RU2844900C1 - Therapeutic antibodies and use thereof - Google Patents

Abstract

FIELD: pharmaceutics; medicine.

SUBSTANCE: group of inventions refers to medicine and pharmaceutics. 1 object is an isolated antibody, which specifically binds to B-cell maturation antigen (BCMA), 2 and 7 objects are a pharmaceutical composition comprising a therapeutically effective amount of an antibody and a pharmaceutically acceptable carrier, and a method of treating a condition associated with BCMA expressing cells. 3-6 objects are an isolated polynucleotide encoding the antibody; an expression vector comprising a polynucleotide; an isolated host cell; and a method of producing an antibody.

EFFECT: treating conditions associated with BCMA expressing cells.

18 cl, 16 dwg, 14 tbl, 22 ex

Description

Field of invention

The present invention relates to antibodies, such as full-length antibodies or antigen-binding fragments thereof, that specifically bind to BCMA (B-cell maturation antigen) and/or CD3 (cluster of differentiation 3). The invention also relates to antibody conjugates (e.g., antibody-drug conjugates) comprising BCMA antibodies, to compositions comprising BCMA antibodies, and to methods of using BCMA antibodies and conjugates thereof to treat conditions associated with BCMA-expressing cells (e.g., cancer or autoimmune diseases). The invention also relates to heteromultimeric antibodies that specifically bind to CD3 and to a tumor cell antigen (e.g., bispecific antibodies that specifically bind to CD3 and BCMA). Compositions containing such heteromultimeric antibodies, methods for obtaining and purifying such heterodimeric antibodies and their use in diagnostics and therapy are also proposed.

Prior art

B-cell maturation antigen (BCMA, CD269, or TNFRSF17) is a member of the tumor necrosis factor receptor (TNFR) superfamily. BCMA was identified in a human malignant T-cell lymphoma containing the t(4;16) translocation. The gene is expressed selectively in the B-cell lineage, with highest expression levels in plasma blast cells and in plasma cells, the cells that secrete antibodies. BCMA binds to two ligands, B-cell activating factor (BAFF) (also called B-lymphocyte stimulator (BLyS) and Apol-related leukocyte-expressed ligand (TALL-1)) and Apol-related proliferation-inducing ligand (APRIL), with affinities of 1 μM and 16 nM, respectively. Binding of APRIL or BAFF to BCMA stimulates a signaling cascade involving NF-kappa B, Elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, which produce signals for cell survival and proliferation.

BCMA is also expressed on malignant B cells and in several types of cancer that involve B lymphocytes, including multiple myeloma, plasmacytoma, Hodgkin lymphoma, and chronic lymphocytic leukemia. In autoimmune diseases that involve plasmablasts, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, BCMA-expressing antibody-producing cells secrete autoantibodies that attack themselves.

In the case of multiple myeloma, approximately 24,000 new cases are diagnosed each year in the United States, and this number represents approximately 15% of newly diagnosed hematologic cancers in the United States. On average, 11,000 deaths are due to multiple myeloma each year, and the average 5-year survival rate is approximately 44%, with a median survival of 50-55 months. Current treatment for multiple myeloma focuses on plasma cell apoptosis and/or decreasing osteoclast activity (eg, chemotherapy, thalidomide, lenalidomide, bisphosphonates, and/or proteasome inhibitors such as bortezomib (VELCADE®) or carfilzomib). However, multiple myeloma remains an incurable disease, and almost all patients develop resistance to these agents and eventually relapse. Accordingly, alternative treatments for multiple myeloma, such as the use of a BCMA antagonist, including antibodies and other immunotherapeutic agents (e.g. bispecific antibodies or antibody-drug conjugates), will provide an effective therapeutic agent.

Brief summary of the invention

The invention disclosed herein relates to therapeutic antibodies that bind to BCMA and/or CD3. Also provided are antibody conjugates (e.g., antibody-drug conjugates) comprising BCMA. Furthermore, provided are heteromultimeric antibodies (e.g., bispecific antibodies) that specifically bind to CD3 and a tumor cell antigen (e.g., bispecific antibodies that specifically bind to CD3 and BCMA).

In one aspect of the invention there is provided an isolated antibody or antigen-binding fragment thereof that specifically binds to a B cell maturation antigen (BCMA), wherein the antibody comprises (a) a heavy chain variable region (VH) comprising (1) a complementarity determining region, one (CDR1) of the VH comprising the sequence SYX ₁ MX ₂ , wherein X ₁ is A or P; and X ₂ is T, N or S (SEQ ID NO: 301), GFTFX ₁ SY, wherein X ₁ is G or S (SEQ ID NO: 302), or GFTFX ₁ SYX ₂ MX ₃ , wherein X ₁ is G or S, X ₂ is A or P; and X ₃ is T, N or S (SEQ ID NO: 303); (2) a VH CDR2 comprising the sequence AX ₁ X ₂ X ₃ X ₄ GX ₅ X ₆ X ₇ X ₈ YADX ₉ X ₁₀ KG, wherein X ₁ is I, V, T, H, L, A, or C; X ₂ is S, D, G, T, I, L, F, M, or V; X ₃ is G, Y, L, H, D, A, S, or M; X ₄ is S, Q, T, A, F, or W; X ₅ is G or T; X ₆ is N, S, P, Y, W, or F; X ₇ is S, T, I, L, T, A, R, V, K, G, or C; X ₈ is F, Y, P, W, H, or G; X ₉ is V, R, or L; and _X10 is G or T (SEQ ID NO: ₃₀₅ ) or _X1X2X3X4X5X6 , wherein _X1 is S, _V , I, D, G, _{T, L, F or M; X2 is} G, Y, L, H, D, A, S or M; _X3 is S, G, F or W; _X4 is G or S; _X5 is G or T; and _X6 is N, S _, P, Y or W (SEQ ID NO: ₃₀₆ ); and 3) _a VH CDR3 comprising the sequence _{VSPIX1X2X3X4 ,} wherein _X1 is A or Y; _X2 is A or S; and _X3 is G, Q, L, P or E (SEQ ID NO: ₃₀₇ ), or _YWPMX1X2 , wherein _X1 is D, S _, T or A; and _X2 is I, S, L, P or D (SEQ ID NO: 308); and/or (b) a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence _{X1 X2 X3 X4 X5 X6 X7 X8 X9 X10 X11 X12} , wherein _X1 is R, G, W, A or C; _X2 is A, P, G, L, C or S; _X3 is S, G or R; _X4 is Q, C, E, V or I; _X5 is S, P, G, A, R or D; _X6 is V, G, I or L; _X7 is S, E, D, P or G; _X8 is S, P, F, A, M, E, V, N, D or Y; X ₉ is I, T, V, E, S, A, M, Q, Y, H, R or F; X ₁₀ is Y or F; X ₁₁ is L, W or P; and X ₁₂ is A, S or G (SEQ ID NO: 309); (2) a VL CDR2 comprising the sequence X ₁ ASX ₂ RAX ₃ , wherein X ₁ is G or D; X ₂ is S or I; and X ₃ is T or P (SEQ ID NO: 310); and (3) a VL CDR3 comprising the sequence QQYX ₁ X ₂ X ₃ PX ₄ T, wherein X ₁ is G, Q, E, L, F, A, S, M, K, R or Y; X ₂ is S, R, T, G, V, F, Y, D, A, H, V, E, K or C; X ₃ is W, F or S; and X ₄ is L or I (SEQ ID NO: 311), or QQYX ₁ X ₂ X ₃ PX ₄ , wherein X ₁ is G, Q, E, L, F, A, S, M, R, K or Y; X ₂ is S, R, T, G, R, V, D, A, H, E, K, C, F or Y; X ₃ is W, S or F; and X ₄ is L or I (SEQ ID NO: 312).

In another aspect of the invention there is provided an isolated antibody or antigen-binding fragment thereof that specifically binds to BCMA, wherein the antibody comprises: a VH region comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH sequence set forth in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 125, 127, 313, 314, 363 or 365; and/or a VL region comprising VL CDR1, VL CDR2 and VL CDR3 of the VL sequence shown in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 315, 316 or 364. In some embodiments, the VH region comprises (1) a VH CDR1 comprising SEQ ID NO: 150, 151, 152, 156 or 157; (2) a VH CDR2 comprising SEQ ID NO: 169, 154, 194, 159, 195, 196, 162, 158, 198, 177, 178, 199, 200, 201, 202, 203, 204, 206, 207, 208, 172, 203, or 204; and (3) a VH CDR3 comprising SEQ ID NO: 155, 161, 197, 205, or 164; and/or wherein the VL region comprises (1) a VL CDR1 comprising SEQ ID NO: 209, 271, 273, 275, 251, 277, 260, 279, 245, 283, 285, 287, 290, 292, 235, 297 or 299; (2) a VL CDR2 comprising SEQ ID NO: 221; and (3) a VL CDR3 comprising SEQ ID NO: 225, 272, 274, 276, 278, 280, 281, 282, 284, 286, 288, 289, 291, 293, 294, 229, 296, 298 or 300. In some embodiments, the VH region comprises the sequence presented in SEQ ID NO: 112 or a variant with one or more conservative amino acid substitutions at residues that are not included in the CDRs, and/or the VL region comprises the amino acid sequence presented in SEQ ID NO: 38 or a variant thereof with one or more amino acid substitutions that are not included in the CDRs. In some embodiments, the antibody comprises a light chain comprising the sequence presented in SEQ ID NO: 357 and a heavy chain comprising the sequence presented in SEQ ID NO: 358. In some embodiments, the antibody comprises a VH region produced by the expression vector having ATCC accession number PTA-122094. In some embodiments, the antibody comprises a VL region produced by the expression vector having ATCC accession number PTA-122093.

In another aspect of the invention, there is provided an isolated antibody comprising an acyl donor glutamine-containing tag generated at a specific site of a BCMA antibody of the present invention. In some embodiments, the tag comprises an amino acid sequence selected from the group consisting of Q, LQG, LLQGG (SEQ ID NO:318), LLQG (SEQ ID NO:454), LSLSQG (SEQ ID NO:455), GGGLLQGG (SEQ ID NO:456), GLLQG (SEQ ID NO:457), LLQ, GSPLAQSHGG (SEQ ID NO:458), GLLQGGG (SEQ ID NO:459), GLLQGG (SEQ ID NO:460), GLLQ (SEQ ID NO:461), LLQLLQGA (SEQ ID NO:462), LLQGA (SEQ ID NO:463), LLQYQGA (SEQ ID NO:464), LLQGSG (SEQ ID NO:465), LLQYQG (SEQ ID NO: 466), LLQLLQG (SEQ ID NO: 467), SLLQG (SEQ ID NO: 468), LLQLQ (SEQ ID NO: 469), LLQLLQ (SEQ ID NO: 470), LLQGR (SEQ ID NO: 471), LLQGPP (SEQ ID NO: 472), LLQGPA (SEQ ID NO: 473), GGLLQGPP (SEQ ID NO: 474), GGLLQGA (SEQ ID NO: 475), LLQGPGK (SEQ ID NO: 476), LLQGPG (SEQ ID NO: 477), LLQGP (SEQ ID NO: 478), LLQP (SEQ ID NO: 479), LLQPGK (SEQ ID NO: 480), LLQAPGK (SEQ ID NO: 481), LLQGAPG (SEQ ID NO: 482), LLQGAP (SEQ ID NO: 483), and LLQLQG (SEQ ID NO: 484).

In one embodiment, the invention provides an isolated antibody comprising an acyl donor glutamine-containing tag and an amino acid modification at positions 222, 340 or 370 of a BCMA antibody of the present invention. In some embodiments, the amino acid modification is a lysine to arginine substitution.

In some embodiments, the BCMA antibody of the present invention further comprises a linker. In some embodiments, the linker is selected from the group consisting of Ac-Lys-Gly (acetyl-lysine-glycine), aminocaproic acid, Ac-Lys-β-Ala (acetyl-lysine-β-alanine), amino-PEG2 (polyethylene glycol)-C2, amino-PEG3-C2, amino-PEG6-C2, Ac-Lys-Val-Cit-PABC (acetyl-lysine-valine-citrulline -p-amino benzyloxycarbonyl), amino-PEG6-C2-Val-Cit-PABC, aminocaproyl-Val-Cit-PABC, [(3R,5R)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidine-3,5-diyl]bis-Val-Cit-PABC, [(3S,5S)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidin-3,5-diyl] bis-Val-Cit-PABC, putrescine and Ac-Lys-putrescine.

In another aspect, the invention provides a BCMA-antibody or antigen-binding fragment conjugate as described herein, wherein the antibody or antigen-binding fragment is conjugated to an agent selected from the group consisting of a cytotoxic agent, an immunomodulatory agent, an imaging agent, a therapeutic protein, a biopolymer, and an oligonucleotide. In some embodiments, the agent is a cytotoxic agent, including, but not limited to, an anthracycline, auristatin, camptothecin, combretastatin, dolastatin, duocarmycin, enediyne, geldanamycin, indolino-benzodiazepine dimer, maytansine, puromycin, pyrrole-benzodiazepine dimer, taxane, vinca alkaloid, tubulysin, hemiasterlin, spliceostatin, pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof. For example, the cytotoxic agent is MMAD (Monomethyl Auristatin D), 0101 (2-methylalanyl- N- [( 3R, 4S, 5S )-3-methoxy-1-{( 2S )-2-[( 1R, 2R )-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl] -N- methyl-L-valinanide), 3377 (N,2-dimethylalanyl-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxyl-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N-methyl-L-valinanamide), 0131 (2-methyl-L-prolyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide) or 0121 (2-methyl-L-prolyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide).

In some embodiments, the present invention provides a conjugate comprising the formula: antibody-(acyl donor glutamine-containing tag)-(linker)-(cytotoxic agent). In some embodiments, the acyl donor glutamine-containing tag comprises the amino acid sequence LLQG (SEQ ID NO: 319) and/or GGLLQGPP (SEQ ID NO: 339), and the linker comprises acetyl-lysine-valine-citrulline- para- aminobenzyloxycarbonyl or amino-PEG6-C2. In some embodiments, the conjugate is selected from the group consisting of 1) antibody-GGLLQGPP (SEQ ID NO: 339)-(acetyl-lysine-valine-citrulline- para -aminobenzyloxycarbonyl (AcLys-VC-PABC))-0101; 2) antibody-LLQG (SEQ ID NO: 319)-amino-PEG6-C2-0131; and 3) antibody-LLQG (SEQ ID NO: 319)-amino-PEG6-C2-3377. In some embodiments, the conjugate further comprises an amino acid substitution of lysine to arginine at position 222 of the antibody. In some embodiments, the conjugate further comprises amino acid substitutions at position N297Q or N297A of the antibody.

In another aspect, a method for producing a BCMA antibody as described herein is provided, comprising culturing host cells under conditions that result in the production of BCMA antibodies, and recovering the BCMA antibodies from the host cells or culture.

In another aspect of the invention there is provided the use of BCMA antibodies or BCMA antibody conjugates as described herein in the manufacture of a medicament for treating a condition (e.g., cancer or an autoimmune disorder) associated with BCMA expression. In some embodiments there is provided the use of BCMA antibodies or BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting tumor growth or progression. In some embodiments there is provided the use of BCMA antibodies or BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting metastasis of malignant cells expressing BCMA. In some embodiments there is provided the use of BCMA antibodies or BCMA antibody conjugates as described herein in the manufacture of a medicament for inducing tumor regression.

In another aspect of the invention there is provided an isolated antibody or antigen-binding fragment thereof that specifically binds to CD3, wherein the antibody comprises a VH CDR1, VH CDR2 and VH CDR3 from a VH sequence set forth in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398 or 400; and/or a light chain variable region (VL) comprising a VL CDR1, VL CDR2 and VL CDR3 of a VL sequence set forth in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397 or 399. In some embodiments, the antibody comprises a VH CDR1, VH CDR2 and VH CDR3 of a VH sequence set forth in SEQ ID NO: 324 or 388; and/or a light chain variable region (VL) comprising VL CDR1, VL CDR2 and VL CDR3 from a VL sequence set forth in SEQ ID NO: 323 or 387. In some embodiments, the VH region comprises (1) a VH complementarity determining region one (CDR1) comprising a sequence set forth in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447 or 448; (2) a VH CDR2 comprising the sequence set forth in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449 or 450; and (3) a VH CDR3 comprising the sequence set forth in SEQ ID NO: 335, 406, 423, 429 or 451; and/or a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence set forth in SEQ ID NO: 340, 343, 430, 431, 435 or 440, 441; (2) a VL CDR2 comprising the sequence set forth in SEQ ID NO: 341, 433, 452 or 436; and (3) a VL CDR3 comprising the sequence set forth in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453. In some embodiments, the VH region comprises (1) a VH complementarity determining region one (CDR1) comprising the sequence set forth in SEQ ID NO: 331, 332, 333, 401, 407, or 408, (2) a VH CDR2 comprising the sequence set forth in SEQ ID NO: 336, 404, 405, or 417; and (3) a VH CDR3 comprising the sequence set forth in SEQ ID NO: 335 or 406; and/or a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343 or 441; (2) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341 or 436; and (3) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342 or 439. In some embodiments, the antibody comprises a VH region produced by the expression vector having ATCC accession number PTA-122513. In some embodiments, the antibody comprises a VL region produced by the expression vector having ATCC accession number PTA-122512.

In another aspect, there is provided an isolated antibody that specifically binds to CD3 and competes with an anti-CD3 antibody of the present invention as described herein.

In another aspect of the invention there is provided a bispecific antibody, which is a full-length human antibody comprising a first antibody variable domain of the bispecific antibody capable of recruiting the activity of a human immune effector cell by specifically binding to an effector antigen located on this human immune effector cell, and comprising a second antibody variable domain of the bispecific antibody capable of specifically binding to a target antigen, wherein the first antibody variable domain comprises a heavy chain (VH) variable region comprising a VH CDR1, VH CDR2 and VH CDR3 from the VH sequence presented in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398 or 400; and/or a light chain variable region (VL) comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL sequence set forth in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397 or 399. In some embodiments, the first antibody variable domain comprises a heavy chain variable region (VH) comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH sequence set forth in SEQ ID NO: SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447 or 448; (2) a VH CDR2 comprising the sequence shown in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449 or 450; and (3) a VH CDR3 comprising the sequence set forth in SEQ ID NO: 335, 406, 423, 429, or 451; and/or a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence set forth in SEQ ID NO: 340, 343, 430, 431, 435, or 440, 441; (2) a VL CDR2 comprising the sequence set forth in SEQ ID NO: 341, 433, 452, or 436; and (3) a VL CDR3 comprising the sequence set forth in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453. In some embodiments, the first antibody variable domain comprises a heavy chain variable region (VH) comprising the VH CDR1, VH CDR2, and VH CDR3 of the VH sequence set forth in SEQ ID NO: 324 or 388; and/or a light chain variable region (VL) comprising the VL CDR1, VL CDR2, and VL CDR3 of the VL sequence set forth in SEQ ID NO: 323 or 387; and the second antibody variable domain comprises a heavy chain variable region (VH) comprising VH CDR1, VH CDR2 and VH CDR3 from the VH sequence presented in SEQ ID NO: 112; and/or a light chain variable region (VL) comprising VL CDR1, VL CDR2 and VL CDR3 from the VL sequence presented in SEQ ID NO: 38.

