 receptor to IL-33 was tested in an Octet binding assay. Antibodies or human ST2-Fc (SEQ ID NO:6) were captured on Octet tips coated with anti human Fc, free binding sites were blocked with an excess of human IgG1control antibody, and a mixture of IL-33 (R&D) and a second antibody or ST2-Fc was applied to the tips. The complex of IL33-158LS and human IL-33 was able to bind to a control non-neutralizing anti-IL-33 antibody, IL33-271 (SEQ ID NO:254, SEQ ID NO:256) captured on the Octet tip, and conversely, a complex of IL33-271 and human IL-33 was able to bind to immobilized IL33-158LS. Likewise, human ST2-Fc and IL33-271 were able to bind human IL-33 simultaneously in either orientation. However, immobilized IL33-158LS was not able to bind to a complex of IL-33 and ST2-Fc, and conversely, immobilized ST2-Fc was not able to bind to a complex of IL-33 and IL33-158LS. These results indicate that IL33-158LS and ST2-Fc compete for overlapping binding sites on IL-33.

TABLE-US-00032 TABLE 31 Competition of iL33-158LS with the IL-33 receptor ST2 for binding to IL-33 Mixture applied to captured molecule Molecule HC LC IL33- hST2- IL33- catpured on SEQ SEQ 158LS + Fc + 271 + IL-33 anti-Fc tip NO NO IL-33 IL-33 IL-33 alone IL33-158LS 244 209 - - + + hST2-Fc 2 - - + + IL33-271 256 256 + + - + A (+) indicates that the complex of the second antibody and IL-33 bound to the first antibody that had been captured on the Octet tip. A (-) indicates that no increase in signal was observed upon addition of the mixture of IL-33 and the second antibody

Example 24 Thermal Stability of Optimized Anti-IL-33 Antibodies

[0230] Differential scanning calorimetry was used to determine the stability of IL33-158-152, IL33-158LS, IL33-167-153, and IL33-167LS. For this analysis, samples at 0.3 mg/ml were dispensed into the sample tray of a MicroCal VP-Capillary DSC with Autosampler (Malvern Insturments, Inc.), equilibrated for 5 mins at 10.degree. C. and then scanned up to 110.degree. C. at a rate of 100.degree. C. per hr. A filtering period of 16 secs was selected. Raw data was baseline corrected and the protein concentration was normalized. Origin Software 7.0 (OriginLab Corporation, Northampton, Mass.) was used to fit the data to an MN2-State Model with an appropriate number of transitions. Table 32 below shows the melting temperatures (T.sub.m1-T.sub.m3) of the molecules in 20 mM Histidine pH5.8, 8.5% sucrose, 0.05 mg/ml EDTA. All four molecules show good stability, with the first transition in the CH2 domain (T.sub.m1) of greater than 65.degree. C. Additionally, the introduction of the LS mutation has a very small impact (.ltoreq.1.degree. C.) on the stability of the molecules.

TABLE-US-00033 TABLE 32 Thermal stability of optimized 7E8 variants HC SEQ LC SEQ Antibody NO NO T.sub.m1 T.sub.m2 T.sub.m3 IL33-158-152 241 209 71.35 .+-. 0.09 83.58 .+-. 0.61 85.93 .+-. 0.15 IL33-167-153 242 93 71.13 .+-. 0.03 82.71 .+-. 0.08 84.31 .+-. 0.04 IL33-158LS 244 209 70.26 .+-. 0.11 82.20 .+-. 0.38 85.81 .+-. 0.06 IL33-167LS 245 93 70.45 .+-. 0.10 81.38 .+-. 0.43 84.03 .+-. 0.10 Table 32: thermal transitions for IL33-158 and IL33-167-derived molecules in 20 mM Histidine pH 5.8, 8.5% sucrose, 0.05 mg/ml EDTA determined by differential scanning calorimetry.

Example 25 Capture of Cynomolgus Monkey IL-33 by Anti-IL-33 Antibodies Administered In Vivo

[0231] IL33-158LS was tested for its ability to capture native cynomolgus monkey IL-33. Following intravenous dosing of cynomolgus monkeys at 0.14 or 14 mg/kg of IL33-158LS, aluminum hydroxide (alum) was administered by intraperitoneal injection (1 mg in 0.1 ml). Blood samples were drawn up to 72 hrs post alum. Total cynomolgus monkey IL-33 bound to IL33-158LS was measured using an immunoaffinity LC\MS\MS method. Biotin-conjugated anti-human Fc antibodies were incubated with each plasma sample and incubated overnight at 4.degree. C. in order to bind all cytokine bound to the anti-IL-33 antibody. Streptavidin beads were added to each sample and incubated for 30 mins, washed, and then the cytokine was released from the antibodies using a low pH elution buffer, followed by neutralization with Tris buffer. Extended stable isotope-labeled peptides with signature sequences for IL-33 were then added to each sample, and then all samples were reduced with DTT, alkylated with iodoacetamide and digested with trypsin. The tryptic peptides were then identified with a 2D nano UPLC tandem mass spectrometer system. The limit of quantitation for this assay is 50 .mu.g/mL for cynomolgus monkey IL-33 using 20 .mu.L of plasma. Measurements of IL-33 bound to IL33-158LS increased over time following administration of 14.3 mg/kg and alum challenge as compared to the low dose of 0.14 mg/kg of IL33-158LS (Table 33). These results indicate that IL33-158LS binds to native cynomolgus monkey IL-33 in a dose-dependent manner and produces measurable effects that could be used to model pharmacodynamics in humans.

[0232] The terminal serum half-life of IL33-158LS in cynomolgus monkeys was 18 days, which permitted the parameterization of a two-compartment PK model. Allometric scaling of the rate constants with an allometric exponent of 0.75 for clearance resulted in a predicted human serum terminal half-life of 41 days. This is significantly longer compared to the typical observed half-life of 20 days for antibodies in humans (Brekke and Sandlie (2003), Nature Reviews, Vol 2, pp 52-62) and 17 days for human or humanized biotherapeutic IgG antibodies (derived from PK parameters reported in Singh, et al. (Chapter 5. Application of mechanistic pharmacokinetic-pharmacodynamic modeling towards the development of biologics. In: Kumar S, Kumar Singh S, editors. Developability of Biotherapeutics: ComputationalApproaches. CRC Press; 2015: p. 109-34).

[0233] Surprisingly, preliminary evaluation in healthy human volunteers indicates that the serum elimination (.beta. phase) half-life of IL33-158LS is at least 50 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 50 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 55 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 60 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 65 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 70 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 75 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 80 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 85 days. In some aspects of the invention the terminal half-life of the antibody or antigen binding portion thereof is at least about 90 days. The unexpectedly high half-life may be due to modifications in the variable and CDR regions, as well as the Fc domain.

TABLE-US-00034 TABLE 33 Time course of total circulating IL-33 concentration in cynomolgus monkeys dosed with IL33-158LS and challenged with aluminum hydroxide (Alum) 0.14 mg/kg Dose 14.3 mg/kg Dose IL-33 Bound to IL-33 Bound to Time After Alum IL33-158LS (pg/ml) IL33-158LS (pg/ml) Challenge (hrs) Average (n = 3 +/- SEM) Average (n = 3 +/- SEM) 0 52.0 .+-. 12.7 64.5 .+-. 12.7 1 62.5 .+-. 3.6 52.5 .+-. 8.4 2 61 .+-. 4.0 .sup. 59.1 .+-. 11.5 (n = 2) 4 71.3 .+-. 8.9 45.5 .+-. 2.0 8 .sup. 84 .+-. 23.3 63.5 .+-. 4.7 10 .sup. 48 .+-. 10.7 (n = 2) .sup. 84.2 .+-. 11.9 (n = 2) 24 61.7 .+-. 18.7 137.3 .+-. 16.0 48 47.8 .+-. 17.8 .sup. 217 .+-. 22.8 72 54.8 .+-. 11.0 311.3 .+-. 10.4

Example 26 Generation and Testing of Comparator IL-33 Antibodies

[0234] IgG1 versions of a number of hIgG4 antibodies described in WO2014164959 were generated (Table 35) (binding properties of the isolated Fab fragment are independent of the Fc region, and binding properties of the intact IgG4 are expected to be essentially identical in the IgG1). H4H9675P (corresponding to IL33-265), H4H9659P (corresponding to IL33-266), and H4H9665P (corresponding to IL33-267) are disclosed as having the highest affinity against human IL-33 at 37.degree. C. or monkey 11-33 (Tables 3 & 6 of WO2014164959). Initial functional assessment showed IL33-267 to be less potent than IL33-265 and IL-33-266. A more detailed assessment showed that IL33-265 is 8-10-fold more potent than IL33-266 (Table 36). BIAcore analysis of IgG binding to immobilized wild-type human IL-33 showed that IL33-265 bound only to the reduced form of IL-33 and not non-reduced IL-33.

TABLE-US-00035 TABLE 35 Antibody SEQ ID Antibody WO2014164959 SEQ ID (IgG1) HC VL (IgG4) VH VL VH-DNA VL-DNA IL33-265 282 283 H4H9675P 274 282 273 281 IL33-266 H4H9659P 98 106 97 105 IL33-267 H4H9665P 178 186 177 185

TABLE-US-00036 TABLE 36 Titration vs. Titration vs. 0.1 ng/ml pur mm2 0.1 ng/ml R&D rhIL-33 IC50 SEM n IC50 SEM n IL33-265 0.061 0.021 3 0.128 0.018 3 IL33-266 0.719 0.159 2 0.998 0.076 2

[0235] IgG1 antibody IL33-310 (SEQ ID NO:287 (HC) and SEQ ID NO:288 (LC)) was generated, and is derived from 10C12.38.H6. 87Y.581 IgG4 of WO2016077381, which is disclosed as having the high affinity to human and cynomolgus monkey IL-33.

[0236] 10C12.38.H6. 87Y.581 consists of SEQ ID NO: 306 (HC) and SEQ ID NO: 307 (LC) of WO2016077381. To obtain nucleotide sequences for use in expression, the variable region sequences were reverse translated using Vector NTI software. The nucleotide sequence of a standard constant kappa region, which encodes an identical amino acid sequence to that of SEQ ID NO:307 of WO2016077381, was used for the expression construct. The nucleotide sequence of a standard constant IgG4 region encoded an amino acid sequence with three differences from that of SEQ ID NO: 306 of WO2016077381 and was modified in these three codons to encode the constant region of SEQ ID NO: 306 of WO2016077381. A nucleotide sequence encoding a leader sequence SEQ ID NO:402 was placed in-frame upstream of the VH and VL coding sequences. Table 37 shows cell-based assay data comparing IL-167/LS, IL-158/LS, IL33-265, and IL33-310.

TABLE-US-00037 TABLE 37 Titration vs Titration vs. Titration vs 0.1 ng/ml cyno: 0.1 ng/ml 0.1 ng/ml pfe mm2 Titration vs. human R&D rhIL- cyno WT IL-33 cyno: CYS human 0.1 ng/ml IC50 33 (+10 mM (+10 mM DTT human IL-33 cyIL33_3cys ratio: DTT pretreat) pretreat) IC50 IC50 IC50 cys IC50 IC50 ratio: (nM) SEM n (nM) SEM n mutant (nM) SEM n (nM) SEM n WT IL33-167/ 0.037 0.012 2 0.036 0.006 3 1.0 0.250 0.019 4 1.560 0.317 7 6.2 LS IL33-158/ 0.019 0.004 3 0.034 0.009 3 1.8 0.331 0.085 5 1.391 0.331 7 4.2 LS IL33-265 0.014 0.003 5 1.562 0.243 4 108.9 0.050 0.010 6 12.691 2.484 5 255.7 IL33-310 0.018 0.002 3 0.590 0.041 3 32.5 0.061 0.011 3 1.644 0.421 4 27.1

[0237] IgG1 antibody IL33-244 is based on APE04909 disclosed as SEQ ID NO:136 and SEQ ID NO: 171 of WO2015/106080. APE04909 is a neutralizing antibody described in detail, e.g. in example 2 (in vitro cell-based assays) and example 5 (in vivo study of human IL-33 dependent proliferation of eosinophils in mice, example 5). However, when an antibody was generated according to SEQ ID NOs:136/171 of WO2015/106080, it expressed poorly and had a heterogeneous SEC profile. To eliminate the possibility that that poor codon usage contributed to poor expression, DNA sequences from similar, well-expressed antibodies were used as a starting point and adjusted to encode the sequences above using high-frequency human codons where changes were necessary. However, expression was still poor after this step, and SEC patterns still showed heterogeneity (Table 38).

TABLE-US-00038 TABLE 38 Protein IC50 vs 0.1 ng/ml human Antibody VH SEQ VL SEQ yield Area % IL33 mm2 in 239 ST2 NFkB name ID NO: ID NO: (mg/L) (SEC) assay expt rts 16-42 IL33-244 136 171 9 too low to integrate 10.9

[0238] IL33-248 was described in WO2015/099175 as 3H04 and A25 (see FIG. 8), and IL33-247 was described in WO2015/099175 as 1C04 and A10 (see FIG. 9). Variable region nucleotide sequences from WO 2015/099175 were synthesized and cloned into human IgG1 and human lambda expression vectors (see Table 39 for sequences from WO2015/099175). IL33-247 and IL33-248 have a distinct epitope IL-158/LS and IL33-167/LS, and yielded 90.75 mgL CM and an area under the curve of 100% for IL33-247 and 36 mg/L CM and an area under the curve of 85.3% for IL33-248, which also showed an assymetrical peak with a wide retention time.

TABLE-US-00039 TABLE 39 WO2015/099175 SEQ ID Antibody (IgG1) Antibody (IgG4) VH VL VH-DNA VL-DNA IL33-247 1C04/A10 105 79 254 228 IL33-248 3H04/A25 115 92 264 241

[0239] IgG1 antibody IL33-312 is based on 33_640087-7B of WO16156440 (SEQ ID NO: 615 and SEQ ID NO: 617) (see e.g., FIG. 52, & Example 11-12). IgG1 antibody IL33-313 is based on 33 640237-2B of WO16156440 (SEQ ID NO: 623 and SEQ ID NO: 625).

Example 27 Human and Cynomolgus Monkey IL-33 Neutralization Activity of Optimized Anti-IL-33 Antibodies and Comparator Antibodies in Cell-Based Assays

[0240] The antibodies IL33-158LS (SEQ ID NO:244 SEQ ID NO:209), IL33-167LS (SEQ ID NO:245, SEQ ID NO:93), IL33-265 (SEQ ID NO:403 SEQ ID NO:404), and IL33-310 (SEQ ID NO:405 SEQ ID NO:406), were tested in the HEK293 ST2 NFkB reporter assay for neutralization of human and cynomolgus monkey IL-33 (Table 40). IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) showed similar neutralization potency against the cysteine mutant forms of human and cynomolgus IL-33 (with a monkey IC50:human IC50 ratio of 1.8). Likewise, the neutralization potency of IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) against wild-type human and cynomolgus monkey IL-33 (SEQ ID NO:397) was similar (with a monkey IC50:human IC50 ratio of 4.2). IL33-167LS (SEQ ID NO:245, SEQ ID NO:93) showed similarly close neutralization of monkey and human IL-33. Two other antibodies, IL33-265 (SEQ ID NO:403 SEQ ID NO:404), and IL33-310 (SEQ ID NO:405 SEQ ID NO:406) showed a wider difference between neutralization of human and cynomolgus monkey IL-33 (monkey IC50:human IC50 ratios ranging from 28.7 to over 250).

[0241] In a second experiment, IL33-158LS (SEQ ID NO:244, SEQ ID NO:209), IL33-310 (SEQ ID NO:405, SEQ ID NO:406), IL33-312 (SEQ ID NO:407, SEQ ID NO:408), and IL33-313 (SEQ ID NO:409, SEQ ID NO:410), were tested in the HEK293 ST2 NFkB reporter assay for neutralization of human and cynomolgus monkey IL-33 (Table 41). IL33-158LS and IL33-312 had similarly close relative neutralization of monkey and human cysteine mutant IL-33 (cynomolgus monkey IC50: human IC50 ratios of 1.4, and 1.1, respectively). Relative neutralization of wild-type human and cynomolgus monkey IL-33 was also similar for IL33-158LS and IL33-312 (cynomolgus monkey IC50: human IC50 ratios of 9.2 and 5.4, respectively). IL33-310 and IL33-313 showed a wider difference between human and cynomolgus monkey IC50s (monkey IC50:human IC50 ratios ranging from 29.2 to 528.1; Table 41). Together, the data show that IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) has among the most highly similar neutralization of wild-type human and cynomolgous monkey IL-33 within this panel of high-potency anti human IL-33 antibodies, comparable to IL33-312.