In some embodiments, the second antibody variable domain comprises (a) a heavy chain variable region (VH) comprising (1) a VH complementarity determining region one (CDR1) comprising the sequence SYX ₁ MX ₂ , wherein X ₁ is A or P; and X ₂ is T, N, or S (SEQ ID NO: 301), GFTFX ₁ SY, wherein X ₁ is G or S (SEQ ID NO: 302), or GFTFX ₁ SYX ₂ MX ₃ , wherein X ₁ is G or S, X ₂ is A or P; and X ₃ is T, N, or S (SEQ ID NO: 303); (2) a VH CDR2 comprising the sequence AX ₁ X ₂ X ₃ X ₄ GX ₅ X ₆ X ₇ X ₈ YADX ₉ X ₁₀ KG, wherein X ₁ is I, V, T, H, L, A, or C; X ₂ is S, D, G, T, I, L, F, M, or V; X ₃ is G, Y, L, H, D, A, S, or M; X ₄ is S, Q, T, A, F, or W; X ₅ is G or T; X ₆ is N, S, P, Y, W, or F; X ₇ is S, T, I, L, T, A, R, V, K, G, or C; X ₈ is F, Y, P, W, H, or G; X ₉ is V, R, or L; and _X10 is G or T (SEQ ID NO:305), or _{X1X2X3X4X5X6 ,} wherein _X1 is S, _V , I, D, G, T, L, _F or M; _X2 is G, Y, L, H, D, A, S or M; _X3 is S, G, F or W; _X4 is G or S; _X5 is G or T; and _X6 is N, S, _P , Y or W (SEQ ID NO:306); and (3) a VH CDR3 comprising the sequence _VSPIX1X2X3X4 , wherein _X1 is A or Y _{; X2 is A or S; and X3 is G , Q} , L, P or E (SEQ ID _NO :307) or _{YWPMX1X2 ,} wherein _X1 is D, S, T or A; and _X2 is I, S, L, P or D (SEQ ID NO: 308); and/or (b) a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence _{X1 X2 X3 X4 X5 X6 X7 X8 X9 X10 X11 X12} , wherein _X1 is R, G, W, A or C; _X2 is A, P, G, L, C or S; _X3 is S, G or R; _X4 is Q, C, E, V or I; _X5 is S, L, P, G, A, R or D; _X6 is V, G or I; _X7 is S, E, D or P; _X8 is S, P, F, A, M, E, V, N, D or Y; X ₉ is I, T, V, E, S, A, M, Q, Y, H or R; X ₁₀ is Y or F; X ₁₁ is L, W or P; and X ₁₂ is A, S or G (SEQ ID NO: 309); (2) a VL CDR2 comprising the sequence X ₁ ASX ₂ RAX ₃ , wherein X ₁ is G or D; X ₂ is S or I; and X ₃ is T or P (SEQ ID NO: 310); and (3) a VL CDR3 comprising the sequence QQYX ₁ X ₂ X ₃ PX ₄ T, wherein X ₁ is G, Q, E, L, F, A, S, M, K, R or Y; X ₂ is S, R, T, G, V, F, Y, D, A, H, V, E, K or C; X ₃ is W, F or S; and _X4 is L or I (SEQ ID NO:311) or _QQYX1X2X3PX4 , wherein _X1 is G, Q, _E , L, F, A, S, M, R, K or _Y ; _X2 is S, R, _T , G, R, V, D, A, H, E, K, C, F or Y; _X3 is W, S or F; and _X4 is L or I (SEQ ID NO:312). In some embodiments, the second antibody variable domain comprises a heavy chain variable region (VH) comprising (1) a VH CDR1 comprising the sequence set forth in SEQ ID NO:150, 151, 152, 156, 157, 348, 349, 353, 354 or 355; (2) a VH CDR2 comprising a sequence as set forth in SEQ ID NO: 169, 154, 194, 159, 195, 196, 162, 158, 198, 177, 178, 199, 200, 201, 202, 203, 204, 206, 207, 208, 172, 203, 204, 350, 351, 356, or 357; and (3) a VH CDR3 comprising a sequence as set forth in SEQ ID NO: 155, 161, 197, 205,164, or 352 or 358; and/or wherein the light chain variable region (VL) comprises (1) a VL CDR1 comprising the sequence set forth in SEQ ID NO: 209, 271, 273, 275, 251, 277, 260, 279, 245, 283, 285, 287, 290, 292, 235, 297, 299 or 361; (2) a VL CDR2 comprising the sequence set forth in SEQ ID NO: 221, 359 or 362; and (3) a VL CDR3 comprising the sequence set forth in SEQ ID NO: 211, 225, 272, 274, 276, 278, 280, 281, 282, 284, 286, 288, 289, 291, 293, 294, 229, 296, 298, 300, or 360.

In some embodiments, (a) the first antibody variable domain comprises a heavy chain variable region (VH) comprising (1) a VH complementarity determining region one (CDR1) comprising the sequence set forth in SEQ ID NO: 331, 332, 333, 401, 407, or 408, (2) a VH CDR2 comprising the sequence set forth in SEQ ID NO: 336, 417, 404, or 405; and (3) a VH CDR3 comprising the sequence set forth in SEQ ID NO: 335 or 406; and/or a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence set forth in SEQ ID NO: 343 or 441; (2) a VL CDR2 comprising the sequence set forth in SEQ ID NO: 341 or 436; and (3) a VL CDR3 comprising the sequence set forth in SEQ ID NO: 342 or 439; and (b) the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable region (VH) comprising (1) a VH CDR1 comprising the sequence set forth in SEQ ID NO: 151, 156, or 157; (2) a VH CDR2 comprising the sequence set forth in SEQ ID NO: 158 or 159; and (3) a VH CDR3 comprising SEQ ID NO: 155; and/or, wherein the light chain variable region (VL) comprises (1) a VL CDR1 comprising the sequence set forth in SEQ ID NO: 209; (2) VL CDR2 comprising the sequence presented in SEQ ID NO: 221; and (3) VL CDR3 comprising the sequence presented in SEQ ID NO: 225.

In some embodiments, both the first and second antibody variable domains of the bispecific antibody comprise amino acid modifications at positions 223, 225 and 228 of the hinge region and at position 409 or 368 (EU numbering scheme) of the CH3 region of human IgG2 (SEQ ID NO: 493). In some embodiments, the bispecific antibody as described herein further comprises an amino acid modification at position 265 of human IgG2.

In another aspect of the invention, there are provided pharmaceutical compositions comprising any of the antibodies (e.g. BCMA, CD3 or bispecific) or any of the conjugates thereof (e.g. BCMA antibody drug conjugate) described herein.

In another aspect, the invention also provides cell lines that recombinantly produce any of the antibodies (e.g., BCMA, CD3, or bispecific) or any of the conjugates thereof (e.g., BCMA antibody-drug conjugate) described herein.

In another aspect, the invention also provides nucleic acids encoding any of the antibodies (e.g., BCMA, CD3, or bispecific) or any of the conjugates thereof (e.g., BCMA antibody drug conjugate) described herein. The invention also provides nucleic acids encoding the heavy chain variable region and/or the light chain variable region of any of the antibodies described herein.

The invention also provides kits comprising an effective amount of any of the antibodies (e.g. BCMA, CD3 or bispecific) or conjugates thereof (e.g. BCMA antibody drug conjugate) described herein.

The invention also provides methods for treating a condition (e.g., inhibiting tumor growth/progression; inhibiting metastasis of BCMA-expressing malignant cells; inducing tumor regression in subjects with BCMA-expressing malignant cells) in subjects in need thereof, comprising providing isolated antibodies (e.g., BCMA) or binding fragments, bispecific antibodies (BCMA-CD3 bispecific) or conjugates thereof (e.g., BCMA-antibody drug conjugates) described herein, and administering said antibodies or conjugates to said subject.

Also provided are methods for treating a condition associated with malignant cells expressing a tumor antigen in a subject, comprising administering to a subject in need thereof an effective amount of the pharmaceutical compositions of the invention. In some embodiments, the condition is cancer. In some embodiments, the cancer is a B-cell related cancer selected from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular Hodgkin's lymphoma with lymphocyte predominance, Kahler disease and myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor lymphoblastic lymphoma B-cell, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosal lymphoid tissue lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, Burkitt's lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, nodular marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell/histocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (foot type), EBV-positive diffuse large cell B-cell lymphoma of the elderly, diffuse large B-cell inflammation-associated lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising from HHV8-associated multicentric Castleman disease, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma, and other B-cell lymphomas. In some embodiments, the condition is an autoimmune disorder such as systemic lupus erythematosus or rheumatoid arthritis.

In some embodiments, the antibodies described herein comprise a constant region. In some embodiments, the antibodies described herein are of the human IgG1, IgG2 or IgG2Δa, IgG3 or IgG4 subclass. In some embodiments, the antibodies described herein comprise a glycosylated constant region. In some embodiments, the antibodies described herein comprise a constant region having an enhanced binding affinity for one or more human Fc gamma receptors.

Brief description of graphic materials

Fig. 1A - Fig. 1D show dual control sensorgrams with fitting curves for the interaction between selected anti-BCMA antibodies of the present invention and human BCMA.

Fig. 2 shows the in vivo efficacy studies of various anti-BCMA ADCs (antibody-drug complexes) in the orthotopic multiple myeloma model MM1S, including P6E01_VHVL-AcLys-Val-Cit-PABC-Aur0101; P5A2_VHVL-AcLys-Val-Cit-PABC-Aur0101; P5C1_VHVL-AcLys-Val-Cit-PABC-Aur0101; P4G4-AcLys-Val-Cit-PABC-Aur0101; and P1A11-AcLys-Val-Cit-PABC-Aur0101. NNC is a negative control antibody that is not a BCMA antibody. "LCQ05" and "LCQ04" correspond to the glutamine-containing transglutaminase tag sequences of SEQ ID NO: 474 and 475, respectively.

Figure 3 shows the in vivo efficacy of anti-BCMA ADCs in an orthotopic multiple myeloma model MM1S comprising the L3.PY/P6E01 antibody conjugated to 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101. NNC is a non-BCMA control antibody. "LCQ05" and H7c correspond to the glutamine-containing transglutaminase tag sequence of SEQ ID NO: 474 and SEQ ID NO: 454, respectively.

Figure 4 also shows the in vivo efficacy of anti-BCMA ADCs in an orthotopic multiple myeloma model MM1S comprising the L3.PY/P6E01 antibody conjugated to 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101. NNC is a non-BCMA control antibody (antibody-N297Q/K222R-AcLys-VC-PABC-0101). "LCQ05" and H7c correspond to the glutamine-containing transglutaminase tag sequence of SEQ ID NO: 474 and SEQ ID NO: 454, respectively.

Figure 5 also shows the in vivo efficacy of anti-BCMA ADC in the MM1S orthotopic multiple myeloma model. Anti-BCMA antibody COMBO_Rd4_0.6nM-C29 ("Combo C29 DI") is conjugated to H7c/N297A/K222R-amino-PEG6-C2-131 at doses of 0.1 mg/kg, 0.38 mg/kg, 0.75 mg/kg, 1.5 mg/kg compared to NNC, a non-BCMA control antibody (antibody-N297Q/K222R-AcLys-VC-PABC-0101) at a dose of 3 mg/kg. H7c corresponds to the glutamine-containing transglutaminase tag sequence of SEQ ID NO: 454.

Figures 6A-6F show the in vivo efficacy of the bispecific anti-CD3/anti-CD20 antibody in cynomolgus monkeys. B-cell depletion after a single dose of the bispecific antibody is shown as a percentage of pre-assay counts.

Figures 7A-7F show the in vivo efficacy of the bispecific anti-CD3/anti-CD20 antibody in cynomolgus monkeys. CD8+ T cell kinetics were determined after a single dose of the bispecific antibody.

Figure 8A and Figure 8B show the in vivo efficacy of the bispecific anti-CD3/anti-CD20 antibody in cynomolgus monkeys. The effect of monovalent CD3 antibody on T cell kinetics and proliferation was analyzed.

Figures 9A–9D show the in vivo efficacy of the bispecific anti-CD3/anti-CD20 antibody in cynomolgus monkeys. The effect of the affinity of the anti-CD3 fragment on B cell depletion was analyzed.

Fig. 10A and 10B show that selected anti-CD3 antibodies had thymidine incorporation indices on human and cynomolgus monkey PBMCs.

Fig. 11A - 11D show that all bispecific anti-human EpCam_h2B4 antibodies have cell killing activity in vitro.

Fig. 12 shows that a single dose of the human bispecific anti-BCMA/CD3 antibody resulted in tumor regression in a dose-dependent manner in the MM1.S orthotopic myeloma model.

Fig. 13 shows that two doses of human bispecific anti-BCMA/CD3 antibody resulted in enhanced tumor regression in the Molp8 orthotopic myeloma model.

Fig. 14 shows that the bispecific anti-BCMA/CD3 antibody alone or in combination with standard multiple myeloma treatment (lenalidomide or bortezomib) is more effective than the combination of lenalidomide and bortezomib in the Molp8 orthotopic tumor model.

Figs. 15A-15C, respectively, show that carfilzomib, lenalidomide, and doxorubicin do not negatively affect the function of the bispecific anti-BCMA/CD3 antibody in OPM2 cells compared to the bispecific anti-BCMA/CD3 antibody alone.

Fig. 16 shows the synergistic effects on function of the bispecific anti-BCMA/CD3 antibody in combination with carfilzomib and lenalidomide compared to each agent alone.

Detailed description of the invention

The invention disclosed herein provides antibodies and antibody conjugates (e.g., antibody-drug conjugates) that specifically bind to BCMA (e.g., human BCMA). The invention also provides polynucleotides encoding these antibodies and conjugates, compositions comprising these antibodies and conjugates, and methods for producing these antibodies and conjugates. In addition, the invention disclosed herein provides antibodies that specifically bind to CD3 (e.g., human CD3), as well as heterodimeric antibodies (e.g., bispecific antibodies) that specifically bind to CD3 and to a tumor antigen (e.g., BCMA). The invention also provides polynucleotides encoding these antibodies, compositions comprising these antibodies, and methods for producing and using these antibodies. The invention also provides methods for treating a condition associated with malignant BCMA expression in a subject, such as cancer or an autoimmune disease, using antibodies (e.g. BCMA, CD3 or a bispecific antibody) or conjugates thereof (BCMA antibody-drug conjugates) as described herein.

General methods

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are fully described in the literature, for example in Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995).

Definitions

"An antibody" is an immunoglobulin molecule capable of specifically binding to a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., via at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab') ₂ , Fv), single-chain (ScFv) and domain antibodies (including, for example, shark and camel antibodies) and fusion proteins comprising the antibody, and any other modified configuration of the immunoglobulin molecule that contains an antigen recognition site. An antibody includes an antibody of any class, such as IgG, IgA or IgM (or a subclass thereof), and the antibody need not belong to any particular class. Depending on the amino acid sequence of the constant region of the heavy chains of antibodies, immunoglobulins can be classified into different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of them can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant regions of the heavy chains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

The term "antigen-binding fragment" or "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen (e.g., BCMA or CD3). The antigen-binding functions of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include Fab; Fab';F(ab')₂; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of one arm of an antibody; a single-domain antibody (dAb) fragment (Ward et al., Nature 341:544-546, 1989), and an isolated complementarity determining region (CDR).

An antibody, antibody conjugate, or polypeptide that "preferentially binds" or "specifically binds" (used interchangeably herein) to a target (e.g., a BCMA protein or a CD3 protein) is a term well known in the art, and methods for determining 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 interacts or associates more frequently, more rapidly, for a longer duration, and/or with greater affinity with a particular cell or substance than 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 for a longer duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a BCMA epitope or a CD3 epitope is an antibody that binds to that epitope with greater affinity, avidity, more readily, and/or for a longer duration than it binds to other BCMA epitopes, non-BCMA epitopes, CD3 epitopes, or non-CD3 epitopes. It is also understood from this definition that, for example, an antibody (or moiety or epitope) that 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 require (although it may include) that binding is necessarily exclusive. Typically, but not necessarily, reference to binding means preferential binding.

The "variable region" of an antibody refers to the variable region of the light chain of an antibody or the variable region of the heavy chain of an antibody, 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 (FRs) connected by three complementarity determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, together with the CDRs from the other chain, participate in forming the antigen-binding site of the antibody. There are at least two methods for defining CDRs: (1) an approach based on interspecies sequence variation (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda MD)); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., 1997, J. Molec. Biol. 273:927-948). As used herein, CDR may refer to CDRs determined by either approach or a combination of both approaches.

The "CDRs" of a variable domain are amino acid residues in the variable region that are identified according to the definitions of Kabat, Chothia, the Kabat and Chothia summation, AbM, contact and/or conformational definitions, or any method for defining CDRs well known in the art. The CDRs of an antibody may be identified as the hypervariable regions originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. CDR positions may also be identified as structures from the loop structure originally described by Chothia et al. See, for example, Chothia et al., Nature 342:877-883, 1989. Other approaches to identifying CDRs include the "AbM definition," which is a compromise between Kabat and Chothia and is generated using Oxford Molecular's AbM (now Accelrys®) antibody modeling software, or the "contact definition" of CDRs based on observed antigen contacts, as outlined in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach, referred to here as the "conformational definition" of CDRs, CDR positions can be identified as residues that make an enthalpic contribution to antigen binding. See, for example, Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Other definitions of CDR boundaries 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 shorter or longer based on predictions or experimental evidence that certain residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding. As used herein, a CDR may refer to a CDR defined by any approach known in the art, including a combination of approaches. The methods used herein may use CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined according to any of the Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.

As used herein, "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible natural mutations that may be present in minor amounts. Monoclonal antibodies, being directed against a single antigenic site, are highly specific. Furthermore, unlike polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, but should not be construed as requiring production of the antibody by any particular process. For example, monoclonal antibodies for use in the present invention can be prepared using the above-described hybridoma method first described in Kohler and Milstein, Nature 256:495, 1975, or can be prepared by recombinant DNA techniques such as those described in U.S. Patent 4,816,567. Monoclonal antibodies can also be isolated from phage libraries prepared using the techniques described, for example, in McCafferty et al., Nature 348:552-554, 1990.

As used herein, a "humanized" antibody refers to forms of non-human (e.g., murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab') ₂ , or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from a non-human immunoglobulin. Preferably, humanized antibodies are human immunoglobulins (the recipient antibody) in which residues from the complementarity determining region (CDR) of the recipient are replaced by residues from the CDR of a non-human species (the donor antibody), such as mouse, rat, or rabbit, having the desired specificity, affinity, and potency. In some cases, the Fv residues of the framework region (FR) of a human immunoglobulin are replaced by corresponding non-human residues. In addition, a humanized antibody may comprise residues that are not found in either the recipient antibody or the imported CDR or framework sequences, but are included to further improve and optimize antibody performance. In general, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, wherein all or substantially all of the CDR regions correspond to the CDR regions of a non-human immunoglobulin and all or substantially all of the FR regions are human immunoglobulin consensus sequence regions. The humanized antibody optimally also comprises at least a portion of an immunoglobulin constant region or domain (Fc), typically from a human immunoglobulin. Preferred are antibodies having Fc regions modified as described in WO 99/58572. Other forms of humanized antibodies have one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, or CDR H3) that are altered relative to the parent antibody, which are also referred to as one or more CDRs "derived from" one or more CDRs of the parent antibody.

As used herein, "human antibody" means an antibody that has an amino acid sequence corresponding to that of an antibody produced by a human and/or that has been produced using any of the methods for producing human antibodies known to those skilled in the art or disclosed herein. This definition of a human antibody includes antibodies that comprise at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody that comprises murine light and heavy chain polypeptides. Human antibodies can be produced using a variety of methods known in the art. In one embodiment, the human antibody is selected from a phage library, wherein the phage library expresses human antibodies (Vaughan et al., Nature Biotechnology, 14:309-314, 1996; Sheets et al., Proc. Natl. Acad. Sci. (USA) 95:6157-6162, 1998; Hoogenboom and Winter, J. Mol. Biol., 227:381, 1991; Marks et al., J. Mol. Biol., 222:581, 1991). Human antibodies can also be produced by immunizing animals that have been transgenically introduced a human immunoglobulin locus in place of the endogenous locus, such as mice in which the endogenous immunoglobulin genes are partially or completely inactivated. Such an approach is described in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016. Alternatively, the human antibody can be produced by immortalizing human B lymphocytes that produce an antibody directed against a target antigen (such B lymphocytes can be obtained from the subject either by single-cell cloning of cDNA or can be immunized in vitro). See, e.g., Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J. Immunol., 147 (1):86-95, 1991; and U.S. Patent 5,750,373.

The term "chimeric antibody" is intended to mean antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

The terms "polypeptide", "oligopeptide", "peptide" and "protein" are used interchangeably herein to refer to chains of amino acids of any length, preferably relatively short (e.g. 10-100 amino acids). The chain may be linear or branched, it may contain modified amino acids and/or may be interrupted by non-amino acids. These terms also encompass an amino acid chain that is modified naturally or by intervention; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or by any other manipulation or modification, such as conjugation with a labeling component. Also included within this definition are, for example, polypeptides containing one or more amino acid analogues (including, for example, non-naturally occurring amino acids, etc.), as well as other modifications known in the art. It is understood that polypeptides may be in the form of single chains or associated chains.

A "monovalent antibody" contains one antigen-binding site per molecule (e.g., IgG or Fab). In some cases, a monovalent antibody may have more than one antigen-binding site, but these binding sites are from different antigens.

A "monospecific antibody" contains two identical antigen-binding sites on a molecule (e.g. IgG), so that the two binding sites bind to the same epitope on the antigen. They thus compete with each other for binding to a single antigen molecule. Most antibodies found in nature are monospecific. In some cases, a monospecific antibody may also be a monovalent antibody (e.g. Fab).

A "bivalent antibody" contains two antigen-binding sites per molecule (e.g., IgG). In some cases, the two binding sites have the same antigen specificity. However, bivalent antibodies can be bispecific.

A "bispecific antibody" or "dual-specificity antibody" is a hybrid antibody that has two different antigen-binding sites. The two antigen-binding sites of a bispecific antibody bind to two different epitopes, which may be on the same or different protein targets.

A "bifunctional antibody" is an antibody that has identical antigen-binding sites (i.e. identical amino acid sequences) in its two arms, but each binding site can recognize two different antigens.

"Heteromultimer", "heteromultimeric complex" or "heteromultimeric polypeptide" is a molecule comprising at least a first polypeptide and a second polypeptide, wherein the second polypeptide differs from the first polypeptide by at least one amino acid residue in the amino acid sequence. A heteromultimer may comprise a "heterodimer" formed by a first and second polypeptide, or may form higher order tertiary structures wherein, in addition to the first and second polypeptide, polypeptides are present.

A "heterodimer," "heterodimeric protein," "heterodimeric complex," or "heteromultimeric polypeptide" is a molecule comprising a first polypeptide and a second polypeptide, wherein the amino acid sequence of the second polypeptide differs from the amino acid sequence of the first polypeptide by at least one amino acid residue.

"Hinge region,""hingesequence," and variants thereof, when used herein, include the meaning known in the art, as illustrated, for example, in Janeway et al., ImmunoBiology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999); Bloom et al., Protein Science (1997), 6:407-415; Humphreys et al., J. Immunol. Methods (1997), 209:193-202.

"Immunoglobulin-like hinge region", "immunoglobulin-like hinge sequence" and variants thereof, as used herein, refer to a hinge region and hinge sequence of an immunoglobulin-like or antibody-like molecule (e.g., immunoadhesins). In some embodiments, the immunoglobulin-like hinge region may be of or derived from any subtype of IgG1, IgG2, IgG3, or IgG4, or from IgA, IgE, IgD, or IgM, including chimeric forms thereof, such as a chimeric IgG1/2 hinge region.

The term "immune effector cell" or "effector cell," as used herein, refers to a cell in the natural repertoire of cells of the human immune system that can be activated to affect the viability of a target cell. The viability of a target cell may include cell survival, proliferation, and/or the ability to interact with other cells.

The antibodies of the invention can be produced using methods well known in the art, such as recombinant technologies, phage display technology, synthetic methods, or combinations of these or other methods well known in the art (see, for example, Jayasena, S.D., Clin. Chem., 45: 1628-50, 1999 and Fellouse, F.A., et al, J. MoI. Biol., 373(4):924-40, 2007).

As is known in the art, "polynucleotide" or "nucleic acid," as used interchangeably herein, refers to chains of nucleotides of any length and includes DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. A polynucleotide may contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modification of the nucleotide structure may be done before and after assembly of the chain. The nucleotide sequence may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modification include, for example, "caps", substitutions of one or more natural nucleotides with an analogue, internucleotide modifications such as, for example, modifications with uncharged linkages (e.g. methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and with charged linkages (e.g. phosphorothioates, phosphorodithioates, etc.), modifications containing terminal groups such as, for example, proteins (e.g. nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), modifications with intercalators (e.g. acridine, psoralen, etc.), modifications containing chelating agents (e.g. metals, radioactive metals, boron, oxidizing metals, etc.), modifications containing alkylators, modifications with modified linkages (e.g. alpha-anomeric nucleic acids, etc.), as well as unmodified forms polynucleotide(s). In addition, any of the hydroxyl groups normally present in sugars can be replaced, for example, by phosphonate groups, phosphate groups, protected with standard protecting groups, or activated to provide additional linkages to additional nucleotides, or can be conjugated to solid supports. The 5'- and 3'-terminal OH can be phosphorylated or replaced by amines or organic cap groups of 1-20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups. Polynucleotides may also contain analogous forms of ribose or deoxyribose sugars that are commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, alpha- or beta-anomeric sugars, epimeric sugars such as arabinose, xyloses, or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and basic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein the phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR ₂ ("amidate"), P(O)R, P(O)OR', CO, or CH ₂ ("formacetal"), wherein each R or R' is independently H or a substituted or unsubstituted alkyl (1-20C), optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides mentioned herein, including RNA and DNA.

As is known in the art, a "constant region" of an antibody refers to the constant region of an antibody light chain or the constant region of an antibody heavy chain, alone or in combination.

As used herein, “substantially pure” refers to a substance that is at least 50% pure (i.e., free from contaminants), more preferably at least 90% pure, more preferably at least 95% pure, even more preferably at least 98% pure, and most preferably at least 99% pure.

"Host cell" includes a single cell or a cell culture that can be or are recipients of vector(s) for incorporating polynucleotide inserts. Host cells include progeny of a single host cell, and these progeny do not have to be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental or deliberate mutations. A host cell includes cells transfected in vivo with the polynucleotide(s) of the invention.

As is known in the art, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. The "Fc region" may be a native sequence Fc region or a variant Fc region. Although the boundaries of the immunoglobulin heavy chain Fc region may vary, the Fc region of the human IgG heavy chain is typically defined as the region from the amino acid residue at position Cys226, or from Pro230, to its carboxyl terminus. The numbering of the residues of the Fc region follows the EU index, as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The immunoglobulin Fc region typically contains two constant regions, CH2 and CH3.

As used in the art, "Fc receptor" and "FcR" describe a receptor that binds the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Further, a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. FcRs are reviewed in Ravetch and Kinet, Ann. Rev. Immunol., 9:457-92, 1991; Capel et al., Immunomethods, 4:25-34, 1994; and de Haas et al., J. Lab. Clin. Med., 126:330-41, 1995. "FcR" also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol., 117:587, 1976; and Kim et al., J. Immunol., 24:249, 1994).

The term "compete," as used herein with respect to an antibody, means that a first antibody, or antigen-binding fragment (or portion) thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or antigen-binding portion thereof, such that the binding of the first antibody to its cognate epitope is detectably reduced in the presence of the second antibody, compared to the binding of the first antibody in the absence of the second antibody. Alternatively, the binding of the second antibody to its epitope may also be detectably reduced in the presence of the first antibody, but this is not required. That is, the first antibody may inhibit the binding of the second antibody to its epitope without the second antibody inhibiting the binding of the first antibody to its corresponding epitope. However, when each antibody detectably inhibits the binding of the other antibody to its cognate epitope or ligand, either to the same or to a greater or lesser extent, the antibodies are said to "cross-compete" with each other for binding to their respective epitope(s). The present invention includes both competing and cross-competing antibodies. Regardless of the mechanism of such competition or cross-competition (e.g., steric hindrance, conformational change, or binding to a common epitope or portion thereof), one skilled in the art will determine, based on the teachings and guidance provided herein, that such competing and/or cross-competing antibodies are within the scope of the invention and may be useful in the methods described herein.

A "functional Fc region" has at least one effector function of a native sequence Fc region. Typical "effector functions" include C1q binding; complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity; phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptor), etc. Such effector functions typically require the combination of an Fc region with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays for assessing such antibody effector functions known in the art.

A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by at least one amino acid modification, while maintaining at least one effector function of the native sequence Fc region. In some embodiments, a variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to an Fc region of a parent polypeptide, such as from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in an Fc region of a parent polypeptide. The Fc region variant of the present invention preferably has at least about 80% sequence identity with the native sequence Fc region and/or with the Fc region of the parent polypeptide, and most preferably at least about 90% sequence identity therewith, more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% sequence identity therewith.

The term "effector function" refers to biological activities mediated by the Fc region of an antibody. Examples of antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), Fc receptor binding, complement-dependent cytotoxicity (CDC), phagocytosis, C1q binding, and down-regulation of cell surface receptors (e.g., B cell receptor; BCR). See, e.g., U.S. Patent 6,737,056. Such effector functions typically require the combination of an Fc region with a binding domain (e.g., an antibody variable domain) and can be assessed using a variety of antibody effector function assays known in the art. A typical measurement of effector function is by Fcγ3 and/or C1q binding.

As used herein, "antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a cell-mediated interaction in which non-specific cytotoxic cells that express Fc receptors (FcRs) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize an antibody bound to a target cell and subsequently cause lysis of the target cell. ADCC activity of a molecule of interest can be assessed using an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or U.S. Patent No. 5,821,337. Suitable effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and NK cells. Alternatively or additionally, ADCC activity of the molecule of interest can be assessed in vivo , such as in an animal model such as that described in Clynes et al., 1998, PNAS (USA) , 95:652-656.

"Complement-dependent cytotoxicity" or "CDC" refers to the lysis of a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g., an antibody) complexed with a cognate antigen. To assess complement activation, a CDC assay can be performed, such as described in Gazzano-Santoro et al., J. Immunol. Methods , 202: 163 (1996).

As used in this document, "treatment" is an approach to obtaining beneficial or desirable clinical results. In the context of the present invention, useful or desirable clinical results include, but are not limited to, one or more of the following: a decrease in the proliferation (or destruction) of tumor or cancer cells, inhibition of metastasis of neoplastic cells, remission of a BCMA-associated disease (e.g., cancer or an autoimmune disease), a decrease in the symptoms caused by a BCMA-associated disease (e.g., cancer or an autoimmune disease), an improvement in the quality of life of people suffering from a BCMA-associated disease (e.g., cancer or an autoimmune disease), a reduction in the dose of other drugs needed to treat a BCMA-associated disease (e.g., cancer or an autoimmune disease), a delay in the progression of a BCMA-associated disease (e.g., cancer or an autoimmune disease), a cure for a BCMA-associated disease (e.g., cancer or an autoimmune disease), and/or an increase in the survival of patients having a BCMA-associated disease (e.g., cancer or an autoimmune disease).

"Improvement" means a decrease or improvement in one or more symptoms compared to no administration of BCMA antibody or BCMA antibody conjugate. "Improvement" also includes a reduction or decrease in the duration of a symptom.

As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve any one or more beneficial or desirable results. For prophylactic use, beneficial or desirable results include elimination or reduction in the risk of, reduction in the severity of, or delay in the onset of a disease, including biochemical, histological, and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, beneficial or desirable results include clinical results such as a reduction in the incidence of disease or an improvement in one or more symptoms of various BCMA-associated diseases or conditions (e.g., multiple myeloma), a reduction in the dose of other drugs required to treat the disease, an enhancement of the effect of another drug, and/or a slowing of the progression of a BCMA-associated disease in patients. An effective dose may be administered in one or more administrations. In the context of the present invention, an effective dose of a drug, compound or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment directly or indirectly. As understood in a clinical context, an effective dosage of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administering one or more therapeutic agents, and one agent may be considered to be administered in an effective amount if, in combination with one or more other agents, the desired result can be achieved or is achieved.

"Subject" or "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.

As used herein, "vector" means a construct that is capable of delivering to a host cell, and preferably expressing therein, one or more genes or sequences of interest. 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.

As used herein, "expression control sequence" means a nucleic acid sequence that controls the transcription of a nucleic acid. An expression control sequence may be a promoter, such as a constitutive or inducible promoter, or an enhancer. The expression control sequence is operably linked to the nucleic acid sequence being transcribed.

As used herein, a "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any substance that, when combined with an active ingredient, allows the ingredient to retain biological activity and does not interact with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as phosphate buffered saline, water, emulsions such as an oil-in-water emulsion, and various types of humectants. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions containing such carriers are formulated into formulations by well-known conventional methods (see, e.g., Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005).

The term "acyl donor glutamine-containing tag" or "glutamine tag", as used herein, refers to a polypeptide or protein containing one or more Gln residues that acts as an amine transglutaminase acceptor. See, for example, WO2012059882 and WO2015015448.

The term "k _on " or "k _a ", as used herein, refers to the rate constant of association of an antibody with an antigen. More specifically, the rate constants (k _on /k _a and k _off /k _d ) and equilibrium dissociation constants are measured using whole antibody (i.e., bivalent) and monomeric BCMA proteins.

The term "k _off " or "k _d ", as used herein, refers to the rate constant for the dissociation of an antibody from an antibody/antigen complex.

The term "K _D ", as used herein, refers to the equilibrium dissociation constant of the antibody-antigen interaction.

A reference to “about” with respect to a value or parameter in this specification includes (and describes) embodiments that relate to that value or parameter as such. For example, a description that refers to “about X” includes a description of “X.” Numeric ranges include the values that define the range.

It is understood that all embodiments described herein using the word "comprising" also include otherwise similar embodiments described in terms of "consisting of" and/or "consisting essentially of."

When aspects or embodiments of the invention are described in terms of a Markush group or other group of alternatives, the present invention encompasses not only the entire group as a whole, but each member of the group separately and all possible subgroups of the main group, as well as cases where one or more members of the group are missing from the main group. The present invention also provides for the express exclusion of one or more members of the group from the claimed invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the present specification of the invention, including definitions, will control. Throughout the specification and claims, the word "comprise" or its variations such as "comprises" or "comprising" is intended to include the stated integer or group of integers, but does not exclude any other integer or group of integers. Unless the context otherwise requires, singular terms include the plural, and plural terms include the singular.

Examples of 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 are not intended to limit the invention.

BCMA antibodies and methods for their production

The present invention provides an antibody that binds to BCMA (e.g., human BCMA (e.g., SEQ ID NO: 353 or accession number Q02223-2) and is characterized by one or more of the following: (a) treating, preventing, ameliorating one or more symptoms of a condition associated with malignant cells expressing BCMA in a subject (e.g., a B-cell associated cancer such as multiple myeloma); (b) inhibiting tumor growth or progression in a subject (having a malignant tumor expressing BCMA); (c) inhibiting metastasis of cancerous (malignant) cells expressing BCMA in a subject (having one or more malignant cells expressing BCMA); (d) inducing regression (e.g., prolonged regression) of a tumor expressing BCMA; (e) inducing cytotoxic activity in malignant cells expressing BCMA; and (e) blocking the interaction BCMA with other, as yet unidentified factors.

In one aspect, an isolated antibody or antigen-binding fragment thereof is provided that specifically binds to a B cell maturation antigen (BCMA), wherein the antibody comprises (a) a heavy chain variable region (VH) comprising (1) a complementarity determining region, one (CDR1) of the VH comprising the sequence SYX ₁ MX ₂ , wherein X ₁ is A or P; and X ₂ is T, N, or S (SEQ ID NO: 301), GFTFX ₁ SY, wherein X ₁ is G or S (SEQ ID NO: 302), or GFTFX ₁ SYX ₂ MX ₃ , wherein X ₁ is G or S, X ₂ is A or P; and X ₃ is T, N, or S (SEQ ID NO: 303); (2) a VH CDR2 comprising the sequence AX ₁ X ₂ X ₃ X ₄ GX ₅ X ₆ X ₇ X ₈ YADX ₉ X ₁₀ KG, wherein X ₁ is I, V, T, H, L, A, or C; X ₂ is S, D, G, T, I, L, F, M, or V; X ₃ is G, Y, L, H, D, A, S, or M; X ₄ is S, Q, T, A, F, or W; X ₅ is G or T; X ₆ is N, S, P, Y, W, or F; X ₇ is S, T, I, L, T, A, R, V, K, G, or C; X ₈ is F, Y, P, W, H, or G; X ₉ is V, R, or L; and _X10 is G or T (SEQ ID NO: ₃₀₅ ) or _{X1X2X3X4X5X6 ,} wherein _X1 is S, _V , I, D, G, T, L, F or M; _X2 is G, Y, L, H, D, A, S or M; _X3 is S, G, F or W; _X4 is G or S; _X5 is G or T; and _X6 is N, S _, P, Y or W (SEQ ID NO: ₃₀₆ ); and 3) _a VH CDR3 comprising the sequence _VSPIX1X2X3X4 , wherein _X1 is A or Y; _X2 is A or S; and _X3 is G, Q, L, P or E (SEQ ID NO: ₃₀₇ ) or _{YWPMX1X2 ,} wherein _X1 is D, S _, T or A; and X ₂ is I, S, L, P or D (SEQ ID NO: 308); and/or a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence X ₁ X ₂ X ₃ X ₄ X ₅ X ₆ X ₇ X ₈ X ₉ X ₁₀ X ₁₁ X ₁₂ , wherein X ₁ is R, G, W, A or C; X ₂ is A, P, G, L, C or S; X ₃ is S, G or R; X ₄ is Q, C, E, V or I; X ₅ is S, P, G, A, R or D; X ₆ is V, G, I or L; X ₇ is S, E, D, P or G; X ₈ is S, P, F, A, M, E, V, N, D or Y; X ₉ is I, T, V, E, S, A, M, Q, Y, H, R or F; X ₁₀ is Y or F; X ₁₁ is L, W or P; and X ₁₂ is A, S or G (SEQ ID NO: 309); (2) a VL CDR2 comprising the sequence X ₁ ASX ₂ RAX ₃ , wherein X ₁ is G or D; X ₂ is S or I; and X ₃ is T or P (SEQ ID NO: 310); and (3) a VL CDR3 comprising the sequence QQYX ₁ X ₂ X ₃ PX ₄ T, wherein X ₁ is G, Q, E, L, F, A, S, M, K, R or Y; X ₂ is S, R, T, G, V, F, Y, D, A, H, V, E, K or C; X ₃ is W, F or S; and X ₄ is L or I (SEQ ID NO: 311) or QQYX ₁ X ₂ X ₃ PX ₄ , wherein X ₁ is G, Q, E, L, F, A, S, M, R, K or Y; X ₂ is S, R, T, G, R, V, D, A, H, E, K, C, F or Y; X ₃ is W, S or F; and X ₄ is L or I (SEQ ID NO: 312).

In another aspect, there is provided an isolated antibody or antigen-binding fragment thereof that specifically binds to BCMA, wherein the antibody comprises: a VH region comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH sequence set forth in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 112, 125, 127, 313, 314, 363 or 365; and/or a VL region comprising VL CDR1, VL CDR2 and VL CDR3 of the VL sequence shown in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 80, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 315, 316 or 364.

In some embodiments, an antibody is provided having any of the light chain subsequences shown in Table 1 and/or any of the heavy chain subsequences shown in Table 1.