TABLE-US-00040 TABLE 40 Neutralization of human and cynomolgus monkey IL-33 in HEK29 ST2 NFkB reporter cell assay HEK293 HEK293 HEK293 ST2 NFkB Cyno- ST2 NFkB Cyno- ST2 cyno- molgus HEK293 cyno- molgus NFkB molgus monkey: ST2 molgus monkey: hIL-33 monkey human NFkB monkey human (mm2) IL- IC50 hIL-33 IL-33 IC50 (nM) .+-. 33 (cys ratio: (R&D) (wild- ratio: HC LC IC.sub.50 mut) IC.sub.50 cysteine IC.sub.50 type) wild- SEQ SEQ SEM (nM) .+-. mutant (nM) .+-. IC.sub.50 (nM) .+-. type Antibody NO NO (n) SEM (n) IL-33 SEM (n) SEM (n) IL-33 IL33- 244 209 0.019 .+-. 0.034 .+-. 1.8 0.331 .+-. 1.391 .+-. 4.2 158L5 0.004 0.009 0.085 0.331 (3) (3) (5) (7) IL33- 245 93 0.037 .+-. 0.036 .+-. 1.0 0.250 .+-. 1.560 .+-. 6.2 167L5 0.012 0.006 0.019 0.317 (2) (3) (4) (7) IL33- 403 404 0.014 .+-. 1.562 .+-. 108.9 0.050 .+-. 12.691 .+-. 255.7 265 0.003 0.243 0.010 2.484 (5) (4) (6) (5) IL33- 405 406 0.018 .+-. 0.590 .+-. 32.5 0.061 .+-. 1.644 .+-. 27.1 310 0.002 0.041 0.011 0.421 (3) (3) (3) (4)

TABLE-US-00041 TABLE 41 Neutralization of human and cynomolgus monkey IL-33 in HEK293 ST2 NFkB reporter cell assay HEK293 HEK293 ST2 Cyno- ST2 Cyno- NFkB molgus NFkB molgus HEK293 cyno- monkey: HEK293 cyno- monkey: ST2 molgus human ST2 molgus human NFkB monkey IC50 NFkB monkey IC50 hIL-33 IL-33 ratio: hIL-33 IL-33 ratio: HC LC (mm2) (cys cysteine (R&D) (wild- wild- SEQ SEQ IC.sub.50 mut) mutant IC.sub.50 type) type Antibody NO NO (nM) IC50 (nM) IL-33 (nM) IC.sub.50 (nM) IL-33 IL33- 244 209 0.009 0.013 1.4 0.061 0.562 9.2 158L5 IL33-310 405 406 0.007 0.213 29.2 0.021 2.185 103.5 IL33-312 407 408 0.003 0.003 1.1 0.008 0.043 5.4 IL33-313 409 410 0.006 1.197 206.2 0.027 14.131 528.1 n = 1

Example 28 Kinetic Evaluation of Anti-IL-33 Antibodies Using Surface Plasmon Resonance

[0242] Biacore kinetic assays were conducted at 37.degree. C. at a collection rate of 1 Hz on a Biacore T200 instrument (GE Healthcare). Reduced and non-reduced wild-type human IL-33 and reduced wild-type cynomolgus monkey IL-33 were covalently coupled to a CM5 sensor chip (catalogue number BR100530, GE Healthcare) using an amine coupling kit (catalogue number BR100050, GE Healthcare) according to the manufacturer's protocol. Flow cell 1 was activated and blocked for use as a reference flow cell. In one experiment, immobilization levels were 218 RU of reduced wild-type human IL-33 and 248 RU of reduced wild-type cynomolgus monkey IL-33. In this experiment, titration series of the anti-IL-33 Fabs 158LS and 167LS were injected at a flow rate of 50 ul per min and the dissociation was monitored for 3600 seconds. In a second experiment, immobilization levels were 130 RU of reduced wild-type human IL-33, 97 RU of non-reduced wild-type human IL-33, and 88 RU of reduced wild-type cynomolgus monkey IL-33. In this experiment, titration series of the anti-IL-33 Fabs 158LS, 167LS, and IL33-265 were injected at a flow rate of 50 ul per min and the dissociation was monitored for 900 seconds. The dilution and running buffer was HBS-EP+(10 mM HEPES pH 7.4, 0.15M NaCl, 3 mM EDTA, 0.05% P-20). Rate constants and affinities were determined by fitting the resulting sensorgram data to a 1:1 model in Biacore T200 Evaluation software version 1.0 (GE Healthcare). Intact IL33-0310 IgG was also tested in this format and was observed to bind with rapid association and very slow dissociation to reduced human IL-33 and reduced cynomolgus monkey IL-33, but it did not bind to non-reduced human IL-33 (Table Y). Kinetic properties of the bivalent IgG cannot be directly compared to those of monovalent Fab fragments and are not presented here.

[0243] The anti-IL-33 Fabs 158LS, 167LS, IL33-265, and the anti-IL33 IgG IL33-310 all bound strongly to DTT-treated wild-type human and cynomolgus monkey IL-33. By contrast, none of these antibodies bound to non-reduced wild-type human IL-33 (Table 42).

[0244] The affinities of the Fab of IL33-158LS (SEQ ID NO:244 SEQ ID NO:209) to wild-type human and cynomolgus monkey IL-33 (SEQ ID NO:397) were similar (with a monkey K.sub.D:human K.sub.D ratio of 1.3 and 2.3 in two independent experiments). IL33-167LS (SEQ ID NO:245, SEQ ID NO:93) showed similarly close affinity to monkey and human IL-33. IL33-265 (SEQ ID NO:403 SEQ ID NO:1003) showed a wider difference between affinity to wild-type human and cynomolgus monkey IL-33, with a monkey KD:human KD ratio of 57.8 (Table 42).

TABLE-US-00042 TABLE 42 Kinetic parameters of Fab fragments of Fabs 158LS, 167LS, and IL33-265 binding to wild-type human and cynomolgus monkey IL-33 measured by surface plasmon resonance Ratio of cynomolgus monkey KD/ Fab IL-33 form ka (1/Ms) .+-. SEM kd (1/s) .+-. SEM kD (pM) .+-. SEM (n) human KD Experiment 1 IL33-158LS huIL-33 (WT + DTT) 3.13E+06 .+-. 3.00E+05 3.30E-04 .+-. 5.00E-07 106 .+-. 11 1.3 IL33-158LS cyno IL-33 (WT + DTT) 4.50E+06 .+-. 5.05E+05 6.20E-04 .+-. 3.65E-05 139 .+-. 8 IL33-167LS huIL-33 (WT + DTT) 3.03E+06 .+-. 8.50E+04 2.76E-04 .+-. 1.50E-05 91 .+-. 2 1.5 IL33-167LS cyno IL-33 (WT + DTT) 4.81E+06 .+-. 2.80E+05 6.65E-04 .+-. 3.20E-05 139 .+-. 2 Experiment 2 IL33-158LS huIL-33 (WT no DTT) (no binding) IL33-158LS huIL-33 (WT + DTT) 4.11E+06 .+-. 5.00E3 4.17E-04 .+-. 3.30E-05 101 .+-. 8 2.3 IL33-158LS cyno IL-33 (WT + DTT) 5.32E+06 .+-. 4.82E+05 1.21E-03 .+-. 1.01E-04 228 .+-. 2 IL33-167LS huIL-33 (WT no DTT) (no binding) IL33-167LS huIL-33 (WT + DTT) 3.96E+06 .+-. 5.00E+03 3.50E-04 .+-. 1.30E-05 89 .+-. 3 2.5 IL33-167LS cyno IL-33 (WT + DTT) 5.50E+06 .+-. 5.30E+05 1.19E-03 .+-. 1.04E-04 218 .+-. 2 IL33-265 huIL-33 (WT no DTT) (no binding) IL33-265 huIL-33 (WT + DTT) 2.89E+06 .+-. 6.00E+04 8.07E-05 .+-. 1.27E-05 28 .+-. 5 57.8 IL33-265 cyno IL-33 (WT + DTT) 2.58E+06 .+-. 5.59E+05 3.80E-03 .+-. 1.60E-04 1618 .+-. 342 IL33-310IgG huIL-33 (WT no DTT) (no binding)

Example 29 Self-Interaction and Polyreactivity of Optimized Anti-IL-33 Antibodies and Comparator Antibodies

[0245] The antibodies IL33-158 (SEQ ID NO:227 SEQ ID NO:209), IL33-158L5 (SEQ ID NO:244 SEQ ID NO:209), and IL33-312 (SEQ ID NO: 407 SEQ ID NO: 408) were tested for binding to DNA and insulin, and in addition were tested for self-interaction in an AC-SINS assay (affinity-capture self-interaction nanoparticle spectroscopy; Liu et al., 2014, mAbs 6:483-92). In the AC-SINS assay, mAbs captured on gold nanospheres will induce a shift in the absorbance maximum if they bind to one another and thereby cause the beads to cluster, and high scores in this assay have been suggested to correlate with solubility and nonspecific membrane interactions (Liu et al., 2014, mAbs 6:483-92). IL33-158 and IL33-158L5 had very low AC-SINS scores, comparable to those of the negative control, while IL33-312 had a score comparable to the positive control (Table 43). IL33-312 also had a high DNA-binding score, comparable to the positive control, while IL33-158 and IL33-158L5 showed more moderate scores. Taken together, these results indicate that IL33-158 and IL33-158L5 had substantially lower indicators of nonspecific binding than did IL33-312.

TABLE-US-00043 TABLE 43 Non-specific binding and self-interaction of IL-33 antibodies AC-SINS (wavelength of maximum absorbance DNA binding Insulin binding HC SEQ LC SEQ relative to normalized to normalized to Antibody NO NO blank, nm) blank blank IL33-158 227 209 0 5.25 .+-. 0.09 (2) 6.42 .+-. 1.82 (2) L33-158LS 244 209 0 7.45 .+-. 0.10 (8) 8.08 .+-. 0.48 (8) IL33-312 407 408 18 .+-. 0.22 19.93 8.83 Polyreactivity negative 1 .+-. 0.07 2.14 3.22 control (8.8) Polyreactivity positive 22 .+-. 1.11 21.78 14.77 control (MJ4-2 v1.1/P33)

[0246] The invention thus has been disclosed broadly and illustrated in reference to representative embodiments described above. Those skilled in the art will recognize that various modifications can be made to the present invention without departing from the spirit and scope thereof. All publications, patent applications, and issued patents, are herein incorporated by reference to the same extent as if each individual publication, patent application or issued patent were specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0247] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0248] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention. In particular, any aspect of the invention described in the claims, alone or in combination with one or more additional claims and/or aspects of the description, is to be understood as being combinable with other aspects of the invention set out elsewhere in the claims and/or description and/or sequence listings and/or drawings.

[0249] In so far as specific examples found herein do not fall within the scope of an invention, said specific example may be explicitly disclaimed.

[0250] The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." As used herein the specification, "a" or "an" may mean one or more, unless clearly indicated otherwise. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more. Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The words "comprises/comprising" and the words "having/including" when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0251] Although the disclosed teachings have been described with reference to various applications, methods, and compositions, it will be appreciated that various changes and modifications can be made without departing from the teachings herein and the claimed invention below. The examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings presented herein. While the present teachings have been described in terms of these exemplary embodiments, numerous variations and modifications of these exemplary embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the current teachings.

[0252] Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.

[0253] All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

[0254] The description and examples detail certain specific embodiments of the invention and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the invention may be practiced in many ways and the invention should be construed in accordance with the appended claims and any equivalents thereof.

TABLE-US-00044 TABLE 34 SUMMARY OF ANTIBODY SEQ IDS Heavy Chain (HC) Light Chain (LC) HC HC HC LC LC LC Antibody CDR1 CDR2 CDR3 JH V.sub.H CH1 HINGE CH2 CH3 HC CDR1 CDR2 CDR3 JK V.sub.L CL LC 7E8_chimera 16 17 18 23 14 24 25 26 27 28 20 21 22 29 19 30 31 9B3_chimera 33 34 35 39 32 24 25 26 27 40 37 21 38 41 36 30 42 12F9_thimera 44 45 45 8 43 24 25 26 27 51 48 49 50 52 47 30 53 14D8_chimera 44 55 45 8 54 24 23 26 27 59 57 58 50 41 56 30 60 30A1_chimera 62 63 64 8 61 24 25 26 27 69 66 67 68 70 65 30 71 30B11_chimera 75 74 75 8 72 24 25 26 27 78 77 67 68 79 76 30 80 9B3_chimera_huJseg 33 34 35 39 32 24 25 26 27 40 37 21 38 82 81 30 83 14D8_chimera_huJseg 44 55 45 8 54 24 25 26 27 59 57 58 50 82 84 30 85 30A1_chimera_huJseg 62 63 64 8 61 24 25 26 27 69 66 67 68 12 86 30 87 30B11_chimera_huJseg 73 74 75 8 72 24 25 26 27 78 77 67 68 12 88 30 89 7E8 CDR graft 16 17 18 8 90 24 25 26 27 92 20 21 22 12 91 30 93 IL33-10 16 17 18 8 94 24 25 26 27 95 20 21 22 12 91 30 93 9B3 CDR graft 33 34 35 8 97 24 25 26 27 99 37 21 38 12 98 30 100 12F9 CDR graft 102 45 46 8 101 24 25 26 27 104 48 49 50 12 103 30 105 30B11 CDR graft 107 74 75 8 106 24 25 26 27 109 77 67 68 12 108 30 110 30B11 CDR graft_R71V 107 74 75 8 111 24 25 26 27 112 77 67 68 12 108 30 110 9B3_1 33 34 114 39 113 24 25 26 27 116 37 21 38 82 115 30 117 9B3_2A 33 34 119 39 118 24 25 26 27 120 37 21 38 82 115 30 117 9B3_2B 33 34 122 39 121 24 25 26 27 123 37 21 38 82 115 30 117 9B3_3 33 34 122 39 124 24 25 26 27 125 37 21 38 82 115 30 117 9B3_5 33 34 127 39 126 24 25 26 27 128 37 21 38 82 115 30 117 9B3_7 33 34 130 39 129 24 25 26 27 131 37 21 38 82 115 30 117 9B3_13 33 34 133 39 132 24 25 26 27 134 37 21 38 82 115 30 117 9B3_15 33 34 136 39 135 24 25 26 27 137 37 21 38 82 115 30 117 9B3_17 33 34 139 39 138 24 25 26 27 140 37 21 38 82 115 30 117 9B3_22 33 34 142 39 141 24 25 26 27 143 37 21 38 82 115 30 117 9B3_31V2 33 34 145 39 144 24 25 26 27 146 37 21 38 82 115 30 117 9B3_36 33 34 148 39 147 24 25 26 27 149 37 21 38 82 115 30 117 9B3_79 33 34 148 39 150 24 25 26 27 151 37 21 38 82 115 30 117 9B3_124 33 34 153 39 152 24 25 26 27 154 37 21 38 82 115 30 117 9B3_162 33 34 156 39 155 24 25 26 27 157 37 21 38 82 115 30 117 7E8H/9B3K 16 17 18 23 14 24 25 26 27 28 37 21 38 82 115 30 117 9B3_563 33 34 159 39 158 24 25 26 27 160 57 21 38 82 115 30 117 IL33-11 33 17 18 8 161 24 25 96 27 162 20 21 22 12 91 30 93 IL33-12 16 34 18 8 163 24 25 96 27 164 20 21 22 12 91 30 93 IL33-13 16 17 35 8 165 24 25 96 27 166 20 21 22 12 91 30 93 IL33-45 16 168 18 8 167 24 23 96 27 169 20 21 22 12 91 30 93 IL33-55 16 171 18 8 170 24 25 96 27 172 20 21 22 12 91 30 93 IL33-56 16 174 18 8 173 24 25 96 27 175 20 21 22 12 91 30 93 IL33-57 16 17 177 8 176 24 25 96 27 178 20 21 22 12 91 30 93 IL33-58 16 180 18 8 179 24 25 96 27 181 20 21 22 12 91 30 93 IL33-61 16 174 177 8 182 24 25 96 27 183 20 21 22 12 91 30 43 IL33-62 16 171 177 8 184 24 25 96 27 185 20 21 22 12 91 30 93 IL33-68 16 17 187 8 186 24 25 96 27 188 20 21 22 12 91 30 93 IL33-74 16 17 18 8 94 24 25 96 27 95 190 21 22 12 189 30 191 IL33-75 16 17 18 8 94 24 25 96 27 95 193 21 22 12 192 30 194 IL33-80 16 17 18 8 94 24 25 96 27 95 20 195 22 12 195 30 197 IL33-81 16 17 18 8 94 24 25 96 27 95 20 199 22 12 198 30 200 IL33-103 16 202 18 8 201 24 25 96 27 203 20 21 22 12 91 30 93 IL33-117 16 205 18 8 204 24 25 96 27 206 20 21 22 12 91 30 93 IL33-136 16 174 18 8 173 24 25 96 27 175 20 21 208 12 207 30 209 IL33-153 16 211 18 8 210 24 25 26 27 212 20 21 208 12 207 30 209 IL33-154 16 214 18 8 213 24 25 26 27 215 20 21 208 12 207 30 209 IL33-155 16 217 18 8 216 24 25 26 27 218 20 21 208 12 207 30 209 IL33-156 16 220 18 8 219 24 25 26 27 221 20 21 208 12 207 30 209 IL33-157 16 223 18 8 222 24 25 26 27 224 20 21 208 12 207 30 209 IL33-158 16 226 18 8 225 24 25 26 27 227 20 21 208 12 207 30 209 IL33-167 16 211 18 8 210 24 25 26 27 212 20 21 22 12 91 30 93 IL33-168 16 214 18 8 213 24 25 26 27 215 20 21 22 12 91 30 93 IL33-169 16 217 18 8 216 24 25 26 27 218 20 21 22 12 91 30 93 IL33-170 16 220 18 8 219 24 25 26 27 221 20 21 22 12 91 30 93 IL33-171 16 223 18 8 222 24 25 26 27 224 20 21 22 12 91 30 93 IL33-172 16 226 18 8 225 24 25 26 27 227 20 21 22 12 91 30 93 IL33-175 16 229 18 8 228 24 25 26 27 230 20 21 22 12 91 30 93 IL33-186 16 232 18 8 231 24 25 26 27 233 20 21 208 12 207 30 209 IL33-187 16 235 18 8 234 24 25 26 27 236 20 21 208 12 207 30 209 IL33-188 16 229 18 8 228 24 25 26 27 230 20 21 208 12 207 30 209 IL33-158-152 16 226 18 8 225 24 25 26 240 241 20 21 208 12 207 30 209 IL33-167-153 16 211 18 8 210 24 25 26 240 242 20 21 22 12 91 30 93 IL33-158LS 16 226 18 8 225 24 25 26 243 244 20 21 208 12 207 30 209 IL33-167LS 16 211 18 8 210 24 25 26 243 245 20 21 22 12 91 30 93 IL33-271 247 248 249 8 246 24 25 26 27 254 251 252 253 255 250 30 256