Table 1 mAb Light Chain Heavy Chain P6E01/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYGSPPSFT FGQGTKVEIK (SEQ ID NO: 1) EVQLLESGGGLVQPGGSLRLSCAA SGFTF G SYAMT WVRQAPGKGLEWVS AISGSGGNTFYADSVKG RFTISRDN SKNTLYLQMNSLRAEDTAV YYCAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) P6E01/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYGSPPSFT FGQGTKVEIK (SEQ ID NO: 1) EVQLLESGGGLVQPGGSLRLSCAA SGFTF G SYAMT WVRQAPGKGLEWVS AISGSGGNTFYADSVKG RFTISRDN SKNTLYLQMNSLRAEDTAV YYCAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L1.LGF/ L3.KW /P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 4) EVQLLESGGGLVQPGGSLRLSCAA SGFTF G SYAMT WVRQAPGKGLEWVS AISGSGGNTFYADSVKG RFTISRDN SKNTLYLQMNSLRAEDTAV YYCAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L1.LGF/ L3.NY/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 5) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEWVS AISGSGGNTFYADSVKG RFTISRDN SKNTLYLQMNSLRAEDTAV YYCAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L1.GDF/ L3.NY/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 6) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEWVS AISGSGGNTFYADSVKG RFTISRDN SKNTLYLQMNSLRAEDTAVYYCA R VSPIASGMDY WGQGTLVTVSS(SEQ ID NO: 2) L1.LGF/ L3.KW/ H3.AL EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 4) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEWVS AISGSGGNTFYADSVKG RFTISRDN SKNTLYLQMNSLRAEDTAVYYCA R ARVSPIAALMDY WGQGTLVTVSS (SEQ ID NO: 7) L1.LGF/ L3.KW/ H3.AP EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 4) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYYCAR VSPIAAPMDY WGQGTLVTVSS (SEQ ID NO: 8) L1.LGF/ L3.KW/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 4) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L1.LGF/ L3.PY/ H3.AP EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ iD NO: 9) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAPMDY WGQGTLVTVSS (SEQ ID NO: 8) L1.LGF/ L3.PY/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 9) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L1.LGF/ L3.NY/ H3.AL EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 10) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAALMDY WGQGTLVTVSS (SEQ ID NO: 7) L1.LGF/ L3.NY/ H3.AP EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 10) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAPMDY WGQGTLVTVSS (SEQ ID NO: 8) L1.LGF/ L3.NY/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSLGSFYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 10) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L1.GDF/ L3.KW/ H3.AL EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 11) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAALMDY WGQGTLVTVSS (SEQ ID NO: 7) L1.GDF/ L3.KW/ H3.AP EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 11) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAPMDY WGQGTLVTVSS (SEQ ID NO: 8) L1.GDF/ L3.KW/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 11) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L1.GDF/ L3.PY/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 12) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L1.GDF/ L3.NY/ H3.AL EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 13) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAALMDY WGQGTLVTVSS (SEQ ID NO: 7) L1.GDF/ L3.NY/ H3.AP EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 13) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYYCAR VSPIAAPMDY WGQGTLVTVSS (SEQ ID NO: 8) L1.GDF/ L3.NY/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVGDFYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 14) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.KW/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KHYGWPPSFT FGQGTKVEIK (SEQ ID NO: 15) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.NY/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QHYNYPPSFT FGQGTKVEIK (SEQ ID NO: 17) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L1.PS/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L1.AH/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L1.FF/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L1.PH/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSPHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L3.KY/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L3.KF/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ H2.QR EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQRKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 24) L3.PY/ H2.DY EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AIDYSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 25) L3.PY/ H2.YQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISYQGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 26) L3.PY/ H2.LT EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISLTGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 27) L3.PY/ H2.HA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISHAGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 28) L3.PY/ H2.QL EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQLKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 29) L3.PY/ H3.YA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIYAGMDY WGQGTLVTVSS (SEQ ID NO: 30) L3.PY/ H3.AE EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAEMDY WGQGTLVTVSS (SEQ ID NO: 31) L3.PY/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.PY/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) L3.PY/ P6E01 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 16) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 2) L3.PY/ L1.PS/ H2.QR EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGS GTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQRKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 24) L3.PY/ L1.PS/ H2.DY EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AIDYSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 25) L3.PY/ L1.PS/ H2.YQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISYQGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 26) L3.PY/ L1.PS/ H2.LT EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISLTGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 27) L3.PY/ L1.PS/ H2.HA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISHAGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 28) L3.PY/ L1.PS/ H2.QL EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQLKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 29) L3.PY/ L1.PS/ H3.YA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIYAGMDY WGQGTLVTVSS (SEQ ID NO: 30) L3.PY/ L1.PS/ H3.AE EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAEMDY WGQGTLVTVSS (SEQ ID NO: 31) L3.PY/ L1.PS/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.PY/ L1.PS/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYPS WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 18) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) L3.PY/ L1.AH/ H2.QR EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQRKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 24) L3.PY/ L1.AH/ H2.DY EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AIDYSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 25) L3.PY/ L1.AH/ H2.YQ EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISYQGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 26) L3.PY/ L1.AH/ H2.LT EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISLTGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 27) L3.PY/ L1.AH/ H2.HA EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISHAGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 28) L3.PY/ L1.AH/ H2.QL EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQLKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 29) L3.PY/ L1.AH/ H3.YA EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIYAGMDY WGQGTLVTVSS (SEQ ID NO: 30) L3.PY/ L1.AH/ H3.AE EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAEMDY WGQGTLVTVSS (SEQ ID NO: 31) L3.PY/ L1.AH/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.PY/ L1.AH/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSAHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 19) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) L3.PY/ L1.FF/ H2.QR EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQRKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 24) L3.PY/ L1.FF/ H2.DY EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AIDYSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 25) L3.PY/ L1.FF/ H2.YQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISYQGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 26) L3.PY/ L1.FF/ H2.LT EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISLTGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 27) L3.PY/ L1.FF/ H2.HA EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISHAGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 28) L3.PY/ L1.FF/ H2.QL EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQLKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 29) L3.PY/ L1.FF/ H3.YA EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIYAGMDY WGQGTLVTVSS (SEQ ID NO: 30) L3.PY/ L1.FF/ H3.AE EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAEMDY WGQGTLVTVSS (SEQ ID NO: 31) L3.PY/ L1.FF/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.PY/ L1.FF/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSFFLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 20) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) L3.PY/ L1.PH/ H2.QR EIVLTQSPGTLSLSPGERATLSC RASQSVSPHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQRKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 24) L3.PY/ L1.PH/ H2.HA EIVLTQSPGTLSLSPGERATLSC RASQSVSPHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISHAGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 28) L3.PY/ L1.PH/ H3.AE EIVLTQSPGTLSLSPGERATLSC RASQSVSPHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAEMDY WGQGTLVTVSS (SEQ ID NO: 31) L3.PY/ L1.PH/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSPHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.PY/ L1.PH/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSPHYLA WYQQKPGQAP RLLIY GASSRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QHYPYPPSFT FGQGTKVEIK (SEQ ID NO: 21) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) L3.PY/ L3.KY/ H2.QR EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQRKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 24) L3.PY/ L3.KY/ H2.DY EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AIDYSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 25) L3.PY/ L3.KY/ H2.YQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISYQGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 26) L3.PY/ L3.KY/ H2.LT EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISLTGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 27) L3.PY/ L3.KY/ H2.HA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISHAGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 28) L3.PY/ L3.KY/ H2.QL EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQLKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 29) L3.PY/ L3.KY/ H3.YA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIYAGMDY WGQGTLVTVSS (SEQ ID NO: 30) L3.PY/ L3.KY/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KYYPYPPSFT FGQGTKVEIK (SEQ ID NO: 22) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) L3.PY/ L3.KF/ H2.DY EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AIDYSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYYCAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 25) L3.PY/ L3.KF/ H2.YQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISYQGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 26) L3.PY/ L3.KF/ H2.LT EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISLTGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 27) L3.PY/ L3.KF/ H2.QL EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADQLKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIASGMDY WGQGTLVTVSS (SEQ ID NO: 29) L3.PY/ L3.KF/ H3.YA EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIYAGMDY WGQGTLVTVSS (SEQ ID NO: 30) L3.PY/ L3.KF/ H3.AE EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAEMDY WGQGTLVTVSS (SEQ ID NO: 31) L3.PY/ L3.KF/ H3.AQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 3) L3.PY/ L3.KF/ H3.TAQ EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAT GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC KFYPYPPSFT FGQGTKVEIK (SEQ ID NO: 23) EVQLLESGGGLVQPGGSLRLSCAA SGFTFG SYAMT WVRQAPGKGLEW VS AISGSGGNTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR VSPIAAQMDY WGQGTLVTVSS (SEQ ID NO: 32) P5A2_VHVL EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QQYGSWPLT FGQGTKVEIK (SEQ ID NO: 34) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SDSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 33) A02_Rd4_0.6nM_C06 EIVLTQSPGTLSLSPGERATLSC RASQSVSVlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQRWPLT FGQGTKVEIK (SEQ ID NO: 36) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SDSGGS AWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 35) A02_Rd4_0.6nM_C09 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 38) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SDSGGS MWYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVY YCAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 37) A02_R d4_6n M_C16 EIVLTQSPGTLSLSPGERATLSC RASQSVSDlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQTWPLT FGQGTKVEIK (SEQ ID NO: 40) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdFGGS TYYADSVKGRRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 39) A02_R d4_6n M_C03 EIVLTQSPGTLSLSPGERATLSC RASQSVSNlYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYQGWPLT FGQGTKVEIK (SEQ ID NO: 41) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 33) A02_R d4_6n M_C01 EIVLTQSPGTLSLSPGERATLSC RASQSVSAyYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYERWPLT FGQGTKVEIK (SEQ ID NO: 43) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI TaSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 42) A02_R d4_6n M_C26 EIVLTQSPGTLSLSPGERATLSC RASQSVSSlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQVWPLT FGQGTKVEIK (SEQ ID NO: 45) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 44) A02_R d4_6n M_C25 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYLDWPLT FGQGTKVEIK (SEQ ID NO: 47) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS RWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMTP WGQGTLVTVSS (SEQ ID NO: 46) A02_R d4_6n M_C22 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQVWPLT FGQGTKVEIK (SEQ ID NO: 49) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAV LdSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMTP WGQGTLVTVSS (SEQ ID NO: 48) A02_R d4_6n M_C19 EIVLTQSPGTLSLSPGERATLSC RASQSVSVlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYLAWPLT FGQGTKVEIK (SEQ ID NO: 51) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS RWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSD WGQGTLVTVSS (SEQ ID NO: 50) A02_Rd4_0.6nM_C03 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYFTWPLT FGQGTKVEIK (SEQ ID NO: 53) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS KWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 52) A02_R d4_6n M_C07 EIVLTQSPGTLSLSPGERATLSC RASQSVSPyYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYERWPLT FGQGTKVEIK (SEQ ID NO: 55) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI GGSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 54) A02_R d4_6n M_C23 EIVLTQSPGTLSLSPGERATLSC RASQSVSVEYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYARWPLT FGQGTKVEIK (SEQ ID NO: 57) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS GWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 56) A02_R d4_0.6n M_C18 EIVLTQSPGTLSLSPGERATLSC RASQSVSElYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYFGWPLT FGQGTKVEIK (SEQ ID NO: 59) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAV LdSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 58) A02_R d4_6n M_C10 EIVLTQSPGTLSLSPGERATLSC RASQSVEMSYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYAHWPLT FGQGTKVEIK (SEQ ID NO: 61) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS CWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMTP WGQGTLVTVSS (SEQ ID NO: 60) A02_R d4_6n M_C05 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQRWPLT FGQGTKVEIK (SEQ ID NO: 63) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI FaSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMTP WGQGTLVTVSS (SEQ ID NO: 62) A02_R d4_0.6n M_C10 EIVLTQSPGTLSLSPGERATLSC RASQSVSAQYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYQRWPLT FGQGTKVEIK (SEQ ID NO: 65) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SgWGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 64) A02_R d4_6n M_C04 EIVLTQSPGTLSLSPGERATLSC RASQSVSAlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQVWPLT F GQGTKVEIK (SEQ ID NO: 67) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI MsSGGP LYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMAL WGQGTLVTVSS (SEQ ID NO: 66) A02_R d4_0.6n M_C26 EIVLTQSPGTLSLSPGERATLSC GPSQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 69) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI LmSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 68) A02_R d4_0.6n M_C13 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYWA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYESWPLT FGQGTKVEIK (SEQ ID NO: 71) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGY RYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 70) A02_Rd4_0.6nM_C01 EIVLTQSPGTLSLSPGERATLSC RGGQSVSSSYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 73) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI LsSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 72) A02_R d4_6n M_C08 EIVLTQSPGTLSLSPGERATLSC RASQSVSFlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYGSWPLT FGQGTKVEIK (SEQ ID NO: 75) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI LdSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSP WGQGTLVTVSS (SEQ ID NO: 74) P5C1_VHVL EIVLTQSPGTLSLSPGERATLSC RASQSVSSTYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QQYSTSPLT FGQGTKVEIK (SEQ ID NO: 77) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GGSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 76) C01_R d4_6n M_C24 EIVLTQSPGTLSLSPGERATLSC RASQSVSPEYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QQYSVWPLT FGQGTKVEIK (SEQ ID NO: 79) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GGSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_R d4_6n M_C26 EIVLTQSPGTLSLSPGERATLSC RASQSVSAlYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QQYSAWPLT FGQGTKVEIK (SEQ ID NO: 317) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GGSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS
(SEQ ID NO: 78) C01_R d4_6n M_C10 EIVLTQSPGTLSLSPGERATLSC RASQSVSSvYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QQYSTWPLT FGQGTKVEIK (SEQ ID NO: 79) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_Rd4_0.6nM_C27 EIVLTQSPGTLSLSPGERATLSC RASQSVSSTYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QQYSRWPLT FGQGTKVEIK (SEQ ID NO: 81) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_R d4_6n M_C20 EIVLTQSPGTLSLSPGERATLSC RASQSVSPlYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QQYSAFPLT FGQGTKVEIK (SEQ ID NO: 82) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_R d4_6n M_C12 EIVLTQSPGTLSLSPGERATLSC WLSQSVSSTYLA WYQQKPGQAP RLLIY DASSRAP GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYSEWPLT FGQGTKVEIK (SEQ ID NO: 84) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGW SYYADSVKGRRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 83) C01_Rd4_0.6nM_C16 EIVLTQSPGTLSLSPGERATLSC RASQSVSSTYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QQYSSWPLT FGQGTKVEIK (SEQ ID NO: 85) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_Rd4_0.6nM_C09 EIVLTQSPGTLSLSPGERATLSC RASQSVSSlFLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGSGTD FTLTISRLEPEDFAVYYC QQYSAWPLT FGQGTKVEIK (SEQ ID NO: 86) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_R d4_6n M_C09 EIVLTQSPGTLSLSPGERATLSC ACSQSVSSTYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QQYSAWPLT FGQGTKVEIK (SEQ ID NO: 88) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAT VgSGGS IGYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 87) C01_Rd4_0.6nM_C03 EIVLTQSPGTLSLSPGERATLSC RASCDVSSTYLA WYQQKPGQAP RLLIY DASSRAP GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYMRSPLT FGQGTKVEIK (SEQ ID NO: 89) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_Rd4_0.6nM_C06 EIVLTQSPGTLSLSPGERATLSC RASEAVPSTYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGGTD FTLTISRLEPEDFAVYYC QQYSAFPLT FGQGTKVEIK (SEQ ID NO: 90) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGTISRDN SKNTLYLQMNSLRAEDTAVYYCA R YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) C01_R d4_6n M_C04 EIVLTQSPGTLSLSPGERATLSC CSSQSVSSTYLA WYQQKPGQAPR LLIY DASSRAP GIPDRFSGSGTD FTLTISRLEPEDFAVYYC QQYSAFPLT FGQGTKVEIK (SEQ ID NO: 91) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) COMB O_Rd4_0.6nM_C22 EIVLTQSPGTLSLSPGERATLSC RASVRVSSTYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYMKWPLT FGQGTKVEIK (SEQ ID NO: 93) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGS RWYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CTR YWPMDI WGQGTLVTVSS (SEQ ID NO: 92) COMB O_Rd4_6nM_C21 EIVLTQSPGTLSLSPGERATLSC RASQSVSAAYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYMCWPLT FGQGTKVEIK (SEQ ID NO: 94) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) COMB O_Rd4_6nM_C10 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYWG WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYQCWPLT FGQGTKVEIK (SEQ ID NO: 96) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS IHYADSVKGRRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 95) COMB O_Rd4_0.6nM_C04 EIVLTQSPGTLSLSPGERATLSC RASQSVSSTYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 98) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAH IgSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 97) COMB O_Rd4_6nM_C25 EIVLTQSPGTLSLSPGERATLSC RASQSVSSpYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 100) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDP WGQGTLVTVSS (SEQ ID NO: 99) COMB O_Rd4_0.6nM_C21 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 38) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) COMB O_Rd4_6nM_C11 EIVLTQSPGTLSLSPGERATLSC RASQSVSPlYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYKAWPLT FGQGTKVEIK (SEQ ID NO: 102) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LGYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 101) COMB O_Rd4_0.6nM_C20 EIVLTQSPGTLSLSPGERATLSC RASQSVSYLYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYMEWPLT FGQGTKVEIK (SEQ ID NO: 103) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) COMB O_Rd4_6nM_C09 EIVLTQSPGTLSLSPGERATLSC RASQSVSAQYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYQAWPLT FGQGTKVEIK (SEQ ID NO: 105) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI FaSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 104) COMB O_Rd4_6nM_C08 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQKWPLT FGQGTKVEIK (SEQ ID NO: 107) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GGSGTw TYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVY YCAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 106) COMB O_Rd4_0.6nM_C19 EIVLTQSPGTLSLSPGERATLSC RASQSVSAvYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYRAWPLT FGQGTKVEIK (SEQ ID NO: 108) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) COMB O_Rd4_0.6nM_C02 EIVLTQSPGTLSLSPGERATLSC RASIAVSSTYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QQYMVWPLT FGQGTKVEIK (SEQ ID NO: 109) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 78) COMB O_Rd4_0.6nM_C23 EIVLTQSPGTLSLSPGERATLSC RPRQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQDWPLT FGQGTKVEIK (SEQ ID NO: 111) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAL FgSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 110) COMB O_Rd4_0.6nM_C29 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QQYQSWPLT FGQGTKVEIK (SEQ ID NO: 38) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 112) COMB O_Rd4_0.6nM_C09 EIVLTQSPGTLSLSPGERATLSC RASQSVSSTYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGSGT DFTLTISRLEPEDFAVYYC QQYQEWPLT FGQGTKVEIK (SEQ ID NO: 113) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 112) COMB O_Rd4_6nM_C12 EIVLTQSPGTLSLSPGERATLSC RASQSVSASYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYMSWPLT FGQGTKVEIK (SEQ ID NO: 115) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAA LgSGGS TYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVY YCAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 114) COMB O_Rd4_0.6nM_C30 EIVLTQSPGTLSLSPGERATLSC RASQSVSYMYLA WYQQKPGQAP RLLIY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYKSWPLT FGQGTKVEIK (SEQ ID NO: 116) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 76) COMB O_Rd4_0.6nM_C14 EIVLTQSPGTLSLSPGERATLSC RASQSVSAlYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYYGWPLT FGQGTKVEIK (SEQ ID NO: 117) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 112) COMB O_Rd4_6nM_C07 EIVLTQSPGTLSLSPGERATLSC RASQPISSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQGWPLT FGQGTKVEIK (SEQ ID NO: 119) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMAD WGQGTLVTVSS (SEQ ID NO: 118) COMB O_Rd4_6nM_C02 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYEFWPLT FGQGTKVEIK (SEQ ID NO: 121) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI SdSGGF VYYADSVKGRRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 120) COMB O_Rd4_0.6nM_C05 EIVLTQSPGTLSLSPGERATLSC RASQSVSSTYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYMSWPLT FGQGTKVEIK (SEQ ID NO: 123) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAI GgSGGS TYYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 122) COMB O_Rd4_0.6nM_C17 EIVLTQSPGTLSLSPGERATLSC RASQGISSTYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYAYWPLT FGQGTKVEIK (SEQ ID NO: 124) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAI GgSGGS LPYADSVKGRFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR YWPMDI WGQGTLVTVSS (SEQ ID NO: 112) COMB O_Rd4_6nM_C22 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLMY DASIRAT GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QQYQGWPLT FGQGTKVEIK (SEQ ID NO: 126) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMN WVRQAPGKGLEW VSAC LdSGGS TYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVY YCAR YWPMDS WGQGTLVTVSS (SEQ ID NO: 125) COMB O_Rd4_0.6nM_C11 EIVLTQSPGTLSLSPGERATLSC RASQSVSVRYLA WYQQKPGQAP RLLMY DASIRAT GIPDRFSGSGSG TDFTLTISRLEPEDFAVYYC QQYGSWPIT FGQGTKVEIK (SEQ ID NO: 128) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYPMS WVRQAPGKGLEW VSAA LGSGGS TYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVY YCAR YWPMSL WGQGTLVTVSS (SEQ ID NO: 127) Consensus EIVLTQSPGTLSLSPGERATLSC X ₁ X ₂ X ₃ X ₄ X ₅ X ₆ X ₇ X ₈ X ₉ X ₁₀ X ₁₁ X ₁₂ WYQQKPGQAPRLLMYX ₁₃ ASX ₁₄ RAX ₁₅ GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC X ₁₆ X ₁₇ YX ₁₈ X ₁₉ PPSFTFG QGTKVEIK where X ₁ is R, G, W, A, or C; X ₂ is A, P, G, L, C, or S; X ₃ is S, G, or R; X ₄ is Q, C, E, V, or I; X ₅ is S, P, G, A, R, or D; X ₆ is V, G, I, or L; X ₇ is S, E, D, P, or G; X ₈ is S, P, F, A, M, E, V, N, D or Y; X ₉ is I, T, V, E, S, A, M, Q, Y, H, R or F; X ₁₀ is Y or F; X ₁₁ is L, W or P; X ₁₂ is A, S or G, X ₁₃ is G or D; X ₁₄ is S or I; X ₁₅ is T or P; X ₁₆ is Q or K; X ₁₇ is H or Y; X ₁₈ is G, N or P; and X ₁₉ is S, W or Y (SEQ ID NO: 315); or
EIVLTQSPGTLSLSPGERATLSC X ₁ X ₂ X ₃ X ₄ X ₅ X ₆ X ₇ X ₈ X ₉ X ₁₀ X ₁₁ X ₁₂ WYQQKPGQAPRLLMYX ₁₃ ASX ₁₄ RAX ₁₅ GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQY X ₁₆ X ₁₇ X ₁₈ PX ₁₉ FGQGTKVEIK where X ₁ is R, G, W, A or C; X ₂ is A, P, G, L, C or S; X ₃ is S, G or R; X ₄ is Q, C, E, V or I; X ₅ is S, L, P, G, A, R or D; X ₆ is V, G or I; X ₇ is S, E, D or P; X ₈ is S, P, F, A, M, E, V, N, D or Y; X ₉ is I, T, V, E, S, A, M, Q, Y, H or R; X ₁₀ is Y or F; X ₁₁ is L, W or P; X ₁₂ is A, S or G, X ₁₃ is G or D; X ₁₄ is S or I; X ₁₅ is T or P; X ₁₆ is G, Q, E, L, F, A, S, M, R, K or Y; X ₁₇ is S, R, T, G, R, V, D, A, H, E, K, C, F or Y; X ₁₈ is W, S or F; and X ₁₉ is L or I (SEQ ID NO: 316) EVQLLESGGGLVQPGGSLRLSCAA SGFTFX ₁ SYX ₂ MX ₃ WVRQAPGKGLE WVSAX ₄ X ₅ X ₆ X ₇ GX ₈ X ₉ X ₁₀ X ₁₁ YAD X ₁₂ X ₁₃ KGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCARVSPI X ₁₄ X ₁₅ X ₁₆ MDYWGQGTLVTVSS where X ₁ is G or S, X ₂ is A or P; X ₃ is T, N, or S; X ₄ is I, V, T, H, L, A, or C; X ₅ is S, D, G, T, I, L, F, M, or V; X ₆ is G, Y, L, H, D, A, S, or M; X ₇ is S, Q, T, A, F, or W; X ₈ is G or T; X ₉ is N, S, P, Y, W or F; X ₁₀ is S, T, I, L, T, A, R, V, K, G or C; X ₁₁ is F, Y, P, W, H or G; X ₁₂ is V, R or L; X ₁₃ is G or T; X ₁₄ is A or Y; X ₁₅ is A or S; and X ₁₆ is G, Q, L, P or E (SEQ ID NO: 313); or
EVQLLESGGGLVQPGGSLRLSCAA SGFTFX ₁ SYX ₂ MX ₃ WVRQAPGKGLE WVSAX ₄ X ₅ X ₆ X ₇ GX ₈ X ₉ X ₁₀ X ₁₁ YAD X ₁₂ X ₁₃ KGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCARYWPMX ₁₄ X ₁₅ WGQGTLVTVSS where X ₁ is G or S, X ₂ is A or P; X ₃ is T, N, or S; X ₄ is I, V, T, H, L, A, or C; X ₅ is S, D, G, T, I, L, F, M, or V; X ₆ is G, Y, L, H, D, A, S, or M; X ₇ is S, Q, T, A, F, or W; X ₈ is G or T; X ₉ is N, S, P, Y, W or F; X ₁₀ is S, T, I, L, T, A, R, V, K, G or C; X ₁₁ is F, Y, P, W, H or G; X ₁₂ is V, R or L; X ₁₃ is G or T; X ₁₄ is D, S, T or A; and X ₁₅ is I, S, L, P or D (SEQ ID NO: 314) P4G4 EIVLTQSPGTLSLSPGERATLSC RASQSVSSSYLA WYQQKPGQAPR LLIY GASSRAY GIPDRFSGSGGT DFTLTISRLEPEDFAVYYC QHYGSPPLFT FGQGTKVEIK (SEQ ID NO: 80) EVQLLESGGGLVQPGGSLRLSCAA SGFTFS SYAMS WVRQAPGKGLEW VS AISASGGSTYYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAR LSWSGAFDN WGQGTLVTVSS (SEQ ID NO: 363) P1A11 EIVLTQSPGTLSLSPGERATLSC RASQNVSSSYLA WYQQKPGQAP RLLIY GASYRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QHYGSPPSFT FGQGTKVEIK (SEQ ID NO: 364) EVQLLESGGGLVQPGGSLRLSCAA SGFTFR SYAMS WVRQAPGKGLEW VS AISgSGGSTFYADSVKG RFTISR DNSKNTLYLQMNSLRAEDTAVYY CAT VGTSGAFGI WGQGTLVTVSS (SEQ ID NO: 365)

In Table 1, the underlined sequences are Kabat CDR sequences and the bolded sequences are Chothia CDR sequences, except for the following heavy chain CDR2 sequences, where the underlined sequences are Chothia CDR sequences and the bolded sequences are Kabat CDR sequences:

P5A2_VHVL, A02_Rd4_0.6nM_C06, A02_Rd4_0.6nM_C09

A02_Rd4_6nM_C16, A02_Rd4_6nM_C03, A02_Rd4_6nM_C01, A02_Rd4_6nM_C26

A02_Rd4_6nM_C25, A02_Rd4_6nM_C22, A02_Rd4_6nM_C19, A02_Rd4_0.6nM_C03

A02_Rd4_6nM_C07, A02_Rd4_6nM_C23, A02_Rd4_0.6nM_C18, A02_Rd4_6nM_C10

A02_Rd4_6nM_C05, A02_Rd4_0.6nM_C10, A02_Rd4_6nM_C04, A02_Rd4_0.6nM_C26

A02_Rd4_0.6nM_C13, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C08, P5C1_VHVL,

C01_Rd4_6nM_C24, C01_Rd4_6nM_C26, C01_Rd4_6nM_C10, C01_Rd4_0.6nM_C27

C01_Rd4_6nM_C20, C01_Rd4_6nM_C12, C01_Rd4_0.6nM_C16, C01_Rd4_0.6nM_C09

C01_Rd4_6nM_C09, C01_Rd4_0.6nM_C03, C01_Rd4_0.6nM_C06, C01_Rd4_6nM_C04

COMBO_Rd4_0.6nM_C22, COMBO_Rd4_6nM_C21, COMBO_Rd4_6nM_C10,

COMBO_Rd4_0.6nM_C04, COMBO_Rd4_6nM_C25, COMBO_Rd4_0.6nM_C21,

COMBO_Rd4_6nM_C11, COMBO_Rd4_0.6nM_C20, COMBO_Rd4_6nM_C09,

COMBO_Rd4_6nM_C08, COMBO_Rd4_0.6nM_C19, COMBO_Rd4_0.6nM_C02,

COMBO_Rd4_0.6nM_C23, COMBO_Rd4_0.6nM_C29, COMBO_Rd4_0.6nM_C09,

COMBO_Rd4_6nM_C12, COMBO_Rd4_0.6nM_C30, COMBO_Rd4_0.6nM_C14,

COMBO_Rd4_6nM_C07, COMBO_Rd4_6nM_C02, COMBO_Rd4_0.6nM_C05,

COMBO_Rd4_0.6nM_C17, COMBO_Rd4_6nM_C22 and COMBO_Rd4_0.6nM_C11.

The invention also provides CDR regions of anti-BCMA antibodies (including Chothia, Kabat, and contact CDR regions). The definition of CDR regions is well known in the art. It is understood that in some embodiments, the CDRs may be a combination of Kabat and Chothia CDRs (also referred to as "combined CRs" or "extended CDRs"). In some embodiments, the CDRs are Kabat CDRs. In other embodiments, the CDRs are Chothia CDRs. In other words, in embodiments with more than one CDR, the CDRs may be any of Kabat, Chothia, combined CDRs, or a combination thereof. Table 2 provides exemplary CDR sequences provided herein.

Table 2 Heavy chain mAb CDRH1 CDRH2 CDRH3 P6E01
For the following mAbs:
P6E01/P6E01;L1.LGF/L3.KW/P6EO1; L1.LGF/L3.NY/P6E01; L1.GDF/L3.NY/P6E01; L3.KW/P6E01; L3.PY/P6E01; L3.NY/P6E01; L3.PY/L1.PS/P6E01; L3.PY/L1.AH/P6E01; L3.PY/L1.FF/P6E01; L3.PY/L1.PH/P6E01; L3.PY/L3.KY/P6E01; L3.PY/L3.KF/P6E01; and L3.PY/P6E01. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H3.AQ
For the following mAbs:
P6E01/H3.AQ; L1.LGF/L3.KW/H3.AQ;
L1.LGF/L3.PY/H3.AQ; L1.LGF/L3.NY/H3.AQ; L1.GDF/L3.KW/H3.AQ; L1.GDF/L3.PY/H3.AQ; L1.GDF/L3.NY/H3.AQ; L3.PY/H3.AQ; L3.PY/L1.PS/H3.AQ; L3.PY/L1.AH/H3.AQ; L3.PY/L1.FF/H3.AQ; L3.PY/L1.PH/H3.AQ; and L3.PY/L3.KF/H3.AQ. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIAAQMDY (SEQ ID NO: 135) H3.AL
For the following mAbs:
L1.LGF/L3.KW/H3.AL; L1.LGF/L3.NY/H3.AL; and L1.GDF/L3.NY/H3.AL. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIAALMDY
(SEQ ID NO: 136) H3.AP
For the following mAbs:
L1.LGF/L3.KW/H3.AP; L1.LGF/L3.PY/H3.AP; L1.LGF/L3NY/H3.AP; L1.GDF/L3.KW/H3.AP; and L1.GDF/L3NY/H3.AP. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIAAPMDY
(SEQ ID NO: 137) H2.QR
For the following mAbs:
L3.PY/H2.QR; L3.PY/L1.PS/H2.QR; L3.PY/L1.AH/H2.QR; L3.PY/L1.FF/H2.QR; L3.PY/L1.PH/H2.QR; and L3.PY/L3.KY/H2.QR. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADQRKG (SEQ ID NO: 138) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H2.DY
For the following mAbs:
L3.PY/H2.DY; L3.PY/L1.PS/H2.DY; L3.PY/L1.AH/H2.DY; L3.PY/L1.FF/H2.DY; L3.PY/L3.KY/H2.DY; and L3.PY/L3.KF/H2.DY. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AIDYSGGNTFYADSVKG (SEQ ID NO: 139) (Kabat)
DYSsgN (SEQ ID NO:140) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H2.YQ
For the following mAbs:
L3.PY/H2.YQ; L3.PY/L1.PS/H2.YQ; L3.PY/L1.AH/H2.YQ; L3.PY/L1.FF/H2.YQ; L3.PY/L3.KY/H2.YQ; and L3.PY/L3.KF/H2.YQ. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISYQGGNTFYADSVKG (SEQ ID NO: 141) (Kabat)
SYQGGN (SEQ ID NO:142) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H2.LT
For the following mAbs:
L3.PY/H2.LT; L3.PY/L1.PS/H2.LT; L3.PY/L1.AH/H2.LT; L3.PY/L1.FF/H2.LT; L3.PY/L3.KY/H2.LT; and L3.PY/L3.KF/H2.LT. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISLTGGNTFYADSVKG (SEQ ID NO: 143) (Kabat)
SLTGGN (SEQ ID NO:144) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H2.HA
For the following mAbs:
L3.PY/H2.HA; L3.PY/L1.AH/H2.HA; L3.PY/L1.FF/H2.HA; L3.PY/L1.PH/H2.HA; and L3.PY/L3.KY/H2.HA. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISHAGNTFYADSVKG (SEQ ID NO: 145) (Kabat)
SHAGGN (SEQ ID NO:146) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H2.QL
For the following mAbs:
L3.PY/H2.QL; L3.PY/L1.PS/H2.QL; L3.PY/L1.AH/H2.QL; L3.PY/L1.FF/H2.QL; L3.PY/L3.KY/H2.QL; and L3.PY/L3.KF/H2.QL. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADQLKG (SEQ ID NO: 147) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIASGMDY (SEQ ID NO: 134) H3.YA
For the following mAbs:
L3.PY/H3.YA; L3.PY/L1.PS/H3.YA; L3.PY/L1.AH/H3.YA; L3.PY/L1.FF/H3.YA; L3.PY/L3.KY/H3.YA; and L3.PY/L3.KF/H3.YA. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIYAGMDY (SEQ ID NO: 148) H3.AE
For the following mAbs:
L3.PY/H3.AE; L3.PY/L1.AH/H3.AE; L3.PY/L1.FF/H3.AE; L3.PY/L1.PH/H3.AE; and L3.PY/L3.KF/H3.AE. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIAAEMDY (SEQ ID NO: 149) H3.TAQ
For the following mAbs:
L3.PY/H3.TAQ;
L3.PY/L1.PS/H3.TAQ; L3.PY/L1.AH/H3.TAQ; L3.PY/L1.FF/H3.TAQ; L3.PY/L1.PH/H3.TAQ; and L3.PY/L3.KF/H3.TAQ. syAMT (SEQ ID NO: 129) (Kabat);
gfTFGSY (SEQ ID NO: 130) (Chothia);
gfTFGSYAMT (SEQ ID NO: 131) (extended) AISGSGGNTFYADSVKG (SEQ ID NO: 132) (Kabat)
SGSGGN (SEQ ID NO:133) (Chothia) VSPIAAQMDY (SEQ ID NO: 135) P5A2_VHVL and
A02_Rd4_6nM_C03 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSTYYADSVKG
(SEQ ID NO: 153) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMDI (SEQ ID NO: 155) COMBO_Rd4_0.6nM_C17; COMBO_Rd4_0.6nM_C14; COMBO_Rd4_0.6nM_C29; and COMBO_Rd4_0.6nM_C09 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSLPYADSVKG
(SEQ ID NO: 158) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDI (SEQ ID NO: 155) C01_Rd4_6nM_C04; C01_Rd4_0.6nM_C03; C01_Rd4_0.6nM_C06; COMBO_Rd4_0.6nM_C02; COMBO_Rd4_6nM_C21; C01_Rd4_6nM_C26; COMBO_Rd4_0.6nM_C19; C01_Rd4_6nM_C24; C01_Rd4_6nM_C20; C01_Rd4_0.6nM_C09; COMBO_Rd4_0.6nM_C21; C01_Rd4_0.6nM_C04_C27; C01_Rd4_0.6nM_C16; C01_Rd4_6nM_C10; COMBO_Rd4_0.6nM_C20 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSLPYADSVKG
(SEQ ID NO: 158) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDS (SEQ ID NO: 161) P5C1_VHVL and COMBO_Rd4_0.6nM_C30 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSTYYADSVKG
(SEQ ID NO: 162) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDS (SEQ ID NO: 161) A02_Rd4_0.6nM_C06 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSAWYADSVKG
(SEQ ID NO: 163) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_0.6nM_C09 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSAWYADSVKG
(SEQ ID NO: 163) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_0.6nM_C16 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDFGGSTYYADSVKG
(SEQ ID NO: 165) (Kabat)
SDFGGS (SEQ ID NO: 166) (Chothia) YWPMDI (SEQ ID NO: 155) A02_Rd4_6nM_C01 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AITASGGSTYYADSVKG
(SEQ ID NO: 167) (Kabat)
TASGGS (SEQ ID NO: 168) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_6nM_C26 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSTYYADSVKG
(SEQ ID NO: 153) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_6nM_C25 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSRWYADSVKG
(SEQ ID NO: 169) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMTP (SEQ ID NO: 170) A02_Rd4_6nM_C22 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AVLDSGGSTYYADSVKG
(SEQ ID NO: 171) (Kabat)
LDSGGS (SEQ ID NO: 172) (Chothia) YWPMTP (SEQ ID NO: 170) A02_Rd4_6nM_C19 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSRWYADSVKG
(SEQ ID NO: 169) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMSD (SEQ ID NO: 173) A02_Rd4_0.6nM_C03 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSKWYADSVKG (SEQ ID NO: 174) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_6nM_C07 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AIGGSGGSLPYADSVKG(SEQ ID NO: 158) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDS (SEQ ID NO: 161) A02_Rd4_6nM_C23 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSGWYADSVKG (SEQ ID NO: 175) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_0.6nM_C18 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AVLDSGGSTYYADSVKG
(SEQ ID NO: 171) (Kabat)
LDSGGS (SEQ ID NO: 172) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_6nM_C10 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSCWYADSVKG (SEQ ID NO: 176) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMTP (SEQ ID NO: 170) A02_Rd4_6nM_C05 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AIFASGGSTYYADSVKG
(SEQ ID NO: 177) (Kabat)
FASGGS (SEQ ID NO: 178) (Chothia) YWPMTP (SEQ ID NO: 170) A02_Rd4_0.6nM_C10 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISGWGGSLPYADSVKG
(SEQ ID NO: 304) (Kabat)
SGWGGS (SEQ ID NO: 179) (Chothia) YWPMDS (SEQ ID NO: 161) A02_Rd4_6nM_C04 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AIMSSGGPLYYADSVKG
(SEQ ID NO: 180) (Kabat)
MSSGGP (SEQ ID NO: 181) (Chothia) YWPMAL (SEQ ID NO: 182) A02_Rd4_0.6nM_C26 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AILMSGGSTYYADSVKG
(SEQ ID NO: 183) (Kabat)
LMSGGS (SEQ ID NO: 184) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_0.6nM_C13 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGYRYYADSVKG
(SEQ ID NO: 185) (Kabat)
SDSGGY (SEQ ID NO: 186) (Chothia) YWPMSL (SEQ ID NO: 164) A02_Rd4_0.6nM_C01 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AILSSGGSTYYADSVKG
(SEQ ID NO: 187) (Kabat)
LSSGGS (SEQ ID NO: 188) (Chothia) YWPMDI (SEQ ID NO: 155) A02_Rd4_6nM_C08 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AILDSGGSTYYADSVKG (SEQ ID NO: 160) (Kabat)
LDSGGS (SEQ ID NO: 172) (Chothia) YWPMSP (SEQ ID NO: 189) C01_Rd4_6nM_C12 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGWSYYADSVKG
(SEQ ID NO: 190) (Kabat)
GGSGGW (SEQ ID NO: 191) (Chothia) YWPMDS (SEQ ID NO: 161) C01_Rd4_6nM_C09 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) ATVGSGGSIGYADSVKG
(SEQ ID NO: 192) (Kabat)
VGSGGS (SEQ ID NO: 193) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_0.6nM_C22 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGSRWYADSVKG
(SEQ ID NO: 169) (Kabat)
SDSGGS (SEQ ID NO: 154) (Chothia) YWPMDI (SEQ ID NO: 155) COMBO_Rd4_0.6nM_C10 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSIHYADSVKG (SEQ ID NO: 194) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_0.6nM_C04 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AHIGSGGSTYYADSVKG (SEQ ID NO: 195) (Kabat)
IGSGGS (SEQ ID NO: 196) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_0.6nM_C25 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSTYYADSVKG
(SEQ ID NO: 162) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDP (SEQ ID NO: 197) COMBO_Rd4_6nM_C21 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSLPYADSVKG
(SEQ ID NO: 158) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_6nM_C11 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSLGYADSVKG
(SEQ ID NO: 198) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_6nM_C09 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIFASGGSTYYADSVKG
(SEQ ID NO: 177) (Kabat)
FASGGS (SEQ ID NO: 178) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_6nM_C08 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGTWTYYADSVKG
(SEQ ID NO: 199) (Kabat)
GGSGTW (SEQ ID NO: 200) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_0.6nM_C23 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) ALFGSGGSTYYADSVKG
(SEQ ID NO: 201) (Kabat)
FGSGSGS
(SEQ ID NO: 202) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_0.6nM_C12 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AALGSGGSTYYADSVKG (SEQ ID NO: 203) (Kabat)
LGSGGS (SEQ ID NO: 204) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_6nM_C07 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AIGGSGGSLPYADSVKG
(SEQ ID NO: 158) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMAD (SEQ ID NO: 205) COMBO_Rd4_6nM_C02 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AISDSGGFVYYADSVKG
(SEQ ID NO: 206) (Kabat)
SDSGGF (SEQ ID NO: 207) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_6nM_C05 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) AIGGSGGSTYYADSVKG
(SEQ ID NO: 162) (Kabat)
GGSGGS (SEQ ID NO: 159) (Chothia) YWPMSL (SEQ ID NO: 164) COMBO_Rd4_6nM_C22 syAMN (SEQ ID NO: 150) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMN (SEQ ID NO: 152) (extended) ACLDSGGSTYYADSVKG (SEQ ID NO: 208) (Kabat)
LDSGGS (SEQ ID NO: 172) (Chothia) YWPMDS (SEQ ID NO: 161) COMBO_Rd4_6nM_C11 syPMS (SEQ ID NO: 156) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
GFTFSSYPMS (SEQ ID NO: 157) (extended) AALGSGGSTYYADSVKG (SEQ ID NO: 203) (Kabat)
LGSGGS (SEQ ID NO: 204) (Chothia) YWPMSL (SEQ ID NO: 164) Consensus sequence of the heavy chain SYX ₁ MX ₂ , where X ₁ is A or P; and X ₂ is T, N or S (Kabat) (SEQ ID NO: 301)
GFTFX ₁ SY, where X ₁ is G or S (Chothia) (SEQ ID NO: 302)
GFTFX ₁ SYX ₂ MX ₃ , where X ₁ is G or S, X ₂ is A or P; and X ₃ is T, N or S (SEQ ID NO: 303) (extended) AX ₁ X ₂ X ₃ X ₄ GX ₅ X ₆ X ₇ X ₈ YADX ₉ X ₁₀ KG, where X ₁ is I, V, T, H, L, A or C; X ₂ is S, D, G, T, I, L, F, M or V; X ₃ is G, Y, L, H, D, A, S or M; X ₄ is S, Q, T, A, F or W; X ₅ is G or T; X ₆ is N, S, P, Y, W or F; X ₇ is S, T, I, L, A, R, V, K, G or C; X ₈ is F, Y, P, W, H or G; X ₉ is V, R or L; and X ₁₀ is G or T (Kabat) (SEQ ID NO: 305)
X ₁ X ₂ X ₃ X ₄ X ₅ X _6, wherein X ₁ is S, V, I, D, G, T, L, F or M; X ₂ is G, Y, L, H, D, A, S or M; X ₃ is S, G, F or W; X ₄ is G or S; X ₅ is G or T; and X ₆ is N, S, P, Y or W (Chothia) (SEQ ID NO: 306) VSPIX ₁ X ₂ X ₃ MDY _, where X ₁ is A or Y; X ₂ is A or S; and X ₃ is G, Q, L, P or E (SEQ ID NO: 307)
YWPMX ₁ X _2, where X ₁ is D, S, T, or A; and X ₂ is I, S, L, P, or D (SEQ ID NO: 308) P4G4 syAMS (SEQ ID NO: 366) (Kabat);
gfTFSSY (SEQ ID NO: 151) (Chothia);
gfTFSSYAMS (SEQ ID NO: 367) (extended) SASGGS (SEQ ID NO: 368) (Chotia)
AISASGGSTYYADSVKG (SEQ ID NO: 369) (Kabat) LSWSGAFDN (SEQ ID NO: 370) P1A11 syAMS (SEQ ID NO: 366) (Kabat);
GFTFRSY (SEQ ID NO: 371)
GFTFRSYAMS (SEQ ID NO: 372) SGSGGS (SEQ ID NO: 359) (Chotia)
AISGSGGSTFYADSVKG (SEQ ID NO: 360) (Kabat) VGTSGAFGI (SEQ ID NO: 361) Light Chain mAb CDRL1 CDRL2 CDRL3 P6E01
For the following mAbs:
P6E01/P6E01; and P6E01/H3.AQ. RASQSVSSSYLA (SEQ ID NO: 209) GASSRAT (SEQ ID NO: 210) QHYGSPPSFT (SEQ ID NO: 211) L1.LGF/L3.KW
For the following mAbs:
L1.LGF/L3.KW/P6E01; L1.LGF/L3.KW/H3.AL; L1.LGF/L3.KW/H3.AP; and L1.LGF/L3.KW/H3.AQ RASQSLGSFYLA
(SEQ ID NO: 212) GASSRAT (SEQ ID NO: 210) KHYGWPPSFT (SEQ ID NO: 213) L1.LGF/L3.NY
For the following mAbs:
L1.LGF/L3.NY/P6E01; L1.LGF/L3.NY/H3.AL; L1.LGF/L3.NY/H3.AP; and L1.LGF/L3.NY/H3AQ RASQSLGSFYLA
(SEQ ID NO: 212) GASSRAT (SEQ ID NO: 210) QHYNYPPSFT (SEQ ID NO: 214) L1.GDF/L3.NY
For the following mAbs:
L1.GDF/L3.NY/P6E01; L1.GDF/L3.NY/H3.AL; L1.GDF/L3.NY/H3.AP; and L1.GDF/L3.NY/H3.AQ RASQSVGDFYLA
(SEQ ID NO: 215) GASSRAT (SEQ ID NO: 210) QHYNYPPSFT (SEQ ID NO: 214) L1.LGF/L3.PY
For the following mAbs:
L1.LGF/L3.PY/H3.AP; and L1.LGF/L3.PY/H3.AQ RASQSLGSFYLA
(SEQ ID NO: 212) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT
(SEQ ID NO: 216) L1.GDF /L3.KW
For the following mAbs:
L1.GDF/L3.KW/H3.AL; L1.GDF /L3.KW/H3.AP; and L1.GDF /L3.KW/H3.AQ RASQSVGDFYLA
(SEQ ID NO: 215) GASSRAT (SEQ ID NO: 210) KHYGWPPSFT (SEQ ID NO: 213) L1.GDF/L3.PY/H3.AQ RASQSVGDFYLA
(SEQ ID NO: 215) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT (SEQ ID NO: 216) L3.KW/P6E01 RASQSVSSSYLA (SEQ ID NO: 209) GASSRAT (SEQ ID NO: 210) KHYGWPPSFT (SEQ ID NO: 213) L3.PY
For the following mAbs:
L3.PY/P6E01; L3.PY/H2.QR; L3.PY/H2.DY; L3.PY/H2.YQ; L3.PY/H2.LT; L3.PY/H2.HA; L3.PY/H2.QL; L3.PY/H3.YA; L3.PY/H3.AE; L3.PY/H3.AQ; L3.PY/H3.TAQ RASQSVSSSYLA (SEQ ID NO: 209) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT
(SEQ ID NO: 216) L3.NY/P6E01 RASQSVSSSYLA (SEQ ID NO: 209) GASSRAT (SEQ ID NO: 210) QHYNYPPSFT
(SEQ ID NO: 214) L3.PY/L1.PS
For the following mAbs:
L3.PY/L1.PS
/P6E01;
L3.PY/L1.PS/H2.QR; L3.PY/L1.PS/H2.DY; L3.PY/L1.PS/H2.YQ; L3.PY/L1.PS/H2.LT; L3.PY/L1.PS/H2.HA; L3.PY/L1.PS/H2.QL; L3.PY/L1.PS/H3.YA; L3.PY/L1.PS/H3.AE; L3.PY/L1.PS/H3.AQ; L3.PY/L1.PS/H3.TAQ RASQSVSSSYPS
(SEQ ID NO: 217) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT
(SEQ ID NO: 216) L3.PY/L1.AH
For the following mAbs:
L3.PY/L1.AH/P6E01; L3.PY/L1.AH/H2.QR; L3.PY/L1.AH/H2.DY; L3.PY/L1.AH/H2.YQ; L3.PY/L1.AH/H2.LT; L3.PY/L1.AH/H2.HA; L3.PY/L1.AH/H2.QL; L3.PY/L1.AH/H3.YA; L3.PY/L1.AH/H3.AE; L3.PY/L1.AH/H3.AQ; L3.PY/L1.AH/H3.TAQ RASQSVSAHYLA
(SEQ ID NO: 218) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT
(SEQ ID NO: 216) L3.PY/L1.FF
For the following mAbs:
L3.PY/L1.FF/P6E01; L3.PY/L1.FF/H2.QR; L3.PY/L1.FF/H2.DY; L3.PY/L1.FF/H2.YQ; L3.PY/L1.FF/H2.LT; L3.PY/L1.FF/H2.HA; L3.PY/L1.FF/H2.QL; L3.PY/L1.FF/H3.YA; L3.PY/L1.FF/H3.AE; L3.PY/L1.FF/H3.AQ; and L3.PY/L1.FF/H3.TAQ RASQSVSSFFLA
(SEQ ID NO: 219) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT
(SEQ ID NO: 216) L3.PY/L1.PH
For the following mAbs:
L3.PY/L1.PH/P6E01;
L3.PY/L1.PH/H2.QR; L3.PY/L1.PH/H2.HA; L3.PY/L1.PH/H3.AE; L3.PY/L1.PH/H3.AQ; and L3.PY/L1.PH/H3.TAQ RASQSVSPHYLA
(SEQ ID NO: 219) GASSRAT (SEQ ID NO: 210) QHYPYPPSFT
(SEQ ID NO: 216) L3.PY/L3.KY
For the following mAbs:
L3.PY/L3.KY/P6E01; L3.PY/L3.KY/H2.QR; L3.PY/L3.KY/H2.DY; L3.PY/L3.KY/H2.YQ; L3.PY/L3.KY/H2.LT; L3.PY/L3.KY/H2.HA; L3.PY/L3.KY/H2.QL; L3.PY/L3.KY/H3.YA; and L3.PY/L3.KY/H3.TAQ RASQSVSSSYLA
(SEQ ID NO: 209) GASSRAT (SEQ ID NO: 210) KYYPYPPSFT
(SEQ ID NO: 220) L3.PY/L3.KF
For the following mAbs: L3.PY/L3.KF/H2.DY; L3.PY/L3.KF/H2.YQ; L3.PY/L3.KF/H2.LT; L3.PY/L3.KF/H2.QL; L3.PY/L3.KF/H3.YA; L3.PY/L3.KF/H3.AE; L3.PY/L3.KF/H3.AQ; and L3.PY/L3.KF/H3.TAQ RASQSVSSSYLA
(SEQ ID NO: 209) GASSRAT (SEQ ID NO: 210) KFYPYPPSFT (SEQ ID NO: 220) P5A2_VHVL RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYGSWPLT (SEQ ID NO: 222) A02_Rd4_0.6nM_C06 RASQSVSVlYLA
(SEQ ID NO: 223) DASIRAT
(SEQ ID NO: 221) QQYQRWPLT
(SEQ ID NO: 224) A02_Rd4_0.6nM_C09;
COMBO_Rd_0.6nM_C29; and COMBO_Rd4_0.6nM_C21 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYQSWPLT
(SEQ ID NO: 225) A02_Rd4_6nM_C16 RASQSVSDlYLA
(SEQ ID NO: 226) DASIRAT
(SEQ ID NO: 221) QQYQTWPLT (SEQ ID NO: 227) A02_Rd4_6nM_C03 RASQSVSNlYLA (SEQ ID NO: 228) DASIRAT
(SEQ ID NO: 221) QQYQGWPLT (SEQ ID NO: 229) A02_Rd4_6nM_C01 RASQSVSAYYLA
(SEQ ID NO: 230) DASIRAT
(SEQ ID NO: 221) QQYERWPLT
(SEQ ID NO: 231) A02_Rd4_6nM_C26 RASQSVSSlYLA
(SEQ ID NO: 232) DASIRAT
(SEQ ID NO: 221) QQYQVWPLT
(SEQ ID NO: 233) A02_Rd4_6nM_C25 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYLDWPLT
(SEQ ID NO: 234) A02_Rd4_6nM_C22 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYQVWPLT
(SEQ ID NO: 233) A02_Rd4_6nM_C19 RASQSVSVlYLA
(SEQ ID NO: 223) DASIRAT
(SEQ ID NO: 221) QQYLAWPLT
(SEQ ID NO: 236) A02_Rd4_0.6nM_C03 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYFTWPLT
(SEQ ID NO: 237) A02_Rd4_6nM_C07 RASQSVSPYYLA
(SEQ ID NO: 238) DASIRAT
(SEQ ID NO: 221) QQYERWPLT
(SEQ ID NO: 231) A02_Rd4_6nM_C23 RASQSVSVEYLA
(SEQ ID NO: 239) DASIRAT
(SEQ ID NO: 221) QQYARWPLT
(SEQ ID NO: 240) A02_Rd4_0.6nM_C18 RASQSVSElYLA
(SEQ ID NO: 241) DASIRAT
(SEQ ID NO: 221) QQYFGWPLT
(SEQ ID NO: 242) A02_Rd4_6nM_C10 RASQSVEMSYLA
(SEQ ID NO: 243) DASIRAT
(SEQ ID NO: 221) QQYAHWPLT
(SEQ ID NO: 244) A02_Rd4_6nM_C05 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYQRWPLT
(SEQ ID NO: 224) A02_Rd4_0.6nM_C10 RASQSVSAQYLA
(SEQ ID NO: 245) DASIRAT
(SEQ ID NO: 221) QQYQRWPLT
(SEQ ID NO: 224) A02_Rd4_6nM_C04 RASQSVSALYLA
(SEQ ID NO: 235) DASIRAT
(SEQ ID NO: 221) QQYQVWPLT
(SEQ ID NO: 233) A02_Rd4_0.6nM_C26 GPSQSVSSSYLA
(SEQ ID NO: 246) DASIRAT
(SEQ ID NO: 221) QQYQSWPLT
(SEQ ID NO: 225) A02_Rd4_0.6nM_C13 RASQSVSSSYWA
(SEQ ID NO: 247) DASIRAT
(SEQ ID NO: 221) QQYESWPLT
(SEQ ID NO: 248) A02_Rd4_0.6nM_C01 RGGQSVSSSYLA
(SEQ ID NO: 249) DASIRAT
(SEQ ID NO: 221) QQYQSWPLT
(SEQ ID NO: 225) A02_Rd4_6nM_C08 RASQSVSFlYLA
(SEQ ID NO: 250) DASIRAT
(SEQ ID NO: 221) QQYGSWPLT (SEQ ID NO: 222) P5C1_VHVL RASQSVSSTYLA
(SEQ ID NO: 251) DASSRAP
(SEQ ID NO: 252) QQYSTSPLT
(SEQ ID NO: 253) C01_Rd4_6nM_C24 RASQSVSPEYLA
(SEQ ID NO: 254) DASSRAP
(SEQ ID NO: 252) QQYSVWPLT
(SEQ ID NO: 255) C01_Rd4_6nM_C26 RASQSVSALYLA
(SEQ ID NO: 235) DASSRAP
(SEQ ID NO: 252) QQYSAWPLT
(SEQ ID NO: 256) C01_Rd4_6nM_C10 RASQSVSSVYLA
(SEQ ID NO: 257) DASSRAP
(SEQ ID NO: 252) QQYSTWPLT
(SEQ ID NO: 258) C01_Rd4_0.6nM_C27 RASQSVSSTYLA
(SEQ ID NO: 251) DASSRAP
(SEQ ID NO: 252) QQYSRWPLT
(SEQ ID NO: 259) C01_Rd4_6nM_C20 RASQSVSPlYLA
(SEQ ID NO: 260) DASSRAP
(SEQ ID NO: 252) QQYSAFPLT
(SEQ ID NO: 261) C01_Rd4_6nM_C12 WLSQSVSSTYLA
(SEQ ID NO: 262) DASSRAP
(SEQ ID NO: 252) QQYSEWPLT
(SEQ ID NO: 263) C01_Rd4_0.6nM_C16 RASQSVSSTYLA
(SEQ ID NO: 251) DASSRAP
(SEQ ID NO: 252) QQYSSWPLT
(SEQ ID NO: 264) C01_Rd4_0.6nM_C09 RASQSVSSlFLA
(SEQ ID NO: 265) DASSRAP
(SEQ ID NO: 252) QQYSAWPLT
(SEQ ID NO: 256) C01_Rd4_6nM_C09 ACSQSVSSTYLA
(SEQ ID NO: 266) DASSRAP
(SEQ ID NO: 252) QQYSAWPLT
(SEQ ID NO: 256) C01_Rd4_0.6nM_C03 RASCDVSSTYLA
(SEQ ID NO: 267) DASSRAP
(SEQ ID NO: 252) QQYMRSPLT
(SEQ ID NO: 268) C01_Rd4_0.6nM_C06 RASEAVPSTYLE
(SEQ ID NO: 269) DASSRAP
(SEQ ID NO: 252) QQYSAFPLT
(SEQ ID NO: 261) C01_Rd4_0.6nM_C04 CSSQSVSSTYLA
(SEQ ID NO: 270) DASSRAP
(SEQ ID NO: 252) QQYSAFPLT
(SEQ ID NO: 261) COMBO_Rd4_0.6nM_C22 RASVRVSSTYLA
(SEQ ID NO: 271) DASIRAT
(SEQ ID NO: 221) QQYMKWPLT
(SEQ ID NO: 272) COMBO_Rd4_6nM_C21 RASQSVSAAYLA
(SEQ ID NO: 273) DASIRAT
(SEQ ID NO: 221) QQYMCWPLT
(SEQ ID NO: 274) COMBO_Rd4_6nM_C10 RASQSVSSSYWG
(SEQ ID NO: 275) DASIRAT
(SEQ ID NO: 221) QQYQCWPLT
(SEQ ID NO: 276) COMBO_Rd4_0.6nM_C04 RASQSVSSTYLA
(SEQ ID NO: 251) DASIRAT
(SEQ ID NO: 221) QQYQSWPLT
(SEQ ID NO: 225) COMBO_Rd4_6nM_C25 RASQSVSSPYLA (SEQ ID NO: 277) DASIRAT
(SEQ ID NO: 221) QQYQSWPLT
(SEQ ID NO: 225) COMBO_Rd4_6nM_C11 RASQSVSPlYLA
(SEQ ID NO: 260) DASIRAT
(SEQ ID NO: 221) QQYKAWPLT
(SEQ ID NO: 278) COMBO_Rd4_0.6nM_C20 RASQSVSYLYLA
(SEQ ID NO: 279) DASIRAT
(SEQ ID NO: 221) QQYMEWPLT
(SEQ ID NO: 280) COMBO_Rd4_6nM_C09 RASQSVSAQYLA
(SEQ ID NO: 245) DASIRAT
(SEQ ID NO: 221) QQYQAWPLT
(SEQ ID NO: 281) COMBO_Rd4_6nM_C08 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYQKWPLT
(SEQ ID NO: 282) COMBO_Rd4_0.6nM_C19 RASQSVSAVYLA
(SEQ ID NO: 283) DASIRAT
(SEQ ID NO: 221) QQYRAWPLT
(SEQ ID NO: 284) COMBO_Rd4_0.6nM_C02 RASIAVSSTYLA
(SEQ ID NO: 285) DASIRAT
(SEQ ID NO: 221) QQYMVWPLT
(SEQ ID NO: 286) COMBO_Rd4_0.6nM_C23 RPRQSVSSSYLA
(SEQ ID NO: 287) DASIRAT
(SEQ ID NO: 221) QQYQDWPLT
(SEQ ID NO: 288) COMBO_Rd4_0.6nM_C09 RASQSVSSTYLA
(SEQ ID NO: 251) DASIRAT
(SEQ ID NO: 221) QQYQEWPLT
(SEQ ID NO: 289) COMBO_Rd4_6nM_C12 RASQSVSASYLA
(SEQ ID NO: 290) DASIRAT
(SEQ ID NO: 221) QQYMSWPLT
(SEQ ID NO: 291) COMBO_Rd4_0.6nM_C30 RASQSVSYMYLA
(SEQ ID NO: 292) DASIRAT
(SEQ ID NO: 221) QQYKSWPLT
(SEQ ID NO: 293) COMBO_Rd4_0.6nM_C14 RASQSVSALYLA
(SEQ ID NO: 235) DASIRAT
(SEQ ID NO: 221) QQYYGWPLT
(SEQ ID NO: 294) COMBO_Rd4_6nM_C07 RASQPISSSYLA
(SEQ ID NO: 295) DASIRAT
(SEQ ID NO: 221) QQYQGWPLT
(SEQ ID NO: 229) COMBO_Rd4_6nM_C02 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYEFWPLT
(SEQ ID NO: 296) COMBO_Rd4_0.6nM_C05 RASQSVSSTYLA
(SEQ ID NO: 251) DASIRAT
(SEQ ID NO: 221) QQYMSWPLT
(SEQ ID NO: 291) COMBO_Rd4_0.6nM_C17 RASQGISSTYLA
(SEQ ID NO: 297) DASIRAT
(SEQ ID NO: 221) QQYAYWPLT
(SEQ ID NO: 298) COMBO_Rd4_6nM_C22 RASQSVSSSYLA
(SEQ ID NO: 209) DASIRAT
(SEQ ID NO: 221) QQYQGWPLT
(SEQ ID NO: 229) COMBO_Rd4_0.6nM_C11 RASQSVSVRYLA
(SEQ ID NO: 299) DASIRAT
(SEQ ID NO: 221) QQYGSWPIT
(SEQ ID NO: 300) Light chain consensus sequence X ₁ X ₂ X ₃ X ₄ X ₅ X ₆ X ₇ X ₈ X ₉ X ₁₀ X ₁₁ X ₁₂ , where X ₁ is R, G, W, A or C; X ₂ is A, P, G, L, C or S; X ₃ is S, G or R; X ₄ is Q, C, E, V or I; X ₅ is S, P, G, A, R or D; X ₆ is V, G, I or L; X ₇ is S, E, D, P or G; X ₈ is S, P, F, A, M, E, V, N, D or Y; X ₉ is I, T, V, E, FS, A, M, Q, Y, H or R; X ₁₀ is Y or F; X ₁₁ is L, W or P; and X ₁₂ is A, S or G (SEQ ID NO: 309) X ₁ ASX ₂ RAX ₃ , where X ₁ is G or D; X ₂ is S or I; and X ₃ is T or P (SEQ ID NO: 310) X ₁ X ₂ YX ₃ X ₄ PPSFT, where X ₁ is Q or K; X ₂ is H or Y; X ₃ is G, N or P; and X ₄ is S, W or Y (SEQ ID NO: 311)
QQYX ₁ X ₂ X ₃ PX ₄ T, where X ₁ is G, Q, E, L, F, A, S, M, K, R, or Y; X ₂ is S, R, T, G, V, F, Y, D, A, H, V, E, K, or C; X ₃ is W, F, or S; and X ₄ is L or I (SEQ ID NO: 312) P4G4 RASQSVSSSYLA (SEQ ID NO: 209) GASSRAY (SEQ ID NO: 362) QHYGSPPLFT (SEQ ID NO: 499) P1A11 RASQNVSSSYLA (SEQ ID NO: 500) GASYRAT (SEQ ID NO: 501) QHYGSPPSFT (SEQ ID NO: 211)