TABLE-US-00045 SEQUENCE LIST SEQ Description Sequence 1 human IL-33 WT (R&D) SITGISPITE YLASLSTYND QSITFALEDE SYEIYVEDLK KDEKKDKVLL C208, C227, C232, and SYYESQHPSN ESGDGVDGKM LMVTLSPTKD FWLHANNKEH SVELHKCEKP C259, corresponding to LPDQAFFVLH NMHSNCVSFE CKTDPGVFIG VKDNHLALIK VDSSENLCTE C208, C227, C232 and NILFKLSET C259 of SEQ ID NO: 396 are underlined and in bold 2 human ST2-Fc-His (R&D) KFSKQSWGLE NEALIVRCPR QGKPSYTVDW YYSQTNKSIP TQERNRVFAS GQLLKFLPAE VADSGIYTCI VRSPTFNRTG YANVTIYKKQ SDCNVPDYLM YSTVSGSEKN SKIYCPTIDL YNWTAPLEWF KNCQALQGSR YRAHKSFLVI DNVMTEDAGD YTCKFIHNEN GANYSVTATR SFTVKDEQGF SLFPVIGAPA QNEIKEVEIG KNANLTCSAC FGKGTQFLAA VLWQLNGTKI TDFGEPRIQQ EEGQNQSFSN GLACLDMVLR IADVKEEDLL LQYDCLALNL HGLRRHTVRL SRKNPSKECF IEGRMDPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGKHHH HHH 3 human IL-33 (mm2) MSITGISPIT EYLASLSTYN DQSITFALED ESYEIYVEDL KKDEKKDKVL Residues corresponding LSYYESQHPS NESGDGVDGK MLMVTLSPTK DFWLHANNKE HSVELHKSEK to C208, C227, C232 PLPDQAFFVL HNMHSNSVSF ESKTDPGVFI GVKDNHLALI KVDSSENLST and C259 of SEQ ID ENILFKLSET HHHHHH NO: 396 are underlined and in bold 4 human IL-33 WT FLAG SITGISPITE YLASLSTYND QSITFALEDE SYEIYVEDLK KDEKKDKVLL residues corresponding SYYESQHPSN ESGDGVDGKM LMVTLSPTKD FWLHANNKEH SVELHKCEKP to C208, C227, C232 LPDQAFFVLH NMHSNCVSFE CKTDPGVFIG VKDNHLALIK VDSSENLCTE and C259 of SEQ ID NILFKLSETL EDYKDDDDK NO: 396 are underlined and in bold 5 cynomolgus monkey IL- MSITGISPIT ESLASLSTYN DQSITFALED ESYEIYVEDL KKDKKKDKVL 33 (CID42) LSYYESQHPS SESGDGVDGK MLMVTLSPTK DFWLQANNKE HSVELHKSEK Residues corresponding PLPDQAFFVL HNRSFNSVSF ESKTDPGVFI GVKDNHLALI KVDYSENLGS to C208, C227, C232 of ENILFKLSEI HHHHHH SEQ ID NO: 396 underlined and in bold 6 human ST2-hIgG2Fc KFSKQSWGLENEALIVRCPRQGKPSYTVDWYYSQTNKSIPTQERNRVFASGQLL KFLPAAVADSGIYTCIVRSPTFNRTGYANVTIYKKQSDCNVPDYLMYSTVSGSE KNSKIYCPTIDLYNWTAPLEWFKNCQALQGSRYRAHKSFLVIDNVMTEDAGDYT CKFIHNENGANYSVTATRSFTVKDEQGFSLFPVIGAPAQNEIKEVEIGKNANLT CSACFGKGTQFLAAVLWQLNGTKITDFGEPRIQQEEGQNQSFSNGLACLDMVLR LADVKEEDLLLQYDCLALNLHGLRRHTVRLSRKNPSKECFVECPPCPAPPVAGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPR EEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 7 DP-54 framework region EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQD (VH3 sub-group) with a GSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARYFDYWGQGTL JH4 segment VTVSS 8 JH4 WGQGTLVTVSS 9 human IgG1 effector ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP function null constant AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT region CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKFYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 10 human IgG1 wild-type ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP constant region AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK 11 DPK9 framework (VKI DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSL sub-group) with a JK4 QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK segment 12 JK4 FGGGTKVEIK 13 human kappa constant RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE domain SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 14 7E8 chimera V.sub.H EVQLVETGGGLVQPGRSLKLSCKTSGFTFSSYWMYWIRQAPGKGLEWVSSITPN GGNTYYPDSVKGRFTISRDNAENTIYLQMSSLRSEDTATYFCAKGHYYYTSYSL GYWGQGSLVTVSS 15 7E8 chimera V.sub.H MGWSCIILFLVATATGAHS secretory leader 16 7E8 chimera CDRH1 GFTFSSYWMY 17 7E8 chimera CDRH2 SITPNGGNTYYPDSVKG 18 7E8 chimera CDRH3 GHYYYTSYSLGY 19 7E8 chimera V.sub.L EIQMTQSPSVLSASVGDRVTLSCKASQNINKHLDWYQQKLGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDCTLTINSLQPGDVATYFCFQYNNGWTFGGGTKLELD 20 7E8 chimera CDRL1 KASQNINKHLD 21 7E8 chimera CDRL2 FTNNLQT 22 7E8 chimera CDRL3 FQYNNGWT 23 7E8 chimera JH WGQGSLVTVSS 24 CH1 hIgG1 WT ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV 25 Human IgG1 hinge EPKSCDKTHTCPPCP 26 CH2 hIgG1 effector APEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV function null HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AK 27 CH3 hIgG1 WT GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 28 7E8 chimera HC EVQLVETGGGLVQPGRSLKLSCKTSGFTFSSYWMYWIRQAPGKGLEWVSSITPN GGNTYYPDSVKGRFTISRDNAENTIYLQMSSLRSEDTATYFCAKGHYYYTSYSL GYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 29 7E8 chimera JK FGGGTKLELD 30 CL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 31 7E8 chimera LC EIQMTQSPSVLSASVGDRVTLSCKASQNINKHLDWYQQKLGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDCTLTINSLQPGDVATYFCFQYNNGWTFGGGTKLELDRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 32 9B3 chimera V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSF SYWGQGTLVTVSS 33 9B3 chimera CDRH1 GFTFSNYWMY 34 9B3 chimera CDRH2 SINNDGGNTYYLDSVKG 35 9B3 chimera CDRH3 GHYSYSSYSFSY 36 9B3 chimera V.sub.L DIQMTQSPSVLSASVGDRVTLSCKASHNINKHLDWCQQKVGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDYTLTISSLQPEDVATYFCFQYNSGWTFGGGTKLELK 37 9B3 chimera CDRL1 KASHNINKHLD 38 9B3 chimera CDRL3 FQYNSGWT 39 9B3 chimera JH WGQGTLVTVSS 40 9B3 chimera HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSF SYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 41 9B3 chimera JK FGGGTKLELK 42 9B3 chimera LC DIQMTQSPSVLSASVGDRVTLSCKASHNINKHLDWCQQKVGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDYTLTISSLQPEDVATYFCFQYNSGWTFGGGTKLELKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 43 12F9 chimera V.sub.H EVQLVESGGDLVQPGRSLKLSCVTSGFIFKNYWMTWIRQVPGKGLEWVASITNT GGATYYPDSVKGRFTISRDNSENTLYLQMNSLRSEDTATYYCARDRRYNSGSPF AYWGQGTLVTVSS 44 12F9 chimera CDRH1 GFIFKNYWMT 45 12F9 chimera CDRH2 SITNTGGATYYPDSVKG 46 12F9 chimera CDRH3 DRRYNSGSPFAY 47 12F9 chimera VL DIQLTQSPSTLAASLGERVTISCRASQSISNSLIWFQQKPDGTIKRLIYSSSTL ESGVPSRFSGSGSGTDYSLSISSLESEDFAMYYCLQYATYPWTFGGGTKLELR 48 12F9 chimera CDRL1 RASQSISNSLI 49 12F9 chimera CDRL2 SSSTLES 50 12F9 chimera CDRL3 LQYATYPWT 51 12F9 chimera HC EVQLVESGGDLVQPGRSLKLSCVTSGFIFKNYWMTWIRQVPGKGLEWVASITNT GGATYYPDSVKGRFTISRDNSENTLYLQMNSLRSEDTATYYCARDRRYNSGSPF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 52 12F9 chimera JK FGGGTKLELR 53 12F9 chimera LC DIQLTQSPSTLAASLGERVTISCRASQSISNSLIWFQQKPDGTIKRLIYSSSTL ESGVPSRFSGSGSGTDYSLSISSLESEDFAMYYCLQYATYPWTFGGGTKLELRR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 54 14D8 chimera VH EVQLVDSGGDQVQPGRSLKLSCVASGFIFKNYWMTWIRQVPGKGLEWIASITNS GGNTYYPDSVKGRFTISRDNAKDTLYLQMNSLRSEDTATYYCARDRRYNSGSPF AYWGQGTLVTVSS 55 14D8 chimera CDRH2 SITNSGGNTYYPDSVKG 56 14D8 chimera VL DIQLTQSPSTLPASLGERVTISCRTSQSINNNLCWYQQKPDGTVKRLIYSTSTL ESGVPSRFSGSGSGTDYSLSISSLESQDFAMYYCLQYATYPWTFGGGTKLELK

57 14D8 chimera CDRL1 RTSQSINNNLC 58 14D8 chimera CDRL2 STSTLES 59 14D8 chimera HC EVQLVDSGGDQVQPGRSLKLSCVASGFIFKNYWMTWIRQVPGKGLEWIASITNS GGNTYYPDSVKGRFTISRDNAKDTLYLQMNSLRSEDTATYYCARDRRYNSGSPF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 60 14D8 chimera LC DIQLTQSPSTLPASLGERVTISCRTSQSINNNLCWYQQKPDGTVKRLIYSTSTL ESGVPSRFSGSGSGTDYSLSISSLESQDFAMYYCLQYATYPWTFGGGTKLELKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 61 30A1 chimera VH QVNLLQSGATLVKPGASMKMSCKASGYSFTDYWVSWVKQSHGKSLEWIGEIYPN SGANNFNKEFKDKATLTVDKSTSTAYMELTRLTSEDSAVYYCTRGPYYYSSQII FAYWGQGTLVTVSS 62 30A1 chimera CDRH1 GYSFTDYWVS 63 30A1 chimera CDRH2 EIYPNSGANNFNKEFKD 64 30A1 chimera CDRH3 GPYYYSSQIIFAY 65 30A1 chimera VL IIVMTQSPKSMSISVGDRVTMNCKASQNVGNNIAWYRQKPGQSPELLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVELK 66 30A1 chimera CDRL1 KASQNVGNNIA 67 30A1 chimera CDRL2 YASNRYT 68 30A1 chimera CDRL3 QRIYNSPPT 69 30A1 chimera HC QVNLLQSGATLVKPGASMKMSCKASGYSFTDYWVSWVKQSHGKSLEWIGEIYPN SGANNFNKEFKDKATLTVDKSTSTAYMELTRLTSEDSAVYYCTRGPYYYSSQII EAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLEPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK 70 30A1 chimera JK FGGGTKVELK 71 30A1 chimera LC IIVMTQSPKSMSISVGDRVTMNCKASQNVGNNIAWYRQKPGQSPELLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVELKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 72 30B11 chimera VH QVKLLQSGAALVKPGASVKMSCATSGFSFTDYWVSWVKQSHGKGLEWIGEIYPN SGADNFNENFKGKATLTVDKSTSTAYMELSRLTSEDSAIYYCTRGPYYYSTQII FAYWGQGTLVTVSS 73 30B11 chimera CDRH1 GFSFTDYWVS 74 30B11 chimera CDRH2 EIYPNSGADNFNENFKG 75 30B11 chimera CDRH3 GPYYYSTQIIFAY 76 30B11 chimera VL NIVMTQSPKSMSISVGDRVTMNCKASQNVGNNLAWYQQKPGQSPKLLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVELR 77 30B11 chimera CDRL1 KASQNVGNNLA 78 30B11 chimera HC QVKLLQSGAALVKPGASVKMSCATSGFSFTDYWVSWVKQSHGKGLEWIGEIYPN SGADNFNENFKGKATLTVDKSTSTAYMELSRLTSEDSAIYYCTRGPYYYSTQII FAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK 79 30B11 chimera JK FGGGTKVELR 80 30B11 chimera LC NIVMTQSPKSMSISVGDRVTMNCKASQNVGNNLAWYQQKPGQSPKLLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVELRR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 81 9B3 chimera/hu J VL DIQMTQSPSVLSASVGDRVTLSCKASHNINKHLDWCQQKVGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDYTLTISSLQPEDVATYFCFQYNSGWTFGQGTKVEIK 82 9B3 chimera/hu J JK FGQGTKVEIK 83 9B3 chimera/hu J LC DIQMTQSPSVLSASVGDRVTLSCKASHNINKHLDWCQQKVGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDYTLTISSLQPEDVATYFCFQYNSGWTFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 84 14D8 chimera/hu J VL DIQLTQSPSTLPASLGERVTISCRTSQSINNNLCWYQQKPDGTVKRLIYSTSTL ESGVPSRFSGSGSGTDYSLSISSLESQDFAMYYCLQYATYPWTFGQGTKVEIK 85 14D8 chimera/hu J LC DIQLTQSPSTLPASLGERVTISCRTSQSINNNLCWYQQKPDGTVKRLIYSTSTL ESGVPSRFSGSGSGTDYSLSISSLESQDFAMYYCLQYATYPWTFGQGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNEYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 86 30A1 chimera/hu J VL IIVMTQSPKSMSISVGDRVTMNCKASQNVGNNIAWYRQKPGQSPELLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVEIK 87 30A1 chimera/hu J LC IIVMTQSPKSMSISVGDRVTMNCKASQNVGNNIAWYRQKPGQSPELLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 88 30B11 chimera/hu J VL NIVMTQSPKSMSISVGDRVTMNCKASQNVGNNLAWYQQKPGQSPKLLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVEIK 89 30B11 chimera/hu J LC NIVMTQSPKSMSISVGDRVTMNCKASQNVGNNLAWYQQKPGQSPKLLIYYASNR YTGVPDRFTGGGYGTDFTLTINSVQAEDAAFYYCQRIYNSPPTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 90 7E8 CDR graft V.sub.H HSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASIT PNGGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSY SLGYWGQGTLVTVSS 91 7E8 CDR graft V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIK 92 7E8 CDR graft HC HSEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASIT PNGGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSY SLGYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK 93 7E8 CDR graft LC DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 94 IL33-10 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 95 IL33-10 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 96 CH2 hIgG1 WT APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AK 97 9B3 CDR graft V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMYWVRQAPGKGLEWVASINND GGNTYYLDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYSYSSYSF SYWGQGTLVTVSS 98 9B3 CDR graft V.sub.L DIQMTQSPSSLSASVGDRVTITCKASHNINKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNSGWTFGGGTKVEIK 99 9B3 CDR graft HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMYWVRQAPGKGLEWVASINND GGNTYYLDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYSYSSYSF SYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 100 9B3 CDR graft LC DIQMTQSPSSLSASVGDRVTITCKASHNINKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNSGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 101 12F9 CDR graft V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFKNYWMTWVRQAPGKGLEWVASITNT GGATYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRRYNSGSPF AYWGQGTLVTVSS 102 12F9 CDR graft CDRH1 GFTFKNYWMT 103 12F9 CDR graft V.sub.L DIQMTQSPSSLSASVGDRVTITCRASQSISNSLIWYQQKPGKAPKLLIYSSSTL ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYATYPWTFGGGTKVEIK 104 12F9 CDR graft HC EVQLVESGGGLVQPGGSLRLSCAASGFTFKNYWMTWVRQAPGKGLEWVASITNT GGATYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRRYNSGSPF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 105 12F9 CDR graft LC DIQMTQSPSSLSASVGDRVTITCRASQSISNSLIWYQQKPGKAPKLLIYSSSTL ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYATYPWTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 106 30B11 CDR graft V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYWVSWVRQAPGKGLEWVAEIYPN SGADNFNENFKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGPYYYSTQII FAYWGQGTLVTVSS 107 30B11 CDR graft CDRH1 GFTFTDYWVS 108 30B11 CDR graft V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNVGNNLAWYQQKPGKAPKLLIYYASNR YTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQRIYNSPPTFGGGTKVEIK 109 30B11 CDR graft HC EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYWVSWVRQAPGKGLEWVAEIYPN SGADNFNENFKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGPYYYSTQII FAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY

PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK 110 30B11 CDR graft LC DIQMTQSPSSLSASVGDRVTITCKASQNVGNNLAWYQQKPGKAPKLLIYYASNR YTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQRIYNSPPTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 111 30B11_R71V CDR graft EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYWVSWVRQAPGKGLEWVAEIYPN V.sub.H SGADNFNENFKGRFTISVDNAKNSLYLQMNSLRAEDTAVYYCARGPYYYSTQII FAYWGQGTLVTVSS 112 30B11_R71V CDR graft EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYWVSWVRQAPGKGLEWVAEIYPN HC SGADNFNENFKGRFTISVDNAKNSLYLQMNSLRAEDTAVYYCARGPYYYSTQII FAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK 113 9B3-1 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSL GYWGQGTLVTVSS 114 9B3-1 CDRH3 GHYYYSSYSLGY 115 9B3-1 V.sub.L DIQMTQSPSVLSASVGDRVTLSCKASHNINKHLDWYQQKVGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDYTLTISSLQPEDVATYFCFQYNSGWTFGQGTKVEIK 116 9B3-1 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 117 9B3-1 LC DIQMTQSPSVLSASVGDRVTLSCKASHNINKHLDWYQQKVGEAPKLLIYFTNNL QTGIPSRFSGSGSGTDYTLTISSLQPEDVATYFCFQYNSGWTFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 118 9B3-2A V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSF GYWGQGTLVTVSS 119 9B3-2A CDRH3 GHYSYSSYSFGY 120 9B3-2A HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSF GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 121 9B3-2B V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCVKGHYSYSSYSI DYWGQGTLVTVSS 122 9B3-2B CDRH3 GHYSYSSYSIDY 123 9B3-2B HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCVKGHYSYSSYSI DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 124 9B3-3 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSI DYWGQGTLVTVSS 125 9B3-3 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSI DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 126 9B3-5 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYTSYSF GYWGQGTLVTVSS 127 9B3-5 CDRH3 GHYSYTSYSFGY 128 9B3-5 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYTSYSF GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 129 9B3-7 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGRYYYSSYSF AYWGQGTLVTVSS 130 9B3-7 CDRH3 GRYYYSSYSFAY 131 9B3-7 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGRYYYSSYSF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 132 9B3-13 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCARGHYYYNSYSF AHWGQGTLVTVSS 133 9B3-13 CDRH3 GHYYYNSYSFAH 134 9B3-13 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCARGHYYYNSYSF AHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 135 9B3-15 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSF ANWGQGTLVTVSS 136 9B3-15 CDRH3 GHYSYSSYSFAN 137 9B3-15 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYSYSSYSF ANWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 138 9B3-17 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCARGHYYYSSYSF GSWGQGTLVTVSS 139 9B3-17 CDRH3 GHYYYSSYSFGS 140 9B3-17 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCARGHYYYSSYSF GSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 141 9B3-22 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHFSYTSYSF AYWGQGTLVTVSS 142 9B3-22 CDRH3 GHFSYTSYSFAY 143 9B3-22 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHFSYTSYSF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 144 9B3-31V2 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSF AFWGQGTLVTVSS 145 9B3-31V2 CDRH3 GHYYYSSYSFAF 146 9B3-31V2 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSF AFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 147 9B3-36 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYTSYSF AYWGQGTLVTVSS 148 9B3-36 CDRH3 GHYYYTSYSFAY 149 9B3-36 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYTSYSF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 150 9B3-79 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCARGHYYYTSYSF AYWGQGTLVTVSS 151 9B3-79 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCARGHYYYTSYSF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 152 9B3-124 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYTSYSF GYWGQGTLVTVSS 153 9B3-124 CDRH3 GHYYYTSYSFGY 154 9B3-124 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYTSYSF GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 155 9B3-162 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSF GYWGQGTLVTVSS 156 9B3-162 CDRH3 GHYYYSSYSFGY 157 9B3-162 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSF GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 158 9B3-563 V.sub.H EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSF AYWGQGTLVTVSS 159 9B3-563 CDRH3 GHYYYSSYSFAY 160 9B3-563 HC EVQLVETGGGLVQPGRSLKLSCVASGFTFSNYWMYWIRQAPGMGLEWVSSINND GGNTYYLDSVKGRFTISRNNAENTVYLQMNSLRSEDTATYYCAKGHYYYSSYSF AYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 161 IL33-11 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 162 IL33-11 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 163 IL33-12 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASINND GGNTYYLDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 164 IL33-12 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASINND GGNTYYLDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 165 IL33-13 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYSYSSYSF SYWGQGTLVTVSS 166 IL33-13 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYSYSSYSF SYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 167 IL33-45 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPD GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 168 IL33-45 CDRH2 SITPDGGNTYYPDSVKG 169 IL33-45 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPD GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 170 IL33-55 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGDTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 171 IL33-55 CDRH2 SITPNGGDTYYPDSVKG 172 IL33-55 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGDTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 173 IL33-56 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 174 IL33-56 CDRH2 SITPNGGETYYPDSVKG 175 IL33-56 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 176 IL33-57 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTDYSL GYWGQGTLVTVSS 177 IL33-57 CDRH3 GHYYYTDYSLGY 178 IL33-57 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTDYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 179 IL33-58 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPL GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 180 IL33-58 CDRH2 SITPLGGNTYYPDSVKG 181 IL33-58 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPL GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 182 IL33-61 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTDYSL GYWGQGTLVTVSS 183 IL33-61 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTDYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 184 IL33-62 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGDTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTDYSL GYWGQGTLVTVSS 185 IL33-62 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGDTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTDYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 186 IL33-68 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTAYSL GYWGQGTLVTVSS 187 IL33-68 CDRH3 GHYYYTAYSLGY 188 IL33-68 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGNTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTAYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 189 IL33-74 V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNINDHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIK 190 IL33-74 CDRL1 KASQNINDHLD 191 IL33-74 LC DIQMTQSPSSLSASVGDRVTITCKASQNINDHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 192 IL33-75 V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNIDKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIK 193 IL33-75 CDRL1 KASQNIDKHLD 194 IL33-75 LC DIQMTQSPSSLSASVGDRVTITCKASQNIDKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 195 IL33-80 V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIK 196 IL33-80 CDRL2 FTNNLQD 197 IL33-80 LC DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 198 IL33-81 V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIK

199 IL33-81 CDRL2 FTNNLQE 200 IL33-81 LC DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNNGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 201 IL33-103 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 202 IL33-103 CDRH2 AITPNGGETYYPDSVKG 203 IL33-103 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 204 IL33-117 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 205 IL33-117 CDRH2 SITPNGGEDYYPDSVKG 206 IL33-117 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN GGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 207 IL33-136 V.sub.L DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNQGWTFGGGTKVEIK 208 IL33-136 CDRL3 FQYNQGWT 209 IL33-136 LC DIQMTQSPSSLSASVGDRVTITCKASQNINKHLDWYQQKPGKAPKLLIYFTNNL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQYNQGWTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 210 IL33-153 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN AGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 211 IL33-153 CDRH2 SITPNAGEDYYPDSVKG 212 IL33-153 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN AGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 213 IL33-154 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN AGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 214 IL33-154 CDRH2 SITPNAGEDYYPESVKG 215 IL33-154 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN AGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 216 IL33-155 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 217 IL33-155 CDRH2 AITPNGGEDYYPDSVKG 218 IL33-155 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 219 IL33-156 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 220 IL33-156 CDRH2 AITPNGGEDYYPESVKG 221 IL33-156 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 222 IL33-157 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 223 IL33-157 CDRH2 AITPNAGEDYYPDSVKG 224 IL33-157 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 225 IL33-158 V.sub.H EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYWMYWVRQA PGKGLEWVAA ITPNAGEDYY PESVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARGH YYYTSYSLGY WGQGTLVTVS S 226 IL33-158 CDRH2 AITPNAGEDYYPESVKG 227 IL33-158 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 228 IL33-175 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGETYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 229 IL33-175 CDRH2 AITPNAGETYYPESVKG 230 IL33-175 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGETYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 231 IL33-186 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGETYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 232 IL33-186 CDRH2 AITPNGGETYYPESVKG 233 IL33-186 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN GGETYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 234 IL33-187 V.sub.H EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSS 235 IL33-187 CDRH2 AITPNAGETYYPDSVKG 236 IL33-187 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGETYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK 237 human IgG1 effector ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP function null AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT constant region, CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV lysine deleted DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG 238 human IgG1 effector ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP function AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT null constant CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV region, lysine DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE deleted, LS KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSL SLSPG 239 IL33-158-152 V.sub.H MGWSCIILFLVATATGVHS secretory leader 240 CH3 hIgG1 delta K GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 241 IL33-158-152 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPG 242 IL33-167-153 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN AGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPG

243 CH3 hIgG1 LS GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG 244 IL33-158LS HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVAAITPN AGEDYYPESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVL HEALHSHYTQKSLSLSPG 245 IL33-167LS HC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQAPGKGLEWVASITPN AGEDYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGHYYYTSYSL GYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVL HEALHSHYTQKSLSLSPG 246 IL33-271 V.sub.H QVLLVQSGAEVKKPGATVKVSCKASGSTFTGYYMHWVRQAPGQGLEWMGWINPN NGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARELRYNWKSWG QGTLVTVSS 247 IL33-271 CDRH1 GSTFTGYYMH 248 IL33-271 CDRH2 WINPNNGGTNYAQKFQG 249 IL33-271 CDRH3 ELRYNWKS 250 IL33-271 V.sub.L EIVLTQSPGTLSLSPGERVTLSCRASQSVGRPYLAWYQQIPGQAPRLLIYGASS RATDIPDRFSGNGSGTDFTLTISRLEPEDFAVYYCQQYDNSPYTFGQGTRLEIK 251 IL33-271 CDRL1 RASQSVGRPYLA 252 IL33-271 CDRL2 GASSRAT 253 IL33-271 CDRL3 QQYDNSPYT 254 IL33-271 HC QVLLVQSGAEVKKPGATVKVSCKASGSTFTGYYMHWVRQAPGQGLEWMGWINPN NGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARELRYNWKSWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK 255 IL33-271 JK FGQGTRLEIK 256 IL33-271 LC EIVLTQSPGTLSLSPGERVTLSCRASQSVGRPYLAWYQQIPGQAPRLLIYGASS RATDIPDRFSGNGSGTDFTLTISRLEPEDFAVYYCQQYDNSPYTFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 257 Consensus CDR L1 Broad (K/S/H/T/Q/W/Y/F/R)(A/S/G)(S/A/D)(Q/H/S/E/D/T)(N/S/D/R/ K/Y/E/G)(I/V)(N/F/K/H/R/L/M/I/E/S)(K/Q/ E/R/W/F/Y/N/A/S/H)(H/F/R/W)(L/I/V/A)(D/S/A) 258 Consensus CDR L1 7E8 (K/R)AS(Q/H)(N/S)(I/V)(N/S)(K/S/N)HLD 9B3 germline ABS mutagenesis 259 Consensus CDR L1 7E8 (K/R)AS(Q/H)(N/S)I(N/S)(K/S)HLD 9B3 ABS mutagenesis 260 Consensus CDR L1 7E8 (K/R)ASQ(N/S)I(N/S)(K/S)HLD ABS 261 Consensus CDR L2 Broad (F/W/Y/D/E/G/S)(T/G/R/A/N/V)(N/W/Y/R/F/K/Q/E/D/H/S)(N/ F/Y/I/M/Q/L/A/R/G/P/S)(L/I/V/R)(Q/R/K/F/H/L/W/Y/A/E)(T/ S/N/Y) 262 Consensus CDR L2 7E8 (F/Y)(A/T)(N/S)(N/S)L(Q/E)(T/S) germline ABS mutagenesis 263 Consensus CDR L2 7E8 F(T/A)(N/S)(N/S)LQ(T/S) ABS mutagenesis 264 Consensus CDR L2 7E8 F(A/T)(N/S)NLQ(T/S) ABS 265 Consensus CDR L3 Broad (F/Q/W/H/A)(Q/S/T/A)(Y/H/F)(N/W/F/Y/R/K/H/D)(N/S/Q/W/K/ R/H/Y/D/G/T/V)(G/R/P/K/W/F/I/N/Q)(W/H)(T/S/Q) 266 Consensus CDR L3 7E8 (F/Q)Q(Y/F)(N/Y)(N/S/Q/R/Y)GWT 9B3 ABS mutagenesis 267 Consensus CDR L3 7E8 (F/Q)QY(N/Y)(N/S/Q/R)GWT 9B3 ABS 268 Consensus CDR L3 7E8 (F/Q)QY(N/Y)(N/S/Q)GWT ABS 269 Consensus CDR H1 Broad G(F/Y/H)(T/Q/N/S/E/D/R/Y)(F/Y/H)(S/E/D/T/W)(N/S/T/E/D/ H/L/I/Y/R/K/G)(Y/F/H)(W/H/Y/A/G)(M/E/Q/I)(Y/F/H/N) 270 Consensus CDR H1 7E8 GF(T/E)F(S/E)(N/S)YWMY 9B3 ABS mutagenesis 271 Consensus CDR H1 7E8 GFTFS(N/S)YWMY 9B3 ABS 272 Consensus CDR H2 Broad (S/A/T)(I/V)(T/H/N/S)(P/N/F/M)(N/I/ D/Y/W)(G/A)(G/H/D/E/R/K/Y/S)(N/Y/D/E/Q/H)(T/K/E/S/I/A/ D)(Y/H/W)(Y/F/H)(P/V/L/D/S)(D/E/Q/A)(S/A/N/D)(V/D/T)(K/ N/D/S/E/Q)G 273 Consensus CDR H2 7E8 (S/A)I(T/N)(P/N)(N/D)(G/A)(G/S/H)(N/D/E)(T/K/D/E)YY(P/ 9B3 ABS mutagenesis V/L)(D/E)SV(K/Q)G 274 Consensus CDR H2 7E8 (S/A)I(T/N)(P/N)(N/D)(G/A)(G/S)(N/E)(T/K/D)YY(P/V/L)(D/ 9B3 ABS E)SVKG 275 Consensus CDR H2 7E8 (S/A)ITP(N/D)(G/A)(G/S)(N/E)(T/K/D)YY(P/V)(D/E)SVKG ABS 276 Consensus CDR H3 Broad (G/S/A/T/D)(H/K/R/Y)(Y/H/F/S)(Y/H/R/S)(Y/H/W/F/R/S)(T/ N/V/I/S/A/G/Y)(S/N/A/Q/D/G/R/Y)(Y/W/H/F/G/D/N)(S/A/G) (L/M/F/I)(G/A/Y/S/D)(Y/N/S/F/E/D/H/I/V) 277 Consensus CDR H3 7E8 G(H/R/Y)(Y/F)(Y/S)(Y/H)(T/S/N)(S/A)YS(L/F/I)(G/S/A)(Y/ 9B3 mutagenesis and H/N/S/F) repertoire 278 Consensus CDR H3 7E8 G(H/Y)Y(Y/S)(Y/H)(T/S/N)(S/A)YS(L/F)(G/S)Y 9B3 mutagenesis 279 Consensus CDR H3 7E8 GHY(Y/S)Y(T/S)SYS(L/F)(G/S)Y 9B3 See Tables 2 and 3 for SEQ ID NOs 280-352 and 353-395 respectively. 396 Full length human IL- MKPKMKYSTN KISTAKWKNT ASKALCFKLG KSQQKAKEVC PMYFMKLRSG 33 Swiss Prot O95760- LMIKKEACYF PRETTKRRSL KTGRKHKRHL VLAACQQQST VECFAFGISG 1. VQKYTRALHD SSITGISPIT EYLASLSTYN DQSITFALED ESYEIYVEDL Residues C208, C227, KKDEKKDKVL LSYYESQHPS NESGDGVDCK MLMVTLSPTK DFWLHANNKE C232, and C259 are HSVELHKCEK PLPDQAFFVL HNMHSNCVSF ECKTDPGVFI GVKDNHLALI bold and underlined KVDSSENLCT ENILFKLSET 397 Wild-type cynomolgus SITGISPITE SLASLSTYND QSITFALEDE SYEIYVEDLK KDKKKDKVLL monkey IL-33 SYYESQHPSS ESGDGVDGKM LMVTLSPTKD FWLQANNKEH SVELHKCEKP LPDQAFFVLH NRSFNCVSFE CKTDPGVFIG VKDNHLALIK VDYSENLGSE NILFKLSEIH HHHHH 398 DNA sequence encoding GACATCCAGATGACCCAGTCCCCCTCTTCTCTGTCTGCCTCTGTGGGCGACAGA light chain IL33-158LS GTGACCATCACCTGTAAAGCAAGTCAGAATATTAATAAACACTTAGACTGGTAT CAGCAGAAGCCTGGCAAGGCTCCCAAGCTGCTGATCTACTTTACAAACAATTTA CAAACTGGCGTGCCTTCCAGATTCTCCGGCTCTGGCTCTGGCACCGATTTCACC CTGACCATCTCCTCCCTCCAGCCTGAGGATTTCGCCACCTACTACTGCTTTCAG TATAACCAGGGGTGGACCTTTGGCGGCGGAACAAAGGTGGAGATCAAGCGTACG GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTC ACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAG GGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 399 DNA sequence encoding GAGGTGCAGCTGGTGGAGTCTGGCGGCGGACTGGTGCAGCCTGGCGGCTCTCTG heavy chain IL33-158LS AGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCAGTTCCTACTGGATGTACTGG GTGAGGCAGGCCCCTGGCAAGGGCCTGGAGTGGGTGGCCGCCATTACTCCTAAT GCCGGTGAGGACTACTATCCAGAGTCTGTGAAAGGCCGGTTCACCATCTCCAGG GACAACGCCAAGAACTCCCTGTACCTCCAGATGAACTCCCTGAGGGCCGAGGAT ACCGCCGTGTACTACTGTGCCAGAGGCCATTATTACTATACCAGCTATTCGCTT GGATACTGGGGCCAGGGCACCCTGGTGACCGTGTCCTCTGCGTCGACCAAGGGC CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG GCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGC ACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC AAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA GCACCTGAAGCCGCTGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTG GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAG TGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAG GAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC AGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTC ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGTTG CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGA 400 DNA sequence encoding GACATCCAGATGACCCAGTCCCCCTCTTCTCTGTCTGCCTCTGTGGGCGACAGA light chain IL33-167LS GTGACCATCACCTGTAAAGCAAGTCAGAATATTAATAAACACTTAGACTGGTAT CAGCAGAAGCCTGGCAAGGCTCCCAAGCTGCTGATCTACTTTACAAACAATTTA CAAACTGGCGTGCCTTCCAGATTCTCCGGCTCTGGCTCTGGCACCGATTTCACC CTGACCATCTCCTCCCTCCAGCCTGAGGATTTCGCCACCTACTACTGCTTTCAG TATAACAATGGGTGGACCTTTGGCGGCGGAACAAAGGTGGAGATCAAGCGTACG GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAA GTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTC ACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAG GGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 401 DNA sequence encoding GAGGTGCAGCTGGTGGAGTCTGGCGGCGGACTGGTGCAGCCTGGCGGCTCTCTG heavy chain IL33-167LS AGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCAGTTCCTACTGGATGTACTGG GTGAGGCAGGCCCCTGGCAAGGGCCTGGAGTGGGTGGCCTCCATTACTCCTAAT GCCGGTGAGGACTACTATCCAGACTCTGTGAAAGGCCGGTTCACCATCTCCAGG GACAACGCCAAGAACTCCCTGTACCTCCAGATGAACTCCCTGAGGGCCGAGGAT ACCGCCGTGTACTACTGTGCCAGAGGCCATTATTACTATACCAGCTATTCGCTT GGATACTGGGGCCAGGGCACCCTGGTGACCGTGTCCTCTGCGTCGACCAAGGGC CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG GCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGC ACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC AAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA GCACCTGAAGCCGCTGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTG GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAG TGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAG GAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC AGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTC ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGTTG

CATGAGGCTCTGCACTCCCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGA 402 Leader Sequence MGWSCIILFL VATATGAHS 403 IL33-265 heavy chain, EVQLVESGGN LEQPGGSLRL SCTASGFTFS RSAMNWVRRA PGKGLEWVSG based on H4H9675P in ISGSGGRTYY ADSVKGRFTI SRDNSKNTLY LQMNSLSAED TAAYYCAKDS US 2014/0271658, SEQ YTTSWYGGMD VWGHGTTVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL ID NO: 274 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKTHT CPPCPAPEAA GAPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK 404 IL33-265 light chain, DIQMTQSPSS VSASVGDRVT ITCRASQGIF SWLAWYQQKP GKAPKLLIYA based on H4H9675P in ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFAIYYCQQ ANSVPITFGQ US 2014/0271658, SEQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV ID NO: 282 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 405 IL33-310 heavy chain, EVQLVESGGG LVQPGGSLRL SCAASGFTFS SFSMSWVRQA PGKGLEWVAT based on ISGGKTFTDY VDSVKGRFTI SRDDSKNTLY LQMNSLRAED TAVYYCTRAN 10C12.38.H6.87Y.581 YGNWFFEVWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD IgG4 in US YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY 2016/0168242, SEQ ID TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL NO: 306 MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLSCAVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLVSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG 406 IL33-310 light chain, EIVLTQSPAT LSLSPGERAT LSCRASESVA KYGLSLLNWF QQKPGQPPRL based on LIFAASNRGS GIPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQQSKEVPF 10C12.38.H6.87Y.581 TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV IgG4 in US QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 2016/0168242, SEQ ID THQGLSSPVT KSFNRGEC NO: 307 407 IL33-312 heavy chain, EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSG based on 33_640087-7B ISAIDQSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARQK in WO16156440, SEQ ID FMQLWGGGLR YPFGYWGQGT MVTVSSASTK GPSVFPLAPS SKSTSGGTAA NO: 615 LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKRVEPKSCD KTHTCPPCPA PEFEGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAS IEKTISKAKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK 408 IL33-312 light chain, SYVLTQPPSV SVSPGQTASI TCSGEGMGDK YAAWYQQKPG QSPVLVIYRD based on 33_640087-7B TKRPSGIPER FSGSNSGNTA TLTISGTQAM DEADYYCGVI QDNTGVFGGG in WO16156440, SEQ ID TKLTVLGQPK AAPSVTLFPP SSEELQANKA TLVCLISDFY PGAVTVAWKA NO: 617 DSSPVKAGVE TTTPSKQSNN KYAASSYLSL TPEQWKSHRS YSCQVTHEGS TVEKTVAPTE CS 409 IL33-313 heavy chain, EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSG based on 33 640237-2B IADDFTSTYY ADPVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDL in WO16156440, SEQ ID WMMNYAGGLR YPFGYWGQGT MVTVSSASTK GPSVFPLAPS SKSTSGGTAA NO: 623 LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKRVEPKSCD KTHTCPPCPA PEFEGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAS IEKTISKAKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK 410 IL33-313 light chain, SYVLTQPPSV SVSPGQTASI TCSGERMGDK YAAWYQQKPG QSPVLVIYRD based on 33 640237-2B TKRPSGIPER FSGSNSGNTA TLTISGTQAM DEADYYCGVL KQDTGVFGGG in WO16156440, SEQ ID TKLTVLGQPK AAPSVTLFPP SSEELQANKA TLVCLISDFY PGAVTVAWKA NO: 625 DSSPVKAGVE TTTPSKQSNN KYAASSYLSL TPEQWKSHRS YSCQVTHEGS TVEKTVAPTE CS

Sequence CWU 1

1

4101159PRTArtificial SequenceSynthetic Construct 1Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser1 5 10 15Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val 35 40 45Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp 50 55 60Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp65 70 75 80Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met 100 105 110His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser 130 135 140Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr145 150 1552553PRTArtificial SequenceSynthetic Construct 2Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val1 5 10 15Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr 20 25 30Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe 35 40 45Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Glu Val Ala Asp Ser 50 55 60Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly65 70 75 80Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu 115 120 125Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp145 150 155 160Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile225 230 235 240Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300Pro Ser Lys Glu Cys Phe Ile Glu Gly Arg Met Asp Pro Lys Ser Cys305 310 315 320Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 325 330 335Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 340 345 350Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 355 360 365Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 370 375 380His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr385 390 395 400Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 405 410 415Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 420 425 430Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 435 440 445Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 450 455 460Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu465 470 475 480Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 485 490 495Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 500 505 510Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 515 520 525His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 530 535 540Pro Gly Lys His His His His His His545 5503166PRTArtificial SequenceSynthetic Construct 3Met Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu1 5 10 15Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser 20 25 30Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys 35 40 45Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly 50 55 60Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys65 70 75 80Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His 85 90 95Lys Ser Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn 100 105 110Met His Ser Asn Ser Val Ser Phe Glu Ser Lys Thr Asp Pro Gly Val 115 120 125Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser 130 135 140Ser Glu Asn Leu Ser Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr145 150 155 160His His His His His His 1654169PRTArtificial SequenceSynthetic Construct 4Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser1 5 10 15Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val 35 40 45Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp 50 55 60Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp65 70 75 80Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met 100 105 110His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser 130 135 140Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr Leu145 150 155 160Glu Asp Tyr Lys Asp Asp Asp Asp Lys 1655166PRTArtificial SequenceSynthetic Construct 5Met Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu1 5 10 15Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser 20 25 30Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Lys Asp Lys 35 40 45Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly 50 55 60Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys65 70 75 80Asp Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His 85 90 95Lys Ser Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn 100 105 110Arg Ser Phe Asn Ser Val Ser Phe Glu Ser Lys Thr Asp Pro Gly Val 115 120 125Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr 130 135 140Ser Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile145 150 155 160His His His His His His 1656533PRTArtificial SequenceSynthetic Construct 6Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val1 5 10 15Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr 20 25 30Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe 35 40 45Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser 50 55 60Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly65 70 75 80Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu 115 120 125Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp145 150 155 160Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile225 230 235 240Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300Pro Ser Lys Glu Cys Phe Val Glu Cys Pro Pro Cys Pro Ala Pro Pro305 310 315 320Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 325 330 335Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 340 345 350Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Met 355 360 365Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 370 375 380Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu385 390 395 400Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala 405 410 415Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro 420 425 430Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 435 440 445Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 450 455 460Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr465 470 475 480Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 485 490 495Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 500 505 510Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 515 520 525Leu Ser Pro Gly Lys 5307113PRTArtificial SequenceSynthetic Construct 7Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser811PRTArtificial SequenceSynthetic Construct 8Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 109330PRTArtificial SequenceSynthetic Construct 9Ala 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 95Lys 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 Lys 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 Glu Glu225 230 235 240Met 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 Lys 325 33010330PRTArtificial SequenceSynthetic Construct 10Ala 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 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly 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 Lys 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 Glu Glu225 230 235 240Met 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 Lys 325 33011107PRTArtificial SequenceSynthetic Construct 11Asp Ile Gln Met 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 Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser Thr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1051210PRTArtificial SequenceSynthetic Construct 12Phe Gly Gly Gly Thr Lys Val Glu Ile Lys1 5 1013107PRTArtificial SequenceSynthetic Construct 13Arg 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 10514121PRTArtificial SequenceSynthetic Construct 14Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Lys Thr Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Ile Tyr65 70 75 80Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Ser Leu Val Thr Val Ser Ser 115 1201519PRTArtificial SequenceSynthetic Construct 15Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly1 5 10 15Ala His Ser1610PRTArtificial SequenceSynthetic Construct 16Gly Phe Thr Phe Ser Ser Tyr Trp Met Tyr1 5 101717PRTArtificial SequenceSynthetic Construct 17Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly1812PRTArtificial SequenceSynthetic Construct 18Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr1 5 1019106PRTArtificial SequenceSynthetic Construct 19Glu Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Cys Thr Leu Thr Ile Asn Ser Leu Gln Pro65 70 75 80Gly Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Leu Asp 100 1052011PRTArtificial SequenceSynthetic Construct 20Lys Ala Ser Gln Asn Ile Asn Lys His Leu Asp1 5 10217PRTArtificial SequenceSynthetic Construct 21Phe Thr Asn Asn Leu Gln Thr1 5228PRTArtificial SequenceSynthetic Construct 22Phe Gln Tyr Asn Asn Gly Trp Thr1 52311PRTArtificial SequenceSynthetic Construct 23Trp Gly Gln Gly Ser Leu Val Thr Val Ser Ser1 5 102498PRTArtificial SequenceSynthetic Construct 24Ala 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 95Lys Val2515PRTArtificial SequenceSynthetic Construct 25Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro1 5 10 1526110PRTArtificial SequenceSynthetic Construct 26Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys1 5 10 15Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His65 70 75 80Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 100 105 11027107PRTArtificial SequenceSynthetic Construct 27Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu1 5 10 15Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 20 25 30Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly65 70 75 80Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 85 90 95Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 100 10528451PRTArtificial SequenceSynthetic Construct 28Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Lys Thr Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Ile Tyr65 70 75 80Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 4502910PRTArtificial SequenceSynthetic Construct 29Phe Gly Gly Gly Thr Lys Leu Glu Leu Asp1 5 1030107PRTArtificial SequenceSynthetic Construct 30Arg 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 10531213PRTArtificial SequenceSynthetic Construct 31Glu Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Cys Thr Leu Thr Ile Asn Ser Leu Gln Pro65 70 75 80Gly Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Leu Asp Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 21032121PRTArtificial SequenceSynthetic Construct 32Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 1203310PRTArtificial SequenceSynthetic Construct 33Gly Phe Thr Phe Ser Asn Tyr Trp Met Tyr1 5 103417PRTArtificial SequenceSynthetic Construct 34Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val Lys1 5 10 15Gly3512PRTArtificial SequenceSynthetic Construct 35Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr1 5 1036106PRTArtificial SequenceSynthetic Construct 36Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile 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 Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys 100 1053711PRTArtificial SequenceSynthetic Construct 37Lys Ala Ser His Asn Ile Asn Lys His Leu Asp1 5 10388PRTArtificial SequenceSynthetic Construct 38Phe Gln Tyr Asn Ser Gly Trp Thr1 53911PRTArtificial SequenceSynthetic Construct 39Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 1040451PRTArtificial SequenceSynthetic Construct 40Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210

215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 4504110PRTArtificial SequenceSynthetic Construct 41Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys1 5 1042213PRTArtificial SequenceSynthetic Construct 42Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile 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 Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 21043121PRTArtificial SequenceSynthetic Construct 43Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Ile Phe Lys Asn Tyr 20 25 30Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 1204410PRTArtificial SequenceSynthetic Construct 44Gly Phe Ile Phe Lys Asn Tyr Trp Met Thr1 5 104517PRTArtificial SequenceSynthetic Construct 45Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly4612PRTArtificial SequenceSynthetic Construct 46Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr1 5 1047107PRTArtificial SequenceSynthetic Construct 47Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ala Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Ser 20 25 30Leu Ile Trp Phe Gln Gln Lys Pro Asp Gly Thr Ile Lys Arg Leu Ile 35 40 45Tyr Ser Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser65 70 75 80Glu Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg 100 1054811PRTArtificial SequenceSynthetic Construct 48Arg Ala Ser Gln Ser Ile Ser Asn Ser Leu Ile1 5 10497PRTArtificial SequenceSynthetic Construct 49Ser Ser Ser Thr Leu Glu Ser1 5509PRTArtificial SequenceSynthetic Construct 50Leu Gln Tyr Ala Thr Tyr Pro Trp Thr1 551451PRTArtificial SequenceSynthetic Construct 51Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Ile Phe Lys Asn Tyr 20 25 30Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 4505210PRTArtificial SequenceSynthetic Construct 52Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg1 5 1053214PRTArtificial SequenceSynthetic Construct 53Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ala Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Ser 20 25 30Leu Ile Trp Phe Gln Gln Lys Pro Asp Gly Thr Ile Lys Arg Leu Ile 35 40 45Tyr Ser Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser65 70 75 80Glu Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg 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 21054121PRTArtificial SequenceSynthetic Construct 54Glu Val Gln Leu Val Asp Ser Gly Gly Asp Gln Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Lys Asn Tyr 20 25 30Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ala Ser Ile Thr Asn Ser Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 1205517PRTArtificial SequenceSynthetic Construct 55Ser Ile Thr Asn Ser Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly56107PRTArtificial SequenceSynthetic Construct 56Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn 20 25 30Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile 35 40 45Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser65 70 75 80Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys 100 1055711PRTArtificial SequenceSynthetic Construct 57Arg Thr Ser Gln Ser Ile Asn Asn Asn Leu Cys1 5 10587PRTArtificial SequenceSynthetic Construct 58Ser Thr Ser Thr Leu Glu Ser1 559451PRTArtificial SequenceSynthetic Construct 59Glu Val Gln Leu Val Asp Ser Gly Gly Asp Gln Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Lys Asn Tyr 20 25 30Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Ala Ser Ile Thr Asn Ser Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 45060214PRTArtificial SequenceSynthetic Construct 60Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn 20 25 30Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile 35 40 45Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser65 70 75 80Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu 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 21061122PRTArtificial SequenceSynthetic Construct 61Gln Val Asn Leu Leu Gln Ser Gly Ala Thr Leu Val Lys Pro Gly Ala1 5 10 15Ser Met Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asn Asn Phe Asn Lys Glu Phe 50 55 60Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Thr Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Arg Gly Pro Tyr Tyr Tyr Ser Ser Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1206210PRTArtificial SequenceSynthetic Construct 62Gly Tyr Ser Phe Thr Asp Tyr Trp Val Ser1 5 106317PRTArtificial SequenceSynthetic Construct 63Glu Ile Tyr Pro Asn Ser Gly Ala Asn Asn Phe Asn Lys Glu Phe Lys1 5 10 15Asp6413PRTArtificial SequenceSynthetic Construct 64Gly Pro Tyr Tyr Tyr Ser Ser Gln Ile Ile Phe Ala Tyr1 5 1065107PRTArtificial SequenceSynthetic Construct 65Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Lys 100 1056611PRTArtificial SequenceSynthetic Construct 66Lys Ala Ser Gln Asn Val Gly Asn Asn Ile Ala1 5 10677PRTArtificial SequenceSynthetic Construct 67Tyr Ala Ser Asn Arg Tyr Thr1 5689PRTArtificial SequenceSynthetic Construct 68Gln Arg Ile Tyr Asn Ser Pro Pro Thr1 569452PRTArtificial SequenceSynthetic Construct 69Gln Val Asn Leu Leu Gln Ser Gly Ala Thr Leu Val Lys Pro Gly Ala1 5 10 15Ser Met Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asn Asn Phe Asn Lys Glu Phe 50 55 60Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Thr Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Arg Gly Pro Tyr Tyr Tyr Ser Ser Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala225 230 235 240Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Pro Gly Lys 4507010PRTArtificial SequenceSynthetic Construct 70Phe Gly Gly Gly Thr Lys Val Glu Leu Lys1 5 1071214PRTArtificial SequenceSynthetic Construct 71Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Leu 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 21072122PRTArtificial SequenceSynthetic Construct 72Gln Val Lys Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Ala Thr Ser Gly Phe Ser Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95Thr Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1207310PRTArtificial SequenceSynthetic Construct 73Gly Phe Ser Phe Thr Asp Tyr Trp Val Ser1 5 107417PRTArtificial SequenceSynthetic Construct 74Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe Lys1 5 10 15Gly7513PRTArtificial SequenceSynthetic Construct 75Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr1 5 1076107PRTArtificial SequenceSynthetic Construct 76Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Arg 100 1057711PRTArtificial SequenceSynthetic Construct 77Lys Ala Ser Gln Asn Val Gly Asn Asn Leu Ala1 5 1078452PRTArtificial SequenceSynthetic Construct 78Gln Val Lys Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Met Ser Cys Ala Thr Ser Gly Phe Ser Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95Thr Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala225 230 235 240Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Pro Gly Lys 4507910PRTArtificial SequenceSynthetic Construct 79Phe Gly Gly Gly Thr Lys Val Glu Leu Arg1 5 1080214PRTArtificial SequenceSynthetic Construct 80Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Arg 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 21081106PRTArtificial SequenceSynthetic Construct 81Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile 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 Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 1058210PRTArtificial SequenceSynthetic Construct 82Phe Gly Gln Gly Thr Lys Val Glu Ile Lys1 5 1083213PRTArtificial SequenceSynthetic Construct 83Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile 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 Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 21084107PRTArtificial SequenceSynthetic Construct 84Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn 20 25 30Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile 35 40 45Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser

Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser65 70 75 80Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10585214PRTArtificial SequenceSynthetic Construct 85Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn 20 25 30Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile 35 40 45Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser65 70 75 80Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val 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 21086107PRTArtificial SequenceSynthetic Construct 86Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10587214PRTArtificial SequenceSynthetic Construct 87Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val 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 21088107PRTArtificial SequenceSynthetic Construct 88Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10589214PRTArtificial SequenceSynthetic Construct 89Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly1 5 10 15Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala65 70 75 80Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val 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 21090123PRTArtificial SequenceSynthetic Construct 90His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro1 5 10 15Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30Ser Tyr Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45Trp Val Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12091106PRTArtificial SequenceSynthetic Construct 91Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10592453PRTArtificial SequenceSynthetic Construct 92His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro1 5 10 15Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30Ser Tyr Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 35 40 45Trp Val Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp 50 55 60Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser65 70 75 80Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95Tyr Cys Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val145 150 155 160Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala225 230 235 240Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu305 310 315 320Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 355 360 365Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr385 390 395 400Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445Leu Ser Pro Gly Lys 45093213PRTArtificial SequenceSynthetic Construct 93Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 21094121PRTArtificial SequenceSynthetic Construct 94Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12095451PRTArtificial SequenceSynthetic Construct 95Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 45096110PRTArtificial SequenceSynthetic Construct 96Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys1 5 10 15Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