In some embodiments, the present invention provides an antibody that binds to BCMA and competes with an antibody as described herein, including P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ, L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA, L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT, L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ, L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6nM_C06, A02_Rd4_0.6nM_C09, A02_Rd4_6nM_C16, A02_Rd4_6nM_C03, A02_Rd4_6nM_C01, A02_Rd4_6nM_C26, A02_Rd4_6nM_C25, A02_Rd4_6nM_C22, A02_Rd4_6nM_C19, A02_Rd4_0.6nM_C03, A02_Rd4_6nM_C07, A02_Rd4_6nM_C23, A02_Rd4_0.6nM_C18, A02_Rd4_6nM_C10, A02_Rd4_6nM_C05, A02_Rd4_0.6nM_C10, A02_Rd4_6nM_C04, A02_Rd4_0.6nM_C26, A02_Rd4_0.6nM_C13, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C08, P5C1_VHVL, C01_Rd4_6nM_C24, C01_Rd4_6nM_C26, C01_Rd4_6nM_C10, C01_Rd4_0.6nM_C27, C01_Rd4_6nM_C20, C01_Rd4_6nM_C12, C01_Rd4_0.6nM_C16, C01_Rd4_0.6nM_C09, C01_Rd4_6nM_C09, C01_Rd4_0.6nM_C03, C01_Rd4_0.6nM_C06, C01_Rd4_6nM_C04, COMBO_Rd4_0.6nM_C22, COMBO_Rd4_6nM_C21, COMBO_Rd4_6nM_C10, COMBO_Rd4_0.6nM_C04, COMBO_Rd4_6nM_C25, COMBO_Rd4_0.6nM_C21, COMBO_Rd4_6nM_C11, COMBO_Rd4_0.6nM_C20, COMBO_Rd4_6nM_C09, COMBO_Rd4_6nM_C08, COMBO_Rd4_0.6nM_C19, COMBO_Rd4_0.6nM_C02, COMBO_Rd4_0.6nM_C23, COMBO_Rd4_0.6nM_C29, COMBO_Rd4_0.6nM_C09, COMBO_Rd4_6nM_C12, COMBO_Rd4_0.6nM_C30, COMBO_Rd4_0.6nM_C14, COMBO_Rd4_6nM_C07, COMBO_Rd4_6nM_C02, COMBO_Rd4_0.6nM_C05, COMBO_Rd4_0.6nM_C17, COMBO_Rd4_6nM_C22, COMBO_Rd4_0.6nM_C11, COMBO_Rd4_0.6nM_C29, P4G4 or P1A11.

In some embodiments, the present invention provides an antibody or antigen-binding fragment that specifically binds to BCMA, wherein the antibody comprises a VH region comprising the sequence set forth in SEQ ID NO: 112; and/or a VL region comprising the sequence set forth in SEQ ID NO: 38. In some embodiments, the antibody comprises a light chain comprising the sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLMYDASIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYQSWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 357) and a heavy chain comprising the sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAIGGSGGSLPYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYWPMDIWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 358).

In some embodiments, the present invention provides an antibody or antigen-binding fragment that specifically binds to BCMA, wherein the antibody comprises a VH region comprising the sequence set forth in SEQ ID NO: 2, 32, 42, or 78; and/or a VL region comprising the sequence set forth in SEQ ID NO: 6, 16, 43, or 85.

In some embodiments, the invention also provides CDR regions of anti-BCMA antibodies based on CDR contact regions. CDR contact regions are regions of an antibody that impart specificity to the antibody for an antigen. In general, CDR contact regions include residue positions in the CDRs and Vernier zones that are constrained to maintain the proper loop structure for binding of the antibody to a specific antigen. See, for example, Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. The definition of CDR contact regions is well known in the art.

The binding affinity (K _D ) of a BCMA antibody as described herein to BCMA (such as human BCMA (e.g., SEQ ID NO: 353)) can be from about 0.002 nM to about 6500 nM. In some embodiments, the binding affinity is any of about 6500 nM, 6000 nM, 5986 nM, 5567 nM, 5500 nM, 4500 nM, 4000 nM, 3500 nM, 3000 nM, 2500 nM, 2134 nM, 2000 nM, 1500 nM, 1000 nM, 750 nM, 500 nM, 400 nM, 300 nM, 250 nM, 200 nM, 193 nM, 100 nM, 90 nM, 50 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 10 nM, 8 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 nM or 0.002 nM. In some embodiments, the binding affinity is less than any of about 6500 nM, 6000 nM, 5500 nM, 5000 nM, 4000 nM, 3000 nM, 2000 nM, 1000 nM, 900 nM, 800 nM, 250 nM, 200 nM, 100 nM, 50 nM, 30 nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM or 0.5 nM.

In some embodiments, the invention encompasses compositions, including pharmaceutical compositions, comprising antibodies described herein or produced by methods and having the characteristics described herein. As used herein, the compositions comprise one or more antibodies that bind to BCMA and/or one or more polynucleotides having sequences encoding one or more of these antibodies. These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients, including buffers, as are well known in the art.

The invention also provides methods for producing any of these antibodies. The antibodies of the invention can be produced by methods well known in the art. The polypeptides can be produced by proteolytic or other degradation of the antibodies, by recombinant methods (i.e., single or fusion polypeptides) as described above, or by chemical synthesis. Antibody polypeptides, especially short polypeptides, up to about 50 amino acids, are typically produced by chemical synthesis. Chemical synthesis methods are known in the art and are commercially available. For example, an antibody can be produced by an automated polypeptide synthesizer using a solid phase method. See also U.S. Pat. Nos. 5,807,715; 4,816,567; and 6,331,415.

The present invention also encompasses fusion proteins comprising one or more fragments or regions of the antibodies of the present invention. In one embodiment, there is provided a fusion polypeptide that comprises at least 10 contiguous amino acids of a light chain variable region as set forth in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 80, 315, 36 or 364, and/or at least 10 amino acids of the heavy chain variable region presented in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 112, 125, 127, 313, 314, 363, or 365. Other embodiments provide a fusion polypeptide that comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of a light chain variable region, and/or at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of the heavy chain variable region. In another embodiment, the fusion polypeptide comprises a light chain variable region and/or a heavy chain variable region as shown in any one of the sequence pairs selected from SEQ ID NOs: 1 and 2, 1 and 3, 4 and 2, 5 and 2, 6 and 2, 4 and 7, 4 and 8, 4 and 3, 9 and 8, 9 and 3, 10 and 7, 10 and 8, 10 and 3, 11 and 7, 11 and 8, 11 and 3, 12 and 3, 13 and 7, 13 and 8, 14 and 3, 15 and 2, 16 and 2, 17 and 2, 18 and 2, 19 and 2, 20 and 2, 21 and 2, 22 and 2, 23 and 2, 16 and 24, 16 and 25, 16 and 26, 16 and 27, 16 and 28, 16 and 29, 16 and 30, 16 and 31, 16 and 3, 16 and 32, 16 and 2, 18 and 24, 18 and 25, 18 and 26, 18 and 27, 18 and 28, 18 and 29, 18 and 30, 18 and 31, 18 and 3, 18 and 32, 19 and 24, 19 and 25, 19 and 26, 19 and 27, 19 and 28, 19 and 29, 19 and 30, 19 and 31, 19 and 3, 19 and 32, 20 and 24, 20 and 25, 20 and 26, 20 and 27, 20 and 28, 20 and 29, 20 and 30, 20 and 31, 20 and 3, 20 and 32, 21 and 24, 21 and 28, 21 and 31, 21 and 3, 21 and 32, 22 and 24, 22 and 25, 22 and 26, 22 and 27, 22 and 28, 22 and 29, 22 and 30, 22 and 32, 23 and 25, 23 and 26, 23 and 27, 23 and 29, 23 and 30, 23 and 31, 23 and 3, 23 and 32, 34 and 33, 36 and 35, 38 and 37, 40 and 39, 41 and 33, 43 and 42, 45 and 44, 47 and 46, 49 and 48, 51 and 50, 53 and 52, 55 and 54, 57 and 56, 59 and 58, 61 and 60, 63 and 62, 65 and 64, 67 and 66, 69 and 68, 71 and 70, 73 and 72, 75 and 74, 77 and 76, 79 and 78, 317 and 78, 79 and 78, 81 and 78, 82 and 78, 84 and 83, 85 and 78, 86 and 78, 88 and 87, 89 and 78, 90 and 78, 91 and 78, 93 and 92, 94 and 78, 96 and 95, 98 and 97, 38 and 78, 102 and 101, 103 and 78, 105 and 104, 107 and 106, 108 and 78, 109 and 78, 111 and 110, 38 and 112, 113 and 112, 115 and 114, 116 and 76, 117 and 112, 119 and 118, 121 and 120, 123 and 122, 124 and 112, 126 and 125, 128 and 127, 80 and 363, or 364 and 365. In another embodiment, the fusion polypeptide comprises one or more CDRs. In other embodiments, the fusion polypeptide comprises CDR H3 (VH CDR3) and/or CDR L3 (VL CDR3). As used herein, the fusion protein comprises one or more antibodies and another amino acid sequence to which it is not attached in the native molecule, such as a heterologous sequence or a homologous sequence from another region. Examples of heterologous sequences include, but are not limited to, a "tag" such as a FLAG tag or a 6His tag. Tags are well known in the art.

The invention also provides isolated polynucleotides encoding the antibodies of the invention, and vectors, as well as host cells containing the polynucleotide.

In one embodiment, the polynucleotide comprises a sequence encoding the variable regions of the heavy chain and/or light chain of the antibody P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ, L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA, L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT, L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ, L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6nM_C06, A02_Rd4_0.6nM_C09, A02_Rd4_6nM_C16, A02_Rd4_6nM_C03, A02_Rd4_6nM_C01, A02_Rd4_6nM_C26, A02_Rd4_6nM_C25, A02_Rd4_6nM_C22, A02_Rd4_6nM_C19, A02_Rd4_0.6nM_C03, A02_Rd4_6nM_C07, A02_Rd4_6nM_C23, A02_Rd4_0.6nM_C18, A02_Rd4_6nM_C10, A02_Rd4_6nM_C05, A02_Rd4_0.6nM_C10, A02_Rd4_6nM_C04, A02_Rd4_0.6nM_C26, A02_Rd4_0.6nM_C13, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C08, P5C1_VHVL, C01_Rd4_6nM_C24, C01_Rd4_6nM_C26, C01_Rd4_6nM_C10, C01_Rd4_0.6nM_C27, C01_Rd4_6nM_C20, C01_Rd4_6nM_C12, C01_Rd4_0.6nM_C16, C01_Rd4_0.6nM_C09, C01_Rd4_6nM_C09, C01_Rd4_0.6nM_C03, C01_Rd4_0.6nM_C06, C01_Rd4_6nM_C04, COMBO_Rd4_0.6nM_C22, COMBO_Rd4_6nM_C21, COMBO_Rd4_6nM_C10, COMBO_Rd4_0.6nM_C04, COMBO_Rd4_6nM_C25, COMBO_Rd4_0.6nM_C21, COMBO_Rd4_6nM_C11, COMBO_Rd4_0.6nM_C20, COMBO_Rd4_6nM_C09, COMBO_Rd4_6nM_C08, COMBO_Rd4_0.6nM_C19, COMBO_Rd4_0.6nM_C02, COMBO_Rd4_0.6nM_C23, COMBO_Rd4_0.6nM_C29, COMBO_Rd4_0.6nM_C09, COMBO_Rd4_6nM_C12, COMBO_Rd4_0.6nM_C30, COMBO_Rd4_0.6nM_C14, COMBO_Rd4_6nM_C07, COMBO_Rd4_6nM_C02, COMBO_Rd4_0.6nM_C05, COMBO_Rd4_0.6nM_C17, COMBO_Rd4_6nM_C22, COMBO_Rd4_0.6nM_C11, COMBO_Rd4_0.6nM_C29, P4G4 or P1A11. The sequence encoding the antibody of interest can be maintained in a vector in a host cell, and the host cell can then be expanded and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

The present invention also encompasses scFv antibodies of the invention. Single-chain variable region fragments are prepared by joining the variable regions of the light and/or heavy chain using a short linker peptide (Bird et al., Science 242:423-426, 1988). An example of a linker peptide is (GGGGS) ₃ (SEQ ID NO: 498), which forms a bridge of approximately 3.5 nm in length between the carboxyl terminus of one variable region and the amino terminus of the other variable region. Linkers with other sequences have been designed and used (Bird et al., 1988, supra). Linkers should be short, flexible polypeptides and preferably contain less than about 20 amino acid residues. Linkers can, in turn, be modified for additional functions, such as attachment of drugs or attachment to solid supports. Single-chain variants can be produced either recombinantly or synthetically. For synthetic production of scFv, an automated synthesizer can be used. For recombinant production of scFv, a suitable plasmid containing a polynucleotide encoding an scFv can be introduced into a suitable host cell, either eukaryotic such as yeast, plant, insect or mammalian cells, or prokaryotic such as E. coli. Polynucleotides encoding the scFv of interest can be obtained by routine manipulations such as ligation of polynucleotides. The resulting scFv can be isolated using standard protein purification techniques known in the art.

Also included are other forms of single-chain antibodies, such as diabodies or minibodies. Diabodies are bivalent, bispecific antibodies in which the variable heavy chain (VH) and variable light chain (VL) domains are expressed on a single-chain polypeptide, but using a linker that is too short to allow pairing of the two domains on the same chain, thereby forcing the domains to pair with the complementary domains of another chain and creating two antigen-binding sites (see, e.g., Holliger, P., et al., Proc. Natl. Acad Sci. USA 90:6444–6448, 1993; Poljak, R. J., et al., Structure 2:1121–1123, 1994). The minibody comprises the VL and VH domains of a native antibody fused to the hinge region and the CH3 domain of an immunoglobulin molecule. See, for example, US 5,837,821.

In another aspect of the invention, there are provided compositions (such as pharmaceutical compositions) comprising any of the polynucleotides of the invention. In some embodiments, the composition comprises an expression vector comprising a polynucleotide encoding any of the antibodies described herein. In other embodiments, the composition comprises either or both of the polypeptides set forth in SEQ ID NO: 486 and SEQ ID NO: 485 below:

COMBO_Rd4_0.6nM_C29 variable region of the heavy chain

GAAGTCCAACTCCTCGAATCCGGTGGCGGCCTTGTCCAGCCTGGAGGTTCCTTGCGCCTGTCATGTGCCGCCAGCGGATTCACCTTCTCGTCCTACCCGATGTCGTGGGTCCGCCAGGCTCCGGGAAAGGGCCTGGAATGGGTGTCAGCCATCGGAGGATCGGGGGGCTCCC TGCCCTACGCCGATATCGTGAAGGGAAGGTTCACCATTAGCCGGGACAACTCCAAGAACACTCTGTACCTCCAAATGAACAGCCTGAGAGCGGAGGACACCGCAGTGTACTATTGCGCCCGGTACTGGCCAATGGACATCTGGGGCCAGGGACTCTGGTCACCGTCTCCTCA

(SEQ ID NO: 486)

COMBO_Rd4_0.6nM_C29 variable region of the light chain

GAGATCGTGCTGACTCAGTCCCCTGGAACCCTGTCCCTGTCACCTGGCGAAAGAGCTACCTTGTCCTGTCGCGCATCACAATCCGTGTCGTCGAGCTATCTCGCGTGGTACCAGCAGAAGCCCGGACAGGCCCCAAGGCTGCTTATGTACGACGCCTCCATC CGGGCCACTGGTATCCCCGACCGCTTCTCGGGCTCCGGAAGCGGCACCGACTTCACCCTGACTATTTCCCGGCTCGAACCGGAGGATTTCGCCGTGTACTACTGCCAACAGTACCAGAGCTGGCCGCTGACGTTTGGGCAGGGGACCAAGGTCGAAATCAAA

(SEQ ID NO: 485)

In other embodiments, the composition comprises either or both of the polypeptides set forth in SEQ ID NO: 488 and SEQ ID NO: 487 below:

L3.PY/H3TAQ variable region heavy chain

GAAGTGCAGCTGCTGGAATCTGGCGGAGGACTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCGGCAGCTACGCTATGACCTGGGTGCGCCAGGCCCCTGGCAAAGGACTGGAATGGGTGTCCGCCATCTCTGGCAGCGGCGGCAATACCTTCT ACGCCGAGAGCGTGAAGGGCCGGTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGACACCGCCGTGTACTATTGTACACGGGTGTCCCCTATCGCCGCGCAGATGGATTATTGGGGCCAGGCACTCTGGTCACCGTCTCCTCA

(SEQ ID NO: 488)

L3.PY/H3TAQ variable region heavy chain

GAGATCGTGCTGACACAGAGCCCTGGCACCCTGAGCCTGTCTCCAGGCGAAAGAGCCACCCTGTCCTGCAGAGCCAGCCAGAGCGTGTCCAGCAGCTACCTGGCCTGGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTATGGCGCCTCTTCTA GAGCCACCGGCATCCCCGATAGATTCAGCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGACTGGAACCCGAGGACTTCGCCGTGTACTACTGCCAGCACTACCCTTATCCCCCCAGCTTCACATTTGGCCAGGGCACCAAGGTGGAGATCAAA

(SEQ ID NO: 487)

In other embodiments, the composition comprises either or both of the polypeptides set forth in SEQ ID NO: 490 and SEQ ID NO: 489 below:

A02_Rd4_0.6nM_C01 variable region of heavy chain

GAAGTTCAATTATTGGAATCTGGTGGAGGACTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTACGCCATGAACTGGGTGCGCCAGGCCCCTGGTAAAGGTTTGGAATGGGTTTCTGCTATTACTGCGTCTGGTGGTTCTA CTTACTATGCCGATGTGGTTAAGGGTAGATTCACCATTTCTAGAGACAACTCTAAGAACACCTTGTACTTGCAAATGAACTCCTTGAGAGCTGAAGATACTGCTGTTTATTACTGTGCTAGATACTGGCCAATGTCGTTGTGGGGTCAAGGTACTCTGGTCACCGTCTCCTCA

(SEQ ID NO: 490)

A02_Rd4_0.6nM_C01 variable region of light chain

GAGATCGTGCTGACACAGAGCCCTGGCACCCTGAGCCTGTCTCCTGGTGAAAGAGCTACTTTGTCTTGTAGAGCTTCTCAATCCGTTTCCGCGTATTATTTGGCTTGGTATCAACAAAAACCAGGTCAAGCTCCAAGATTATTGATGTACGATGCTTCTATTAGA GCCACCGGTATTCCAGATAGATTTTCTGGTTCTGGTTCCGGTACTGATTTCACTTTGACTATCTCTAGATTGGAACCAGAAGATTTCGCTGTTTACTACTGTCAACAATATGAGCGTTGGCCATTGACTTTTGGTCAAGGTACAAAGGTTGAAATCAAACGTGAG

(SEQ ID NO: 489)

In other embodiments, the composition comprises either or both of the polypeptides set forth in SEQ ID NO: 492 and SEQ ID NO: 491 below:

A02_Rd4_0.6nM_C16 variable region of heavy chain

GAAGTTCAATTATTGGAATCTGGTGGAGGACTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCAGCTACGCCATGAACTGGGTGCGCCAGGCCCCTGGTAAAGGTTTGGAATGGGTTTCTGCTATTTCTGATTTTGGTGGTTCTA CTTACTATGCCGATATCGTTAAGGGTAGATTCACCATTTCTAGAGACAACTCTAAGAACACCTTGTACTTGCAAATGAACTCCTTGAGAGCTGAAGATACTGCTGTTTATTACTGTGCTAGATACTGGCCAATGGATATTTGGGTCAAGGTACTCTGGTCACCGTCTCCTCA

(SEQ ID NO: 492)

A02_Rd4_0.6nM_C16 variable region light chain

GAGATCGTGCTGACACAGAGCCCTGGCACCCTGAGCCTGTCTCCTGGTGAAAGAGCTACTTTGTCTTGTAGAGCTTCTCAATCCGTTTCCGATCTGTATTTGGCTTGGTATCAACAAAAACCAGGTCAAGCTCCAAGATTATTGATGTACGATGCTTCTATTAGA GCCACCGGTATTCCAGATAGATTTTCTGGTTCTGGTTCCGGTACTGATTTCACTTTGACTATCTCTAGATTGGAACCAGAAGATTTCGCTGTTTACTACTGTCAACAATATCAGACTTGGCCATTGACTTTTGGTCAAGGTACAAAGGTTGAAATCAAACGTGAG

(SEQ ID NO: 491).

In addition, expression vectors and administration of polynucleotide compositions are described in this document.

In another aspect of the invention, a method for producing any of the polynucleotides described herein is provided.

The present invention also encompasses polynucleotides complementary to any such sequence. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA molecules (genomic, cDNA, or synthetic) or RNA molecules. RNA molecules include hnRNA (heterogeneous nuclear RNA) molecules, which contain introns and correspond one-to-one to a DNA molecule, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present in a polynucleotide of the present invention, and the polynucleotide may, but need not, be linked to other molecules and/or support materials.

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 comprise one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not reduced compared to the immunoreactivity of the native molecule. The effect on the immunoreactivity of the encoded polypeptide can generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably at least about 80% identity, even more preferably at least about 90% identity, and most preferably at least about 95% identity with the polynucleotide sequence that encodes the native antibody or a portion thereof.

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 with best fit, as described below. Comparison of two sequences is typically performed by comparing the sequences in 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, typically from 30 to about 75, or from 40 to about 50, in which a sequence can be compared to a reference sequence with the same number of contiguous positions after optimal alignment of the two sequences.

Optimal alignment of sequences for comparison can be performed using the Megalign program in the Lasergene bioinformatics package (DNASTAR, Inc., Madison, WI) using default parameters. Several alignment schemes are implemented in this program, 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 DC 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, CA; 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, CA; Wilbur, W.J. and Lipman, D.J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730.

Preferably, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences in a comparison window of at least 20 positions, wherein a portion of the polynucleotide or polypeptide sequence in the comparison window may contain additions or deletions (i.e., gaps) that are 20 percent or less, typically 5 to 15 percent or 10 to 12 percent, compared to reference sequences (which do not contain additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions with identical nucleobases or amino acid residues in both sequences to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the reference sequence (i.e., the window size), and multiplying the results by 100 to obtain the percent sequence identity.

Variants may also, or alternatively, be substantially homologous to a natural gene or portion thereof, or set of genes. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to the natural DNA sequence encoding the native antibody (or to a complementary sequence).

Suitable “moderately stringent conditions” include pre-washing in 5xSSC (sodium chloride/sodium citrate), 0.5% SDS (sodium dodecyl sulfate), 1.0 mM EDTA (pH 8.0); hybridization at 50°C-65°C, 5xSSC, overnight; followed by two washes at 65°C for 20 minutes each with 2x, 0.5x, and 0.2x SSC containing 0.1% SDS.

As used herein, "very stringent conditions" or "high stringency conditions" are conditions in which: (1) low ionic strength and high temperature are used for washing, such as 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) a denaturing agent such as formamide is used during hybridization, such as 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°C; or (3) use 50% formamide, 5xSSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5x Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42°C, with washes at 42°C in 0.2xSSC (sodium chloride/sodium citrate) and 50% formamide at 55°C, followed by a thorough wash consisting of 0.1xSSC containing EDTA at 55°C. One skilled in the art can determine how to adjust temperature, ionic strength, etc. as needed to accommodate factors such as probe length, etc.

It will be appreciated by those skilled in the art that, due to the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides have minimal homology to the nucleotide sequence of any native gene. However, polynucleotides that differ due to differences in codon usage are specifically contemplated by the present invention. In addition, alleles of genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that have been altered by 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 can be identified using standard techniques (such as hybridization, amplification, and/or sequence database comparison).

The polynucleotides of the present invention can be produced using chemical synthesis, recombinant methods, or PCR. Methods for chemically synthesizing polynucleotides are well known in the art and need not be described in detail here. One skilled in the art can use the sequences provided herein and a commercially available DNA synthesizer to produce the desired DNA sequence.

To produce polynucleotides using recombinant techniques, a polynucleotide containing the desired sequence can be inserted into a suitable vector, and the vector can in turn be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides can be introduced into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide via direct uptake, endocytosis, transfection, F-mating, or electroporation. Once introduced, the exogenous polynucleotide can be maintained in the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The thus amplified polynucleotide can be recovered from the host cell by methods well known in the art. See, for example, Sambrook et al., 1989.

Alternatively, PCR allows DNA sequences to be reproduced. PCR technology is well known in the art and is described in US Patents 4,683,195, 4,800,159, 4,754,065, and 4,683,202, and in PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

RNA can be produced by using isolated DNA in a suitable vector and introducing 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 skilled in the art, as discussed, for example, in Sambrook et al., 1989, supra.

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. Although the cloning vector selected may differ depending on the host cell to be used, suitable cloning vectors will generally have the ability to self-replicate, may have a single target for a particular restriction endonuclease, and/or may carry marker genes that can be used in the selection of clones containing the vector. Suitable examples include plasmids and bacterial viruses, such as 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 suppliers such as BioRad, Strategene, and Invitrogen.

Expression vectors are typically replicable polynucleotide constructs that comprise a polynucleotide of the invention. It is intended that the expression vector will replicate in 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 the expression vector(s) disclosed in PCT Publication WO 87/04462. Vector components may typically 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 control elements (such as promoters, enhancers, and terminators). Expression (i.e., translation) usually also requires one or more translational control elements, such as ribosome binding sites, translation initiation sites, and stop codons.