Trp Tyr 35 40 45Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His65 70 75 80Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 100 105 11097121PRTArtificial SequenceSynthetic Construct 97Glu 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 Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12098106PRTArtificial SequenceSynthetic Construct 98Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10599451PRTArtificial SequenceSynthetic Construct 99Glu 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 Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450100213PRTArtificial SequenceSynthetic Construct 100Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210101121PRTArtificial SequenceSynthetic Construct 101Glu 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 Phe Lys Asn Tyr 20 25 30Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12010210PRTArtificial SequenceSynthetic Construct 102Gly Phe Thr Phe Lys Asn Tyr Trp Met Thr1 5 10103107PRTArtificial SequenceSynthetic Construct 103Asp Ile Gln Met 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 Ser Ile Ser Asn Ser 20 25 30Leu Ile Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ser Ser Thr 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 Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105104451PRTArtificial SequenceSynthetic Construct 104Glu 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 Phe Lys Asn Tyr 20 25 30Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450105214PRTArtificial SequenceSynthetic Construct 105Asp Ile Gln Met 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 Ser Ile Ser Asn Ser 20 25 30Leu Ile Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ser Ser Ser Thr 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 Leu Gln Tyr Ala Thr Tyr Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Val 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 210106122PRTArtificial SequenceSynthetic Construct 106Glu 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 Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12010710PRTArtificial SequenceSynthetic Construct 107Gly Phe Thr Phe Thr Asp Tyr Trp Val Ser1 5 10108107PRTArtificial SequenceSynthetic Construct 108Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr 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 Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105109452PRTArtificial SequenceSynthetic Construct 109Glu 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 Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala225 230 235 240Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275

280 285Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Pro Gly Lys 450110214PRTArtificial SequenceSynthetic Construct 110Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Tyr Ala Ser Asn Arg Tyr Thr 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 Arg Ile Tyr Asn Ser Pro Pro 85 90 95Thr Phe Gly Gly Gly Thr Lys Val 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 210111122PRTArtificial SequenceSynthetic Construct 111Glu 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 Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe 50 55 60Lys Gly Arg Phe Thr Ile Ser Val Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120112452PRTArtificial SequenceSynthetic Construct 112Glu 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 Phe Thr Asp Tyr 20 25 30Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe 50 55 60Lys Gly Arg Phe Thr Ile Ser Val Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala225 230 235 240Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Pro Gly Lys 450113121PRTArtificial SequenceSynthetic Construct 113Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12011412PRTArtificial SequenceSynthetic Construct 114Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Leu Gly Tyr1 5 10115106PRTArtificial SequenceSynthetic Construct 115Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile 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 Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105116451PRTArtificial SequenceSynthetic Construct 116Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450117213PRTArtificial SequenceSynthetic Construct 117Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile 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 Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210118121PRTArtificial SequenceSynthetic Construct 118Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12011912PRTArtificial SequenceSynthetic Construct 119Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Gly Tyr1 5 10120451PRTArtificial SequenceSynthetic Construct 120Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450121121PRTArtificial SequenceSynthetic Construct 121Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Val Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12012212PRTArtificial SequenceSynthetic Construct 122Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr1 5 10123451PRTArtificial SequenceSynthetic Construct 123Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Val Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450124121PRTArtificial SequenceSynthetic Construct 124Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120125451PRTArtificial SequenceSynthetic Construct 125Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450126121PRTArtificial SequenceSynthetic Construct 126Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12012712PRTArtificial SequenceSynthetic Construct 127Gly His Tyr Ser Tyr Thr Ser Tyr Ser Phe Gly Tyr1 5 10128451PRTArtificial SequenceSynthetic Construct 128Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450129121PRTArtificial SequenceSynthetic Construct 129Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly Arg Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12013012PRTArtificial SequenceSynthetic Construct 130Gly Arg Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr1 5 10131451PRTArtificial SequenceSynthetic Construct 131Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly Arg Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450132121PRTArtificial SequenceSynthetic Construct 132Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val

35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Asn Ser Tyr Ser Phe Ala His Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12013312PRTArtificial SequenceSynthetic Construct 133Gly His Tyr Tyr Tyr Asn Ser Tyr Ser Phe Ala His1 5 10134451PRTArtificial SequenceSynthetic Construct 134Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Asn Ser Tyr Ser Phe Ala His Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450135121PRTArtificial SequenceSynthetic Construct 135Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ala Asn Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12013612PRTArtificial SequenceSynthetic Construct 136Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ala Asn1 5 10137451PRTArtificial SequenceSynthetic Construct 137Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ala Asn Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450138121PRTArtificial SequenceSynthetic Construct 138Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Ser Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12013912PRTArtificial SequenceSynthetic Construct 139Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Ser1 5 10140451PRTArtificial SequenceSynthetic Construct 140Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Ser Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450141121PRTArtificial SequenceSynthetic Construct 141Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Phe Ser Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12014212PRTArtificial SequenceSynthetic Construct 142Gly His Phe Ser Tyr Thr Ser Tyr Ser Phe Ala Tyr1 5 10143451PRTArtificial SequenceSynthetic Construct 143Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Phe Ser Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450144121PRTArtificial SequenceSynthetic Construct 144Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Phe Trp Gly 100

105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12014512PRTArtificial SequenceSynthetic Construct 145Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Phe1 5 10146451PRTArtificial SequenceSynthetic Construct 146Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Phe Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450147121PRTArtificial SequenceSynthetic Construct 147Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12014812PRTArtificial SequenceSynthetic Construct 148Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr1 5 10149451PRTArtificial SequenceSynthetic Construct 149Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450150121PRTArtificial SequenceSynthetic Construct 150Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120151451PRTArtificial SequenceSynthetic Construct 151Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450152121PRTArtificial SequenceSynthetic Construct 152Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12015312PRTArtificial SequenceSynthetic Construct 153Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Gly Tyr1 5 10154451PRTArtificial SequenceSynthetic Construct 154Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450155121PRTArtificial SequenceSynthetic Construct 155Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12015612PRTArtificial SequenceSynthetic Construct 156Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Tyr1 5 10157451PRTArtificial SequenceSynthetic Construct 157Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40

45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450158121PRTArtificial SequenceSynthetic Construct 158Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12015912PRTArtificial SequenceSynthetic Construct 159Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr1 5 10160451PRTArtificial SequenceSynthetic Construct 160Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450161121PRTArtificial SequenceSynthetic Construct 161Glu 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 Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120162451PRTArtificial SequenceSynthetic Construct 162Glu 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 Phe Ser Asn Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450163121PRTArtificial SequenceSynthetic Construct 163Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120164451PRTArtificial SequenceSynthetic Construct 164Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450165121PRTArtificial SequenceSynthetic Construct 165Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120166451PRTArtificial SequenceSynthetic Construct 166Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450167121PRTArtificial SequenceSynthetic Construct 167Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asp Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12016817PRTArtificial SequenceSynthetic Construct 168Ser Ile Thr Pro Asp Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly169451PRTArtificial SequenceSynthetic Construct 169Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asp Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450170121PRTArtificial SequenceSynthetic Construct 170Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12017117PRTArtificial SequenceSynthetic Construct 171Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly172451PRTArtificial SequenceSynthetic Construct 172Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450173121PRTArtificial SequenceSynthetic Construct 173Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12017417PRTArtificial SequenceSynthetic Construct 174Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly175451PRTArtificial SequenceSynthetic Construct 175Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450176121PRTArtificial SequenceSynthetic Construct 176Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12017712PRTArtificial SequenceSynthetic Construct 177Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr1 5 10178451PRTArtificial SequenceSynthetic Construct 178Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450179121PRTArtificial SequenceSynthetic Construct 179Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Leu Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12018017PRTArtificial SequenceSynthetic Construct 180Ser Ile Thr Pro Leu Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly181451PRTArtificial SequenceSynthetic Construct 181Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Leu Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450182121PRTArtificial SequenceSynthetic Construct 182Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120183451PRTArtificial SequenceSynthetic Construct 183Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450184121PRTArtificial SequenceSynthetic Construct 184Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120185451PRTArtificial SequenceSynthetic Construct 185Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450186121PRTArtificial SequenceSynthetic Construct 186Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ala Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12018712PRTArtificial SequenceSynthetic Construct 187Gly His Tyr Tyr Tyr Thr Ala Tyr Ser Leu Gly Tyr1 5 10188451PRTArtificial SequenceSynthetic Construct 188Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ala Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290

295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450189106PRTArtificial SequenceSynthetic Construct 189Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Asp His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10519011PRTArtificial SequenceSynthetic Construct 190Lys Ala Ser Gln Asn Ile Asn Asp His Leu Asp1 5 10191213PRTArtificial SequenceSynthetic Construct 191Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Asp His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210192106PRTArtificial SequenceSynthetic Construct 192Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asp Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10519311PRTArtificial SequenceSynthetic Construct 193Lys Ala Ser Gln Asn Ile Asp Lys His Leu Asp1 5 10194213PRTArtificial SequenceSynthetic Construct 194Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asp Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210195106PRTArtificial SequenceSynthetic Construct 195Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Asp 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1051967PRTArtificial SequenceSynthetic Construct 196Phe Thr Asn Asn Leu Gln Asp1 5197213PRTArtificial SequenceSynthetic Construct 197Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Asp 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210198106PRTArtificial SequenceSynthetic Construct 198Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Glu 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1051997PRTArtificial SequenceSynthetic Construct 199Phe Thr Asn Asn Leu Gln Glu1 5200213PRTArtificial SequenceSynthetic Construct 200Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Glu 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 Phe Gln Tyr Asn Asn Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210201121PRTArtificial SequenceSynthetic Construct 201Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12020217PRTArtificial SequenceSynthetic Construct 202Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly203451PRTArtificial SequenceSynthetic Construct 203Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450204121PRTArtificial SequenceSynthetic Construct 204Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12020517PRTArtificial SequenceSynthetic Construct 205Ser Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly206451PRTArtificial SequenceSynthetic Construct 206Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450207106PRTArtificial SequenceSynthetic Construct 207Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Gln Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 1052088PRTArtificial SequenceSynthetic Construct 208Phe Gln Tyr Asn Gln Gly Trp Thr1 5209213PRTArtificial SequenceSynthetic Construct 209Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Ile Asn Lys His 20 25 30Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Phe Thr Asn Asn Leu Gln Thr 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 Phe Gln Tyr Asn Gln Gly Trp Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210210121PRTArtificial SequenceSynthetic Construct 210Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12021117PRTArtificial SequenceSynthetic Construct 211Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly212451PRTArtificial SequenceSynthetic Construct 212Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450213121PRTArtificial SequenceSynthetic Construct 213Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12021417PRTArtificial SequenceSynthetic Construct 214Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val Lys1 5 10 15Gly215451PRTArtificial SequenceSynthetic Construct 215Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450216121PRTArtificial SequenceSynthetic Construct 216Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12021717PRTArtificial SequenceSynthetic Construct 217Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly218451PRTArtificial SequenceSynthetic Construct 218Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450219121PRTArtificial SequenceSynthetic Construct 219Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12022017PRTArtificial SequenceSynthetic Construct 220Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Glu Ser Val Lys1 5 10 15Gly221451PRTArtificial SequenceSynthetic Construct 221Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450222121PRTArtificial SequenceSynthetic Construct 222Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12022317PRTArtificial SequenceSynthetic Construct 223Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly224451PRTArtificial SequenceSynthetic Construct 224Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450225121PRTArtificial SequenceSynthetic Construct 225Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12022617PRTArtificial SequenceSynthetic Construct 226Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val Lys1 5 10 15Gly227451PRTArtificial SequenceSynthetic Construct 227Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450228121PRTArtificial SequenceSynthetic Construct 228Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12022917PRTArtificial SequenceSynthetic Construct 229Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Glu Ser Val Lys1 5 10 15Gly230451PRTArtificial SequenceSynthetic Construct 230Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450231121PRTArtificial SequenceSynthetic Construct 231Glu 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 Phe Ser Ser Tyr 20 25

30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12023217PRTArtificial SequenceSynthetic Construct 232Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Glu Ser Val Lys1 5 10 15Gly233451PRTArtificial SequenceSynthetic Construct 233Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450234121PRTArtificial SequenceSynthetic Construct 234Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115 12023517PRTArtificial SequenceSynthetic Construct 235Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Asp Ser Val Lys1 5 10 15Gly236451PRTArtificial SequenceSynthetic Construct 236Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450237329PRTArtificial SequenceSynthetic Construct 237Ala 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 95Lys 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 Lys 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 Glu Glu225 230 235 240Met 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 325238329PRTArtificial SequenceSynthetic Construct 238Ala 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 95Lys 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 Lys 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 Glu Glu225 230 235 240Met 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 Leu His Glu Ala Leu His Ser His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly 32523919PRTArtificial SequenceSynthetic Construct 239Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly1 5 10 15Val His Ser240106PRTArtificial SequenceSynthetic Construct 240Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu1 5 10 15Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 20 25 30Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly65 70 75 80Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 85 90 95Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 100 105241450PRTArtificial SequenceSynthetic Construct 241Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 450242450PRTArtificial SequenceSynthetic Construct 242Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 450243106PRTArtificial SequenceSynthetic Construct 243Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu1 5 10 15Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 20 25 30Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 35 40 45Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 50 55 60Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly65 70 75 80Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr 85 90 95Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 100 105244450PRTArtificial SequenceSynthetic Construct 244Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 420 425 430His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 450245450PRTArtificial SequenceSynthetic Construct 245Glu 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 Phe Ser Ser Tyr 20 25 30Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly225 230 235 240Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 420 425 430His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 450246117PRTArtificial SequenceSynthetic Construct 246Gln Val Leu Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Thr Val Lys Val Ser Cys Lys Ala Ser Gly Ser Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Arg Tyr Asn Trp Lys Ser Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser 11524710PRTArtificial SequenceSynthetic Construct 247Gly Ser Thr Phe Thr Gly Tyr Tyr Met His1 5 1024817PRTArtificial SequenceSynthetic Construct 248Trp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly2498PRTArtificial SequenceSynthetic Construct 249Glu Leu Arg Tyr Asn Trp Lys Ser1 5250108PRTArtificial SequenceSynthetic Construct 250Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Arg Pro 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser 50 55 60Gly Asn Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Ser Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 10525112PRTArtificial SequenceSynthetic Construct 251Arg Ala Ser Gln Ser Val Gly Arg Pro Tyr Leu Ala1 5 102527PRTArtificial SequenceSynthetic Construct 252Gly Ala Ser Ser Arg Ala Thr1 52539PRTArtificial SequenceSynthetic Construct 253Gln Gln Tyr Asp Asn Ser Pro Tyr Thr1 5254447PRTArtificial SequenceSynthetic Construct 254Gln Val Leu Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Thr Val Lys Val Ser Cys Lys Ala Ser Gly Ser Thr Phe Thr Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Leu Arg Tyr Asn Trp Lys Ser Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val225 230 235 240Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys305 310 315 320Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser385 390 395 400Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 44525510PRTArtificial SequenceSynthetic Construct 255Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys1 5 10256215PRTArtificial SequenceSynthetic Construct 256Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Arg Pro 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser 50 55 60Gly Asn Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Ser Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr

His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 21525711PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be K, S, H, T, Q, W, Y, F or RMISC_FEATURE(2)..(2)Xaa can be A, S or GMISC_FEATURE(3)..(3)Xaa can be S, A or DMISC_FEATURE(4)..(4)Xaa can be Q, H, S, E, D, or TMISC_FEATURE(5)..(5)Xaa can be N, S, D, R, K, Y, E or GMISC_FEATURE(6)..(6)Xaa can be I or VMISC_FEATURE(7)..(7)Xaa can be N, F, K, H, R, L, M, I, E or SMISC_FEATURE(8)..(8)Xaa can be K, Q, E, R, W, F, Y, N, A, S or HMISC_FEATURE(9)..(9)Xaa can be H, F, R or WMISC_FEATURE(10)..(10)Xaa can be L, I, V or AMISC_FEATURE(11)..(11)Xaa can be D, S or A 257Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 1025811PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be K or RMISC_FEATURE(4)..(4)Xaa can be Q or HMISC_FEATURE(5)..(5)Xaa can be N or SMISC_FEATURE(6)..(6)Xaa can be I or VMISC_FEATURE(7)..(7)Xaa can be N or SMISC_FEATURE(8)..(8)Xaa can be K, S or N 258Xaa Ala Ser Xaa Xaa Xaa Xaa Xaa His Leu Asp1 5 1025911PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be K or RMISC_FEATURE(4)..(4)Xaa can be Q or HMISC_FEATURE(5)..(5)Xaa can be N or SMISC_FEATURE(7)..(7)Xaa can be N or SMISC_FEATURE(8)..(8)Xaa can be K or S 259Xaa Ala Ser Xaa Xaa Ile Xaa Xaa His Leu Asp1 5 1026011PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be K or RMISC_FEATURE(5)..(5)Xaa can be N or SMISC_FEATURE(7)..(7)Xaa can be N or SMISC_FEATURE(8)..(8)Xaa can be K or S 260Xaa Ala Ser Gln Xaa Ile Xaa Xaa His Leu Asp1 5 102617PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be F, W, Y, D, E, G or SMISC_FEATURE(2)..(2)Xaa can be T, G, R, A, N or VMISC_FEATURE(3)..(3)Xaa can be N, W, Y, R, F, K,Q, E, D, H or SMISC_FEATURE(4)..(4)Xaa can be N, F, Y, I, M, Q, L, A, R, G, P or SMISC_FEATURE(5)..(5)Xaa can be L, I, V or RMISC_FEATURE(6)..(6)Xaa can be Q, R, K, F, H, L, W, Y, A or EMISC_FEATURE(7)..(7)Xaa can be T, S, N or Y 261Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 52627PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be F or YMISC_FEATURE(2)..(2)Xaa can be A or TMISC_FEATURE(3)..(3)Xaa can be N or SMISC_FEATURE(4)..(4)Xaa can be N or SMISC_FEATURE(6)..(6)Xaa can be Q or EMISC_FEATURE(7)..(7)Xaa can be T or S 262Xaa Xaa Xaa Xaa Leu Xaa Xaa1 52637PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa cn be T or AMISC_FEATURE(3)..(3)Xaa cn be N or SMISC_FEATURE(4)..(4)Xaa cn be N or SMISC_FEATURE(7)..(7)Xaa cn be T or S 263Phe Xaa Xaa Xaa Leu Gln Xaa1 52647PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa can be A or TMISC_FEATURE(3)..(3)Xaa can be N or SMISC_FEATURE(7)..(7)Xaa can be T or S 264Phe Xaa Xaa Asn Leu Gln Xaa1 52658PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be F, Q, W, H or AMISC_FEATURE(2)..(2)Xaa can be Q, S, T or AMISC_FEATURE(3)..(3)Xaa can be Y, H or FMISC_FEATURE(4)..(4)Xaa can be N, W, F, Y, R, K, H or DMISC_FEATURE(5)..(5)Xaa can be N, S,Q, W, K, R, H, Y, D, G, T or VMISC_FEATURE(6)..(6)Xaa can be G, R, P, K, W, F, I, N or QMISC_FEATURE(7)..(7)Xaa can be W or HMISC_FEATURE(8)..(8)Xaa can be T, S or Q 265Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 52668PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be F or QMISC_FEATURE(3)..(3)Xaa can be Y or FMISC_FEATURE(4)..(4)Xaa can be N or YMISC_FEATURE(5)..(5)Xaa can be N, S, Q, R or Y 266Xaa Gln Xaa Xaa Xaa Gly Trp Thr1 52678PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be F or QMISC_FEATURE(4)..(4)Xaa can be N or YMISC_FEATURE(5)..(5)Xaa can be N, S, Q or R 267Xaa Gln Tyr Xaa Xaa Gly Trp Thr1 52688PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be F or QMISC_FEATURE(4)..(4)Xaa can be N or YMISC_FEATURE(5)..(5)Xaa can be N, S or Q 268Xaa Gln Tyr Xaa Xaa Gly Trp Thr1 526910PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa can be F, Y or HMISC_FEATURE(3)..(3)Xaa can be T, Q, N, S, E, D, R or YMISC_FEATURE(4)..(4)Xaa can be F, Y or HMISC_FEATURE(5)..(5)Xaa can be S, E, D, T or WMISC_FEATURE(6)..(6)Xaa can be N, S, T, E, D, H, L, I, Y, R, K or GMISC_FEATURE(7)..(7)Xaa can be Y, F or HMISC_FEATURE(8)..(8)Xaa can be W, H, Y, A or GMISC_FEATURE(9)..(9)Xaa can be M, E, Q or IMISC_FEATURE(10)..(10)Xaa can be Y, F, H or N 269Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 1027010PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(3)..(3)Xaa can be T or EMISC_FEATURE(5)..(5)Xaa can be S or EMISC_FEATURE(6)..(6)Xaa can be N or S 270Gly Phe Xaa Phe Xaa Xaa Tyr Trp Met Tyr1 5 1027110PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(6)..(6)Xaa can be N or S 271Gly Phe Thr Phe Ser Xaa Tyr Trp Met Tyr1 5 1027217PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be S, A or TMISC_FEATURE(2)..(2)Xaa can be I or VMISC_FEATURE(3)..(3)Xaa can be T, H, N or SMISC_FEATURE(4)..(4)Xaa can be P, N, F or MMISC_FEATURE(5)..(5)Xaa can be N, I, D, Y or WMISC_FEATURE(6)..(6)Xaa can be G or AMISC_FEATURE(7)..(7)Xaa can be G, H, D, E, R, K, Y or SMISC_FEATURE(8)..(8)Xaa can be N, Y, D, E, Q or HMISC_FEATURE(9)..(9)Xaa can be T, K, E, S, I, A or DMISC_FEATURE(10)..(10)Xaa can be Y, H or WMISC_FEATURE(11)..(11)Xaa can be Y, F or HMISC_FEATURE(12)..(12)Xaa can be P, V, L, D or SMISC_FEATURE(13)..(13)Xaa can be D, E, Q or AMISC_FEATURE(14)..(14)Xaa can be S, A, N or DMISC_FEATURE(15)..(15)Xaa can be V, D or TMISC_FEATURE(16)..(16)Xaa can be K, N, D, S, E or Q 272Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Gly27317PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be S or AMISC_FEATURE(3)..(3)Xaa can be T or NMISC_FEATURE(4)..(4)Xaa can be P or NMISC_FEATURE(5)..(5)Xaa can be N or DMISC_FEATURE(6)..(6)Xaa can be G or AMISC_FEATURE(7)..(7)Xaa can be G, S or HMISC_FEATURE(8)..(8)Xaa can be N, D or EMISC_FEATURE(9)..(9)Xaa can be T, K, D or EMISC_FEATURE(12)..(12)Xaa can be P, V or LMISC_FEATURE(13)..(13)Xaa can be D or EMISC_FEATURE(16)..(16)Xaa can be K or Q 273Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Tyr Xaa Xaa Ser Val Xaa1 5 10 15Gly27417PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be S or AMISC_FEATURE(3)..(3)Xaa can be T or NMISC_FEATURE(4)..(4)Xaa can be P or NMISC_FEATURE(5)..(5)Xaa can be N or DMISC_FEATURE(6)..(6)Xaa can be G or AMISC_FEATURE(7)..(7)Xaa can be G or SMISC_FEATURE(8)..(8)Xaa can be N or EMISC_FEATURE(9)..(9)Xaa can be T, K or DMISC_FEATURE(12)..(12)Xaa can be P, V or LMISC_FEATURE(13)..(13)Xaa can be D or E 274Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Tyr Xaa Xaa Ser Val Lys1 5 10 15Gly27517PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be S or AMISC_FEATURE(5)..(5)Xaa can be N or DMISC_FEATURE(6)..(6)Xaa can be G or AMISC_FEATURE(7)..(7)Xaa can be G or SMISC_FEATURE(8)..(8)Xaa can be N or EMISC_FEATURE(9)..(9)Xaa can be T, K or DMISC_FEATURE(12)..(12)Xaa can be P or VMISC_FEATURE(13)..(13)Xaa can be D or E 275Xaa Ile Thr Pro Xaa Xaa Xaa Xaa Xaa Tyr Tyr Xaa Xaa Ser Val Lys1 5 10 15Gly27612PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be G, S, A, T or DMISC_FEATURE(2)..(2)Xaa can be H, K, R or YMISC_FEATURE(3)..(3)Xaa can be Y, H, F or SMISC_FEATURE(4)..(4)Xaa can be Y, H, R or SMISC_FEATURE(5)..(5)Xaa can be Y, H, W, F, R or SMISC_FEATURE(6)..(6)Xaa can be T, N, V, I, S, A, G or YMISC_FEATURE(7)..(7)Xaa can be S, N, A, Q, D, G, R or YMISC_FEATURE(8)..(8)Xaa can be Y, W,H, F, G, D or NMISC_FEATURE(9)..(9)Xaa can be S, A or GMISC_FEATURE(10)..(10)Xaa can be L, M, F or IMISC_FEATURE(11)..(11)Xaa can be G, A, Y, S or DMISC_FEATURE(12)..(12)Xaa can be Y, N, S, F, E, D, H, I or V 276Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 1027712PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa can be H, R or YMISC_FEATURE(3)..(3)Xaa can be Y or FMISC_FEATURE(4)..(4)Xaa can be Y or SMISC_FEATURE(5)..(5)Xaa can be Y or HMISC_FEATURE(6)..(6)Xaa can be T, S or NMISC_FEATURE(7)..(7)Xaa can be S or AMISC_FEATURE(10)..(10)Xaa can be L, F or IMISC_FEATURE(11)..(11)Xaa can be G, S or AMISC_FEATURE(12)..(12)Xaa can be Y, H, N, S or F 277Gly Xaa Xaa Xaa Xaa Xaa Xaa Tyr Ser Xaa Xaa Xaa1 5 1027812PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa can be H or YMISC_FEATURE(4)..(4)Xaa can be Y or SMISC_FEATURE(5)..(5)Xaa can be Y or HMISC_FEATURE(6)..(6)Xaa can be T, S or NMISC_FEATURE(7)..(7)Xaa can be S or AMISC_FEATURE(10)..(10)Xaa can be L or FMISC_FEATURE(11)..(11)Xaa can be G or S 278Gly Xaa Tyr Xaa Xaa Xaa Xaa Tyr Ser Xaa Xaa Tyr1 5 1027912PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(4)..(4)Xaa can be Y or SMISC_FEATURE(6)..(6)Xaa can be T or SMISC_FEATURE(10)..(10)Xaa can be L or FMISC_FEATURE(11)..(11)Xaa can be G or S 279Gly His Tyr Xaa Tyr Xaa Ser Tyr Ser Xaa Xaa Tyr1 5 1028011PRTArtificial SequenceSynthetic Construct 280Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1 5 102817PRTArtificial SequenceSynthetic Construct 281Ala Ala Ser Ser Leu Gln Ser1 52827PRTArtificial SequenceSynthetic Construct 282Gln Gln Ser Tyr Ser Thr Pro1 528316PRTArtificial SequenceSynthetic Construct 283Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Tyr1 5 10 152847PRTArtificial SequenceSynthetic Construct 284Glu Val Ser Asn Arg Phe Ser1 52857PRTArtificial SequenceSynthetic Construct 285Met Gln Ser Ile Gln Leu Pro1 528616PRTArtificial SequenceSynthetic Construct 286Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn1 5 10 152877PRTArtificial SequenceSynthetic Construct 287Lys Val Ser Asn Arg Asp Ser1 52887PRTArtificial SequenceSynthetic Construct 288Met Gln Gly Thr His Trp Pro1 528917PRTArtificial SequenceSynthetic Construct 289Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu1 5 10 15Ala2907PRTArtificial SequenceSynthetic Construct 290Trp Ala Ser Thr Arg Glu Ser1 52917PRTArtificial SequenceSynthetic Construct 291Gln Gln Tyr Tyr Ser Thr Pro1 529211PRTArtificial SequenceSynthetic Construct 292Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala1 5 102937PRTArtificial SequenceSynthetic Construct 293Asp Ala Ser Ser Leu Glu Ser1 52947PRTArtificial SequenceSynthetic Construct 294Gln Gln Tyr Asn Ser Tyr Ser1 529511PRTArtificial SequenceSynthetic Construct 295Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn1 5 102967PRTArtificial SequenceSynthetic Construct 296Asp Ala Ser Asn Leu Glu Thr1 52977PRTArtificial SequenceSynthetic Construct 297Gln Gln Tyr Asp Asn Leu Pro1 529811PRTArtificial SequenceSynthetic Construct 298Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala1 5 102997PRTArtificial SequenceSynthetic Construct 299Ala Ala Ser Thr Leu Gln Ser1 53007PRTArtificial SequenceSynthetic Construct 300Gln Gln Leu Asn Ser Tyr Pro1 530111PRTArtificial SequenceSynthetic Construct 301Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala1 5 103027PRTArtificial SequenceSynthetic Construct 302Gly Ala Ser Thr Arg Ala Thr1 53037PRTArtificial SequenceSynthetic Construct 303Gln Gln Tyr Asn Asn Trp Pro1 530411PRTArtificial SequenceSynthetic Construct 304Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala1 5 103057PRTArtificial SequenceSynthetic Construct 305Asp Ala Ser Asn Arg Ala Thr1 53067PRTArtificial SequenceSynthetic Construct 306Gln Gln Arg Ser Asn Trp Pro1 530712PRTArtificial SequenceSynthetic Construct 307Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 103087PRTArtificial SequenceSynthetic Construct 308Gly Ala Ser Ser Arg Ala Thr1 53097PRTArtificial SequenceSynthetic Construct 309Gln Gln Tyr Gly Ser Ser Pro1 531016PRTArtificial SequenceSynthetic Construct 310Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp1 5 10 153117PRTArtificial SequenceSynthetic Construct 311Leu Gly Ser Asn Arg Ala Ser1 53127PRTArtificial SequenceSynthetic Construct 312Met Gln Ala Leu Gln Thr Pro1 531311PRTArtificial SequenceSynthetic Construct 313Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser1 5 103147PRTArtificial SequenceSynthetic Construct 314Gly Lys Asn Asn Arg Pro Ser1 53159PRTArtificial SequenceSynthetic Construct 315Asn Ser Arg Asp Ser Ser Gly Asn His1 531614PRTArtificial SequenceSynthetic Construct 316Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His1 5 103177PRTArtificial SequenceSynthetic Construct 317Gly Asn Ser Asn Arg Pro Ser1 53189PRTArtificial SequenceSynthetic Construct 318Gln Ser Tyr Asp Ser Ser Leu Ser Gly1 531913PRTArtificial SequenceSynthetic Construct 319Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn Tyr Val Gln1 5 103207PRTArtificial SequenceSynthetic Construct 320Glu Asp Asn Gln Arg Pro Ser1 53217PRTArtificial SequenceSynthetic Construct 321Gln Ser Tyr Asp Ser Ser Asn1 532212PRTArtificial SequenceSynthetic Construct 322Thr Gly Ser Ser Ser Gly Gly Ser Tyr Tyr Val Ser1 5 1032314PRTArtificial SequenceSynthetic Construct 323Thr Gly Ser Ser Ser Asp Val Gly Gly Ser Tyr Tyr Val Ser1 5 103248PRTArtificial SequenceSynthetic Construct 324Glu Asn Asp Ser Asn Arg Pro Ser1 532512PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(6)..(6)Xaa can be S or DMISC_FEATURE(8)..(8)Xaa can be Q or G 325Glu Asp Ser Asn Arg Xaa Lys Xaa Gln Lys Pro Ser1 5 103268PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N or T 326Gln Ser Trp Asp Ser Ser Ala Xaa1 532711PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N or TMISC_FEATURE(10)..(10)Xaa can be F or VMISC_FEATURE(11)..(11)Xaa can be G or V 327Gln Ser Trp Asp Ser Ser Ala Xaa Phe Xaa Xaa1 5 1032813PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(11)..(11)Xaa can be A or YMISC_FEATURE(13)..(13)Xaa can be N, H or S 328Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Xaa Val Xaa1 5 1032914PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(12)..(12)Xaa can be A or YMISC_FEATURE(14)..(14)Xaa can be N, H or S 329Ser Gly Ser Ser Ser Asn Ile Ile Gly Asn Asn Xaa Val Xaa1 5 103307PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(4)..(4)Xaa can be K, N or Q 330Gly Asn Asn Xaa Arg Pro Ser1 53319PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N or S 331Ala Ala Trp Asp Asp Ser Leu Xaa Gly1 533212PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(5)..(5)Xaa can be A or VMISC_FEATURE(8)..(8)Xaa can be K or S 332Cys Ser Gly Asp Xaa Leu Gly Xaa Lys Tyr Ala His1 5 103337PRTArtificial SequenceSynthetic Construct 333Lys Asp Ser Glu Arg Pro Ser1 53348PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N, D, T or A 334Gln Ser Trp Asp Ser Ser Gly Xaa1 53359PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N, D, T, or A 335Gln Ser Trp Asp Ser Ser Gly Xaa His1 533617PRTArtificial SequenceSynthetic Construct 336Arg Ala Ser Gln Ser Leu Leu His Ser Asp Gly Ile Ser Ser Tyr Leu1 5 10 15Ala33711PRTArtificial SequenceSynthetic Construct 337Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala1 5 103387PRTArtificial SequenceSynthetic Construct 338Ala Ala Ser Ser Arg Ala Ser1 53397PRTArtificial SequenceSynthetic Construct 339Gln Gln Tyr Asn Ser Tyr Pro1 534011PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N or S 340Arg Ala Ser Gln Gly Ile Ser Xaa Tyr Leu Ala1 5 103417PRTArtificial SequenceSynthetic Construct 341Ala Ala Ser Ser Leu Gln Ser1 53427PRTArtificial SequenceSynthetic Construct 342Gln Gln Tyr Asn Ser Tyr Pro1 534316PRTArtificial SequenceSynthetic Construct 343Arg Ser Ser Gln Ser Leu Leu His Ser Asp Gly Asn Thr Tyr Leu Asp1 5

10 1534417PRTArtificial SequenceSynthetic Construct 344Arg Ser Ser Gln Ser Leu Leu His Ser Asp Asp Gly Asn Thr Tyr Leu1 5 10 15Asp3457PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa can be K or TMISC_FEATURE(2)..(2)Xaa can be V or IMISC_FEATURE(6)..(6)Xaa can be A or F 345Xaa Xaa Ser Asn Arg Xaa Ser1 53467PRTArtificial SequenceSynthetic Construct 346Met Gln Ala Thr Gln Phe Pro1 534712PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(6)..(6)Xaa can be S or VMISC_FEATURE(7)..(7)Xaa can be S or V 347Arg Ala Ser Gln Ser Xaa Xaa Ser Ser Tyr Leu Ala1 5 103487PRTArtificial SequenceSynthetic Construct 348Gly Ala Ser Thr Arg Ala Thr1 53497PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(4)..(4)Xaa can be S, N, G or H 349Gln Gln Tyr Xaa Asn Trp Pro1 535011PRTArtificial SequenceSynthetic Construct 350Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly1 5 103517PRTArtificial SequenceSynthetic Construct 351Ala Ala Ser Ser Leu Gln Ser1 53529PRTArtificial SequenceSynthetic Construct 352Leu Gln Asp Tyr Asn Tyr Pro Leu Thr1 535310PRTArtificial SequenceSynthetic Construct 353Gly Phe Thr Phe Ser Ser Tyr Trp Met Ser1 5 1035418PRTArtificial SequenceSynthetic Construct 354Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val1 5 10 15Lys Gly35510PRTArtificial SequenceSynthetic Construct 355Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser1 5 1035617PRTArtificial SequenceSynthetic Construct 356Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly35710PRTArtificial SequenceSynthetic Construct 357Gly Gly Ser Ile Ser Ser Tyr Tyr Trp Ser1 5 1035817PRTArtificial SequenceSynthetic Construct 358Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys1 5 10 15Ser35910PRTArtificial SequenceSynthetic Construct 359Gly Tyr Thr Phe Thr Gly Tyr Tyr Met His1 5 1036018PRTArtificial SequenceSynthetic Construct 360Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe1 5 10 15Gln Gly36110PRTArtificial SequenceSynthetic Construct 361Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser1 5 1036218PRTArtificial SequenceSynthetic Construct 362Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe1 5 10 15Gln Gly36310PRTArtificial SequenceSynthetic Construct 363Gly Tyr Thr Gly Thr Ser Tyr Tyr Met His1 5 1036418PRTArtificial SequenceSynthetic Construct 364Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe1 5 10 15Gln Gly36510PRTArtificial SequenceSynthetic Construct 365Gly Phe Thr Phe Ser Ser Tyr Gly Met His1 5 1036618PRTArtificial SequenceSynthetic Construct 366Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val1 5 10 15Lys Gly36710PRTArtificial SequenceSynthetic Construct 367Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn1 5 1036818PRTArtificial SequenceSynthetic Construct 368Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val1 5 10 15Lys Gly36910PRTArtificial SequenceSynthetic Construct 369Gly Phe Thr Phe Ser Asn Ala Trp Met Ser1 5 1037020PRTArtificial SequenceSynthetic Construct 370Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala1 5 10 15Pro Val Lys Gly 2037112PRTArtificial SequenceSynthetic Construct 371Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr Trp Gly1 5 1037217PRTArtificial SequenceSynthetic Construct 372Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys1 5 10 15Ser37312PRTArtificial SequenceSynthetic Construct 373Gly Gly Ser Ile Ser Ser Gly Asp Tyr Tyr Trp Ser1 5 1037417PRTArtificial SequenceSynthetic Construct 374Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys1 5 10 15Ser37510PRTArtificial SequenceSynthetic Construct 375Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly1 5 1037618PRTArtificial SequenceSynthetic Construct 376Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe1 5 10 15Gln Gly37710PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(10)..(10)Xaa can be H or S 377Gly Phe Thr Phe Ser Ser Tyr Ala Met Xaa1 5 1037812PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(10)..(10)Xaa can be H or S 378Gly Phe Thr Phe Ser Ser Tyr Ala Met Xaa Trp Ser1 5 1037918PRTArtificial SequenceSynthetic Construct 379Gly Trp Ile Ser Pro Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val1 5 10 15Lys Gly38020PRTArtificial SequenceSynthetic Construct 380Gly Trp Ile Ser Pro Lys Ala Asn Gly Gly Ser Thr Tyr Tyr Ala Asp1 5 10 15Ser Val Lys Gly 2038110PRTArtificial SequenceSynthetic Construct 381Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser1 5 1038218PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be G or S 382Ser Val Ile Ser Ser Asp Gly Xaa Ser Thr Tyr Tyr Ala Asp Ser Val1 5 10 15Lys Gly38320PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(10)..(10)Xaa can be G or S 383Ser Val Ile Ser Ser Lys Ala Asp Gly Xaa Ser Thr Tyr Tyr Ala Asp1 5 10 15Ser Val Lys Gly 2038410PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(10)..(10)Xaa can be S, G or H 384Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Xaa1 5 1038518PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(2)..(2)Xaa can be R, I or S 385Gly Xaa Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe1 5 10 15Gln Gly38610PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be A or YMISC_FEATURE(9)..(9)Xaa can be I or M 386Gly Tyr Thr Phe Thr Ser Tyr Xaa Xaa His1 5 1038717PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(6)..(6)Xaa can be G or Y 387Gly Trp Ile Asn Pro Xaa Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe1 5 10 15Gln38812PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(8)..(8)Xaa can be N or Y 388Gly Gly Ser Ile Ser Ser Gly Xaa Tyr Tyr Trp Ser1 5 1038917PRTArtificial SequenceSynthetic Construct 389Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys1 5 10 15Ser39010PRTArtificial SequenceSynthetic Construct 390Gly Phe Thr Phe Ser Ser Tyr Gly Met His1 5 1039117PRTArtificial SequenceSynthetic Construct 391Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Ala Lys1 5 10 15Gly39210PRTArtificial SequenceSynthetic Construct 392Gly Phe Thr Phe Ser Ser Tyr Ala Met His1 5 1039317PRTArtificial SequenceSynthetic Construct 393Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly39410PRTArtificial SequenceSynthetic Construct 394Gly Phe Thr Phe Asp Asp Tyr Ala Met His1 5 1039517PRTArtificial SequenceSynthetic Construct 395Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys1 5 10 15Gly396270PRTArtificial SequenceSynthetic Construct 396Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys1 5 10 15Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu65 70 75 80Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu145 150 155 160Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile225 230 235 240Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270397165PRTArtificial SequenceSynthetic Construct 397Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu Ser1 5 10 15Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Lys Asp Lys Val 35 40 45Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly Asp 50 55 60Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp65 70 75 80Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Arg 100 105 110Ser Phe Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr Ser 130 135 140Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile His145 150 155 160His His His His His 165398639DNAArtificial SequenceSynthetic Construct 398gacatccaga tgacccagtc cccctcttct ctgtctgcct ctgtgggcga cagagtgacc 60atcacctgta aagcaagtca gaatattaat aaacacttag actggtatca gcagaagcct 120ggcaaggctc ccaagctgct gatctacttt acaaacaatt tacaaactgg cgtgccttcc 180agattctccg gctctggctc tggcaccgat ttcaccctga ccatctcctc cctccagcct 240gaggatttcg ccacctacta ctgctttcag tataaccagg ggtggacctt tggcggcgga 300acaaaggtgg agatcaagcg tacggtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600agctcgcccg tcacaaagag cttcaacagg ggagagtgt 6393991350DNAArtificial SequenceSynthetic Construct 399gaggtgcagc tggtggagtc tggcggcgga ctggtgcagc ctggcggctc tctgagactg 60tcttgtgccg cctccggctt caccttcagt tcctactgga tgtactgggt gaggcaggcc 120cctggcaagg gcctggagtg ggtggccgcc attactccta atgccggtga ggactactat 180ccagagtctg tgaaaggccg gttcaccatc tccagggaca acgccaagaa ctccctgtac 240ctccagatga actccctgag ggccgaggat accgccgtgt actactgtgc cagaggccat 300tattactata ccagctattc gcttggatac tggggccagg gcaccctggt gaccgtgtcc 360tctgcgtcga ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga agccgctggg 720gcaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc gtgttgcatg aggctctgca ctcccactac 1320acgcagaaga gcctctccct gtccccggga 1350400639DNAArtificial SequenceSynthetic Construct 400gacatccaga tgacccagtc cccctcttct ctgtctgcct ctgtgggcga cagagtgacc 60atcacctgta aagcaagtca gaatattaat aaacacttag actggtatca gcagaagcct 120ggcaaggctc ccaagctgct gatctacttt acaaacaatt tacaaactgg cgtgccttcc 180agattctccg gctctggctc tggcaccgat ttcaccctga ccatctcctc cctccagcct 240gaggatttcg ccacctacta ctgctttcag tataacaatg ggtggacctt tggcggcgga 300acaaaggtgg agatcaagcg tacggtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600agctcgcccg tcacaaagag cttcaacagg ggagagtgt 6394011350DNAArtificial SequenceSynthetic Construct 401gaggtgcagc tggtggagtc tggcggcgga ctggtgcagc ctggcggctc tctgagactg 60tcttgtgccg cctccggctt caccttcagt tcctactgga tgtactgggt gaggcaggcc 120cctggcaagg gcctggagtg ggtggcctcc attactccta atgccggtga ggactactat 180ccagactctg tgaaaggccg gttcaccatc tccagggaca acgccaagaa ctccctgtac 240ctccagatga actccctgag ggccgaggat accgccgtgt actactgtgc cagaggccat 300tattactata ccagctattc gcttggatac tggggccagg gcaccctggt gaccgtgtcc 360tctgcgtcga ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga agccgctggg 720gcaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc gtgttgcatg aggctctgca ctcccactac 1320acgcagaaga gcctctccct gtccccggga 135040219PRTArtificial SequenceSynthetic Construct 402Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly1 5 10 15Ala His Ser403452PRTArtificial SequenceSynthetic Construct 403Glu Val Gln Leu Val Glu Ser Gly Gly Asn Leu Glu Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Arg Ser 20 25 30Ala Met Asn Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val 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 Ser Ala Glu Asp Thr Ala Ala Tyr Tyr Cys 85 90 95Ala Lys Asp Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Met Asp Val Trp

100 105 110Gly His Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala225 230 235 240Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Pro Gly Lys 450404214PRTArtificial SequenceSynthetic Construct 404Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Phe Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln 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 Ile Tyr Tyr Cys Gln Gln Ala Asn Ser Val Pro Ile 85 90 95Thr Phe Gly Gln Gly Thr Arg 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 210405445PRTArtificial SequenceSynthetic Construct 405Glu 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 Phe Ser Ser Phe 20 25 30Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Thr Ile Ser Gly Gly Lys Thr Phe Thr Asp Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Ala Asn Tyr Gly Asn Trp Phe Phe Glu Val Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445406218PRTArtificial SequenceSynthetic Construct 406Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ala Lys Tyr 20 25 30Gly Leu Ser Leu Leu Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45Arg Leu Leu Ile Phe Ala Ala Ser Asn Arg Gly Ser Gly Ile Pro Ala 50 55 60Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser65 70 75 80Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys 85 90 95Glu Val Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 110Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser145 150 155 160Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215407456PRTArtificial SequenceSynthetic Construct 407Glu 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 Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Ala Ile Asp Gln Ser Thr Tyr Tyr Ala Asp Ser Val 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 Val Tyr Tyr Cys 85 90 95Ala Arg Gln Lys Phe Met Gln Leu Trp Gly Gly Gly Leu Arg Tyr Pro 100 105 110Phe Gly Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser 115 120 125Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 130 135 140Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro145 150 155 160Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 165 170 175His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 180 185 190Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 195 200 205Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 210 215 220Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala225 230 235 240Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 275 280 285Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln305 310 315 320Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 325 330 335Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 340 345 350Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr385 390 395 400Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445Ser Leu Ser Leu Ser Pro Gly Lys 450 455408212PRTArtificial SequenceSynthetic Construct 408Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Glu Gly Met Gly Asp Lys Tyr Ala 20 25 30Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45Arg Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr Tyr Cys Gly Val Ile Gln Asp Asn Thr Gly Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu145 150 155 160Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205Thr Glu Cys Ser 210409456PRTArtificial SequenceSynthetic Construct 409Glu 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 Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ala Asp Asp Phe Thr Ser Thr Tyr Tyr Ala Asp Pro Val 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 Val Tyr Tyr Cys 85 90 95Ala Arg Asp Leu Trp Met Met Asn Tyr Ala Gly Gly Leu Arg Tyr Pro 100 105 110Phe Gly Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser 115 120 125Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 130 135 140Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro145 150 155 160Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 165 170 175His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 180 185 190Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 195 200 205Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 210 215 220Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala225 230 235 240Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 275 280 285Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln305 310 315 320Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 325 330 335Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 340 345 350Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr385 390 395 400Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445Ser Leu Ser Leu Ser Pro Gly Lys 450 455410212PRTArtificial SequenceSynthetic Construct 410Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln1 5 10 15Thr Ala Ser Ile Thr Cys Ser Gly Glu Arg Met Gly Asp Lys Tyr Ala 20 25 30Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45Arg Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met65 70 75 80Asp Glu Ala Asp Tyr

Tyr Cys Gly Val Leu Lys Gln Asp Thr Gly Val 85 90 95Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu145 150 155 160Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205Thr Glu Cys Ser 210

Claims

1. An isolated nucleic acid molecule, comprising one or more nucleotide sequences encoding an antibody, or antigen-binding fragment thereof, that specifically binds to human IL-33, comprising one from each of the following: (a) a light chain complementarity determining region 1 (CDR-L1) selected from the group consisting of SEQ ID NO:20, 37, 190, 193, 257, 258, 259, and 260; (b) a CDR-L2 selected from the group consisting of SEQ ID NO:21, 196, 199, 261, 262, 263, and 264; (c) a CDR-L3 selected from the group consisting of SEQ ID NO:22, 38, 208, 265, 26, 267, and 268; (d) a heavy chain complementarity determining region 1 (CDR-H1) selected from the group consisting of SEQ ID NO:16, 33, 269, 270, and 271; (e) a CDR-H2 selected from the group consisting of SEQ ID NO:17, 34, 168, 171, 174, 180, 202, 205, 211, 214, 217, 220, 223, 226, 229, 232, 235, 272, 273, 274, and 275; and (f) a CDR-H3 selected from the group consisting of SEQ ID NO:18, 35, 114, 119, 122, 127, 130, 133, 136, 139, 142, 145, 148, 153, 156, 159, 177, 187, 276, 277, 278, and 279.

2. An isolated nucleic acid molecule, comprising one or more nucleotide sequences encoding an antibody, or antigen-binding fragment thereof, comprising the CDR-H1, CDR-H2, and CDR-H3 sequences as set forth in SEQ ID NO:225, and the CDR-L1, CDR-L2, and CDR-L3 sequences as set forth in SEQ ID NO:207.

3. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises: (i) a CDR-L1 comprising SEQ ID NO:20; (ii) a CDR-L2 comprising SEQ ID NO:21; (iii) a CDR-L3 comprising SEQ ID NO:208; (iv) a CDR-H1 comprising SEQ ID NO:16; (v) a CDR-H2 comprising SEQ ID NO:226; and (vi) a CDR-H3 comprising SEQ ID NO: 18.

4. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises a VL framework sequence and a VH framework sequence, and wherein one or both of the VL framework sequence or VH framework sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the human germline sequence from which it was derived, and wherein the human germline VL sequence from which the VL framework sequence is derived is selected from the group consisting of DPK9, DPK12, DPK18, DPK24, HK102_V1, DPK1, DPK8, DPK3, DPK21, Vg_38K, DPK22, DPK15, DPL16, DPL8, V1-22, VA consensus, V.lamda.1 consensus, V.lamda.3 consensus, V.kappa.1 consensus, V.kappa.1 consensus, V.kappa.2 consensus, and V.kappa.3, and wherein the human germline VH sequence from which the VH framework sequence is derived is selected from the group consisting of DP54, DP47, DP50, DP31, DP46, DP71, DP75, DP10, DP7, DP49, DP51, DP38, DP79, DP78, DP73, VH3, VH5, VH1, and VH4.

5. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:225, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:207.

6. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises an Fc domain, and wherein the Fc domain is the Fc domain of an IgA1 IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3, or IgG4.

7. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:244, and a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:209.

8. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:244, and a light chain comprising the amino acid sequence of SEQ ID NO:209.

9. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment binds human IL-33 with a KD about or less than a value selected from the group consisting of 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, and 1 pM, and optionally, wherein the antibody, or antigen binding fragment thereof, binds cynomolgus monkey IL-33 with a KD about or less than a value selected from the group consisting of 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 13 pM, 10 pM, 5 pM, and 1 pM.

10. The isolated nucleic acid molecule as claimed in claim 2, wherein the binding KD of the antibody, or antigen binding fragment, to cynomolgus IL-33 is within 10-fold of the binding KD to human IL-33.

11. The isolated nucleic acid molecule of claim 2, wherein the terminal half-life in a human of the antibody or antigen binding fragment is at least about 31 days.

12. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises a VH framework sequence derived from a human germline DP54 sequence.

13. The isolated nucleic acid molecule of claim 2, wherein the antibody or antigen binding fragment comprises a VL framework sequence derived from a human germline DPK9 sequence.

14. The isolated nucleic acid molecule of claim 2, wherein the ratio of binding KD of the antibody or antigen binding fragment to human IL-33 compared with the binding to cynomolgus IL-33 is between 5:1 and 1:5.

15. The isolated nucleic acid molecule of claim 2, wherein the KD of the antibody, or antigen binding fragment thereof, binding to active IL-33 is at least 10, 100, 1.times.10.sup.3, 1.times.10.sup.4, 1.times.10.sup.5, 1.times.10.sup.6, 1.times.10.sup.7 times less than the KD of the antibody, or antigen binding fragment thereof, binding to an inactive form of IL-33.

16. The isolated nucleic acid molecule of claim 2, wherein the terminal half life of the antibody or binding fragment thereof in cynomolgus monkeys is at least about 15 days.

17. An isolated nucleic acid molecule comprising a nucleic acid sequence as set forth in one or more of SEQ ID NOs: 398, 399, 400, and 401.

18. An isolated nucleic acid molecule comprising the nucleic acid sequence of the nucleic acid insert in the plasmid deposited with the ATCC and having Accession No. PTA-122724, the nucleic acid insert in the plasmid deposited with the ATCC and having Accession No. PTA-122725, or both.

19. A vector comprising the nucleic acid molecule of claim 17.

20. A host cell comprising the nucleic acid molecule of claim 17.

21. The host cell as claimed in claim 20, wherein said cell is a mammalian cell.

22. A vector comprising the nucleic acid molecule of claim 1.

23. A host cell comprising the nucleic acid molecule of claim 1.

24. A host cell comprising the vector of claim 22.

25. A method of producing the antibody of claim 1, the method comprising growing the host cell of claim 24 under conditions where the antibody is produced, and, optionally, isolating the antibody produced.

26. A vector comprising the nucleic acid molecule of claim 3.

27. A host cell comprising the nucleic acid molecule as claimed in claim 3.

28. A host cell comprising the vector of claim 26.

29. A method of producing the antibody of claim 3, the method comprising growing the host cell of claim 28 under conditions where the antibody is produced, and, optionally, isolating the antibody produced.