Vectors containing the polynucleotides of interest may be introduced into the host cell by any of a number of suitable methods, including electroporation; transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; ballistic transfection; lipofection; and infection (e.g., when the vector is an infectious agent such as vaccinia virus). The choice of vectors or polynucleotides to be introduced often depends on the characteristics of the host cell.

The invention also provides host cells comprising any of the polynucleotides described herein. Any host cell capable of overexpressing heterologous DNAs can be used to isolate genes encoding an antibody, polypeptide, or protein of interest. Non-limiting examples of mammalian host cells include, but are not limited to, COS, HeLa, and CHO cells. See also PCT Publication WO 87/04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtillis ) and yeast (such as S. cerevisae , S. pombe ; or K. lactis ). Preferably, the host cells express the cDNA at a level of about 5 times higher, more preferably 10 times higher, even more preferably 20 times higher than the level of the corresponding endogenous antibody or protein of interest, if present, in the host cells. Screening of the host cells for specific binding to BCMA or a domain of BCMA (e.g. domains 1-4) is performed by immunoassay or FACS (fluorescence-activated cell sorting). A cell overexpressing the antibody or protein of interest can be identified.

Representative materials of the present invention were deposited with the American Type Culture Collection (ATCC) on April 15, 2015. The vector with ATCC Accession Number PTA-122094 is a polynucleotide encoding the heavy chain variable region of a humanized BCMA antibody, and the vector with ATCC Accession Number PTA-122093 is a polynucleotide encoding the light chain variable region of a humanized BCMA antibody. The deposits were made pursuant to the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and the Guidelines thereunder (Budapest Treaty). This ensures that the deposited culture will be maintained in viable condition for 30 years from the date of deposit. The deposit will be provided to the ATCC pursuant to the provisions of the Budapest Treaty and as agreed upon by Pfizer, Inc. and the ATCC, which guarantees the perpetual and unrestricted availability of the progeny of the deposited crop to the public upon the grant of a corresponding U.S. patent or upon the publication in the public domain of any U.S. or foreign patent application, whichever occurs first, and guarantees the availability of the progeny to anyone determined by the Commissioner of the United States Patent and Trademark Office to be entitled thereto pursuant to 35 U.S.C. Section 122 and the Commissioner's regulations thereunder (including 37 C.F.R. Section 1.14 with particular reference to 886 OG 638).

The patentee of this application agrees that in the event of loss, destruction or destruction of deposited materials during cultivation under suitable conditions, these materials will be promptly replaced upon notice to the other. Availability of deposited material should not be construed as a license to practice the invention in violation of rights granted under the laws of any state in accordance with its patent laws.

BCMA-antibody conjugates

The present invention also provides a BCMA antibody conjugate (or immunoconjugate) as described herein, or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment is conjugated to an agent (e.g., a cytotoxic agent) for targeted immunotherapy (e.g., antibody-drug conjugates) directly or indirectly through a linker. For example, a cytotoxic agent can be linked or conjugated to a BCMA antibody or antigen-binding fragment thereof as described herein for targeted local delivery of a cytotoxic agent moiety to tumors (e.g., a BCMA-expressing tumor).

Methods for conjugating a cytotoxic agent or other therapeutic agents to antibodies have been described in various publications. For example, chemical modification can be achieved in antibodies either through lysine side chain amines or through cysteine sulfhydryl groups activated by reduction of interchain disulfide bonds to allow the conjugation reaction to occur. See, for example, Tanaka et al., FEBS Letters 579:2092-2096, 2005, and Gentle et al., Bioconjugate Chem. 15:658-663, 2004. Reactive cysteine residues engineered at specific sites on antibodies for specific drug conjugation with defined stoichiometry have also been described. See, for example, Junutula et al., Nature Biotechnology, 26:925-932, 2008. Conjugation using an acyl donor glutamine-containing tag or endogenous glutamine made reactive (i.e., capable of forming a covalent bond as an acyl donor) with a polypeptide engineered in the presence of transglutaminase and an amine (e.g., a cytotoxic agent containing or attached to a reactive amine) is also described in International Applications WO2012/059882 and WO2015015448 .

In some embodiments, a BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site on the antibody (e.g., the carboxyl terminus, amino terminus, or other site on the BCMA antibody). In some embodiments, the tag comprises the amino acid glutamine (Q) or the amino acid sequence LQG, LLQGG (SEQ ID NO:318), LLQG (SEQ ID NO:454), LSLSQG (SEQ ID NO:455), GGGLLQGG (SEQ ID NO:456), GLLQG (SEQ ID NO:457), LLQ, GSPLAQSHGG (SEQ ID NO:458), GLLQGGG (SEQ ID NO:459), GLLQGG (SEQ ID NO:460), GLLQ (SEQ ID NO:461), LLQLLQGA (SEQ ID NO:462), LLQGA (SEQ ID NO:463), LLQYQGA (SEQ ID NO:464), LLQGSG (SEQ ID NO:465), LLQYQG (SEQ ID NO: 466), LLQLLQG (SEQ ID NO: 467), SLLQG (SEQ ID NO: 468), LLQLQ (SEQ ID NO: 469), LLQLLQ (SEQ ID NO: 470), LLQGR (SEQ ID NO: 471), LLQGPP (SEQ ID NO: 472), LLQGPA (SEQ ID NO: 473), GGLLQGPP (SEQ ID NO: 474), GGLLQGA (SEQ ID NO: 475), LLQGPGK (SEQ ID NO: 476), LLQGPG (SEQ ID NO: 477), LLQGP (SEQ ID NO: 478), LLQP (SEQ ID NO: 479), LLQPGK (SEQ ID NO: 480), LLQAPGK (SEQ ID NO: 481), LLQGAPG (SEQ ID NO: 482), LLQGAP (SEQ ID NO: 483) and LLQLQG (SEQ ID NO: 484).

In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody, wherein the tag comprises the amino acid sequence GGLLQGPP (SEQ ID NO: 474) or GGLLQGA (SEQ ID NO: 475) engineered at the carboxyl terminus of the light chain of the BCMA antibody. In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody, wherein the tag comprises the amino acid sequence LLQG (SEQ ID NO: 454) engineered after residue T135 in the heavy chain of the BCMA antibody. In other embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag engineered at a specific site of the antibody, wherein the tag comprises the amino acid sequence LLQGA (SEQ ID NO: 463) or LLQGPP (SEQ ID NO: 472) engineered at the carboxyl terminus of the heavy chain of the BCMA antibody, and wherein the lysine residue at the carboxyl terminus of the heavy chain is removed. In some embodiments, the BCMA antibody or conjugate as described herein comprises an amino acid substitution at position 297 of the BCMA antibody (EC numbering scheme). For example, the amino acid asparagine (N) can be replaced by glutamine (Q) or alanine (A) at position 297 of the BCMA antibody.

Also provided is an isolated antibody comprising an acyl donor glutamine-containing tag and an amino acid modification at position 222, 340, or 370 of the antibody (EC numbering scheme), wherein the modification is an amino acid deletion, insertion, substitution, mutation, or any combination thereof. Accordingly, in some embodiments, there is provided a BCMA antibody or conjugate as described herein comprising an acyl donor glutamine-containing tag (e.g., Q, LQG, LLQGG (SEQ ID NO:318), LLQG (SEQ ID NO:454), LSLSQG (SEQ ID NO:455), GGGLLQGG (SEQ ID NO:456), GLLQG (SEQ ID NO:457), LLQ, GSPLAQSHGG (SEQ ID NO:458), GLLQGGG (SEQ ID NO:459), GLLQGG (SEQ ID NO:460), GLLQ (SEQ ID NO:461), LLQLLQGA (SEQ ID NO:462), LLQGA (SEQ ID NO:463), LLQYQGA (SEQ ID NO: LLQGSG (SEQ ID NO: 465), LLQYQG (SEQ ID NO: 466), LLQLLQG (SEQ ID NO: 467), SLLQG (SEQ ID NO: 468), LLQLQ (SEQ ID NO: 469), LLQLLQ (SEQ ID NO: 470), LLQGR (SEQ ID NO: 471), LLQGPP (SEQ ID NO: 472), LLQGPA (SEQ ID NO: 473), GGLLQGPP (SEQ ID NO: 474), GGLLQGA (SEQ ID NO: 475), LLQGPGK (SEQ ID NO: 476), LLQGPG (SEQ ID NO: 477), LLQGP (SEQ ID NO: 478), LLQP (SEQ ID NO: 479) LLQPGK (SEQ ID NO: 480), LLQAPGK (SEQ ID NO: 481), LLQGAPG (SEQ ID NO: 482), LLQGAP (SEQ ID NO: 483), and LLQLQG (SEQ ID NO: 484)), conjugated at a specific site (e.g., at the carboxyl terminus of the heavy or light chain, residue T135 in the heavy chain of an antibody, or at another site) of a BCMA antibody, and an amino acid modification at position 222, 340, or 370 of the antibody (EC numbering scheme). In some embodiments, the amino acid modification is a lysine to arginine substitution (e.g., K222R, K340R, or K370R).

In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence GGLLQGPP (SEQ ID NO: 474) constructed at the C-terminus of the light chain of the BCMA antibody and an amino acid substitution of lysine to arginine at position 222 of the antibody (EC numbering scheme). In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence GGLLQGA (SEQ ID NO: 475) placed at the C-terminus of the light chain of the BCMA antibody and an amino acid substitution of lysine to arginine at position 222 of the antibody (EC numbering scheme). In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence LLQGA (SEQ ID NO: 463) engineered at the C-terminus of the heavy chain of the BCMA antibody and an amino acid substitution of lysine to arginine at position 222 of the antibody (EC numbering scheme), wherein the lysine residue at the carboxyl terminus of the heavy chain is removed. In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence LLQG (SEQ ID NO: 454) engineered after residue T135 in the heavy chain of the BCMA antibody and an amino acid substitution of lysine to arginine at position 222 of the antibody (EC numbering scheme).

In some embodiments, a BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising a glutamine engineered at position 297, or an amino acid substitution at position 297 from asparagine (N) to another amino acid in the BCMA antibody and an amino acid substitution from lysine to arginine at position 222 of the antibody (EC numbering scheme). For example, in some embodiments, a BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence GGLLQGPP (SEQ ID NO: 474) engineered at the C-terminus of the light chain of the BCMA antibody, an asparagine (N) to glutamine (Q) amino acid substitution at position 297 of the BCMA antibody, and a lysine to arginine amino acid substitution at position 222 of the antibody (EC numbering scheme). In some embodiments, the BCMA antibody or conjugate as described herein comprises an acyl donor glutamine-containing tag comprising the sequence LLQG (SEQ ID NO: 454) constructed after residue T135 in the heavy chain of the BCMA antibody, an asparagine (N) to alanine (A) amino acid substitution at position 297 of the BCMA antibody, and a lysine to arginine amino acid substitution at position 222 of the antibody (EC numbering scheme).

Agents that can be conjugated to the BCMA antibodies or antigen-binding fragments of the present invention include, but are not limited to, cytotoxic agents, immunomodulatory agents, imaging agents, therapeutic proteins, biopolymers, or oligonucleotides.

Examples of cytotoxic agents include, but are not limited to, anthracycline, auristatin, dolastatin, combretastatin, duocarmycin, pyrrole benzodiazepine dimer, indolino benzodiazepine dimer, enediyne, geldanamycin, maytansine, puromycin, taxane, vinca alkaloid, camptothecin, tubulysin, hemiasterlin, spliceostatin, pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof.

Anthracyclines are derived from Streptomyces bacteria and are used to treat a wide range of cancers, including leukemia, lymphoma, breast, uterine, ovarian, and lung cancer. Typical anthracyclines include, but are not limited to, daunorubicin, doxorubicin (i.e., adriamycin), epirubicin, idarubicin, valrubicin, and mitoxantrone.

Dolastatins and their peptide analogs and derivatives, auristatins, are highly potent antimitotic agents that have been shown to have antitumor and antifungal activity. See, e.g., U.S. Patent 5,663,149 and Pettit et al., Antimicrob. Agents Chemother . 42:2961-2965, 1998. Representative dolastatins and auristatins include, but are not limited to, dolastatin 10, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), MMAD (Monomethyl-auristatin D or monomethyl-dolastatin 10), MMAF (Monomethyl-auristatin F or N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine), MMAE (Monomethyl-auristatin E or N-methylvaline-valine-dolaisoleuine-dolaproine-norephedrine), 5-benzoyl-valeric acid-AE ester (AEVB), and other novel auristatins (such as the auristatins described in US 2013/0129753). In some embodiments, auristatin is 0101 (2-methylalanyl- N -[(3R , 4S , 5S )-3-methoxy-1-{( 2S )-2-[(1R , 2R )-1-methoxy-2-methyl-3-oxo-3-{[( 1S )-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl] -N -methyl-L-valinanide) having the following structure:

In some embodiments, auristatin is 3377 (N,2-dimethylalanyl-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxyl-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N-methyl-L-valinanide) having the following structure:

In some embodiments, auristatin is 0131-OMe (N,2-dimethylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide) having the following structure:

In other embodiments, auristatin is 0131 (2-methyl-L-prolyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide) having the following structure:

In other embodiments, auristatin is 0121 (2-methyl-L-prolyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide) having the following structure:

Camptothecin is a cytotoxic quinoline alkaloid that inhibits the enzyme topoisomerase I. Examples of camptothecin and its derivatives include, but are not limited to, topotecan and irinotecan and their metabolites such as SN-38.

Combretastatins are naturally occurring phenols that have tumor-antivascular properties. Representative combretastatins and their derivatives include, but are not limited to, combretastatin A-4 (CA-4) and ombretabulin.

Duocarmycin and CC-1065 are DNA alkylating agents with cytotoxic activity. See Boger and Johnson, PNAS 92:3642–3649 (1995). Representative duocarmycin and CC-1065 include, but are not limited to,
(+)-duocarmycin A and (+)-duocarmycin SA, (+)-CC-1065 and the compounds disclosed in international application PCT/IB2015/050280, including, but not limited to, N~2~-acetyl-L-lysyl-L-valyl-N~5~-carbamoyl-N-[4-({[(2-{[({(1S)-1-(chloromethyl)-3-[(5-{[(1S)-1-(chloromethyl)-5-(phosphonooxy)-1,2-dihydro-3H-benzo[e]indol-3-yl]carbonyl}thiophen-2-yl)carbonyl]-2,3-dihydro-1H-benzo[e]indol-5-yl}oxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]-oxy}methyl)phenyl]-L-ornithinamide, having the structure:

N~2~-acetyl-L-lysyl-L-valyl-N~5~-carbamoyl-N-[4-({[(2-{[({(8S)-8-(chloromethyl)-6-[(3-{[(1S)-1-(chloromethyl)-8-methyl-5-(phosphonooxy)-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]carbonyl}bicyclo[1.1.1]pent-1-yl)carbonyl]-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-yl}oxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide, having the structure:

N~2~-acetyl-L-lysyl-L-valyl-N~5~-carbamoyl-N-[4-({[(2-{[({(8S)-8-(chloromethyl)-6-[(4-{[(1S)-1-(chloromethyl)-8-methyl-5-(phosphonooxy)-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl]carbonyl}-pentacyclo[4.2.0.0~2,5~.0~3,8~.0~4,7~]oct-1-yl)carbonyl]-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indol-4-yl}oxy)carbonyl](methyl)amino}ethyl)(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide, having the structure:

Enediynes are a class of antitumor bacterial products characterized by either nine- or ten-membered rings or the presence of a cyclic system of conjugated triple-double-triple bonds. Typical enediynes include, but are not limited to, calicheamicin, esperamicin, necialamycin, dynemicin, and their derivatives.

Geldanamycins are benzoquinone-ansamycin antibiotics that bind to Hsp90 (heat shock protein 90) and are used as antineoplastic drugs. Representative geldanamycins include, but are not limited to, 17-AAG (17-N-allylamino-17-demethoxygeldanamycin) and 17-DMAG (17-Dimethylaminoethylamino-17-demethoxygeldanamycin).

Hemiasterlin and its analogs (e.g. HTI-286) bind to tubulin, disrupt normal microtubule dynamics, and depolymerize microtubules in stoichiometric amounts.

Maytansines or their derivatives maytansinoids inhibit cell proliferation by inhibiting microtubule formation during mitosis via inhibition of tubulin polymerization. See Remillard et al., Science 189:1002-1005, 1975. Representative maytansines and maytansinoids include, but are not limited to, mertansine (DM1) and its derivatives, and ansamitocin.

Pyrrole benzodiazepine dimers (PBDs) and indolino benzodiazepine dimers (IGNs) are antineoplastic agents that contain one or more imine functional groups or their equivalents that bind to duplex DNA. PBD and IGN molecules are based on the natural product atramycin and interact with DNA in a sequence-selective manner, with a preference for purine-guanine-purine sequences. Representative PBDs and their analogs include, but are not limited to, SJG-136.

Spliceostatins and pladienolides are antineoplastic compounds that inhibit splicing and interact with the SF3b spliceosome. Examples of spliceostatins include, but are not limited to, spliceostatin A, FR901464, and (2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-hydrazinyl-2-oxoethyl)-4-hydroxy-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-5-oxopent-3-en-2-yl acetate, which has the structure

Examples of pladienolides include, but are not limited to, pladienolide B, pladienolide D, or E7107.

Taxanes are diterpenes that act as antitubulin agents or mitotic inhibitors. Typical taxanes include, but are not limited to, paclitaxel (eg, TAXOL ^® ) and docetaxel (TAXOTERE ^® ).

Tubulysins are natural products isolated from a strain of myxobacteria that have been shown to depolymerize microtubules and induce mitotic arrest. Representative tubulysins include, but are not limited to, tubulysin A, tubulysin B, and tubulysin D.

Vinca alkaloids are also antitubulin agents. Typical vinca alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, and vinorelbine.

Accordingly, in some embodiments, the cytotoxic agent is selected from the group consisting of MMAD (Monomethyl Auristatin D), 0101 (2-methylalanyl- N- [(3R , 4S , 5S )-3-methoxy-1-{( 2S )-2-[( 1R, 2R )-1-methoxy-2-methyl-3-oxo-3-{[( 1S )-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl] -N- methyl-L-valinanide), 3377 (N,2-dimethylalanyl-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxyl-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N-methyl-L-valinanamide), 0131 (2-methyl-L-prolyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanamide), 0131-OMe (N,2-dimethylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide), 0121 (2-methyl-L-prolyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinanide) and (2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-hydrazinyl-2-oxoethyl)-4-hydroxy-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-5-oxopent-3-en-2-yl acetate.

In some embodiments, the agent is an immunomodulatory agent. Examples of an immunomodulatory agent include, but are not limited to, ganciclovir, etanercept, tacrolimus, sirolimus, voclosporin, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, glucocorticoid and its analogs, cytokines, stem cell growth factors, lymphotoxins, tumor necrosis factor (TNF), hematopoietic factors, interleukins (e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, and IL-21), colony stimulating factors (e.g., granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF)), interferons (e.g., interferons-α, -β and -γ), stem cell growth factor designated "factor S 1", erythropoietin and thrombopoietin, or a combination of these.

In some embodiments, part of the agent is an imaging agent (e.g., a fluorophore or chelating agent), such as fluorescein, rhodamine, lanthanide phosphors and derivatives thereof, or a radioisotope associated with a chelating agent. Examples of fluorophores include, but are not limited to, fluorescein isothiocyanate (FITC) (e.g., 5-FITC), fluorescein amidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa ^Fluor® (e.g., Alexa 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 680, 700, or 750), carboxytetramethylrhodamine (TAMRA) (e.g., 5,-TAMRA), tetramethylrhodamine (TMR), and sulforhodamine (SR) (e.g., SR101). Examples of chelating agents include, but are not limited to, 1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-acetylacetoacetic acid (NOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid (deferoxamine), diethylenetriaminepentaacetic acid (DTPA), and 1,2-bis( ortho -aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) (BAPTA).

Examples of fluorophores include, but are not limited to, fluorescein isothiocyanate (FITC) (e.g., 5-FITC), fluorescein amidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa ^Fluor® (e.g., Alexa 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 680, 700, or 750), carboxytetramethylrhodamine (TAMRA) (e.g., 5,-TAMRA), tetramethylrhodamine (TMR), and sulforhodamine (SR) (e.g., SR101).

In some embodiments, therapeutic or diagnostic radioisotopes or other labels (e.g., PET or SPECT labels) may be included in the agent for conjugation with BCMA antibodies or antigen-binding fragments as described herein. Examples of radioisotopes or other labels include, but are not limited to, ³ H, ¹¹ C, ¹³ N, ¹⁴ C, ¹⁵ N, ¹⁵ O, ³⁵ S, ¹⁸ F, ³² P, ³³ P, ⁴⁷ Sc, ⁵¹ Cr, ⁵⁷ Co, ⁵⁸ Co, ⁵⁹ Fe, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁵ Se, ⁷⁶ Br, ⁷⁷ Br, ⁸⁶ Y, ⁸⁹ Zr, ⁹⁰ Y, ⁹⁴ Tc, ⁹⁵ Ru, ⁹⁷ Ru, ⁹⁹ Tc, ¹⁰³ Ru, ¹⁰⁵ Rh, ¹⁰⁵ Ru, ¹⁰⁷ Hg, ¹⁰⁹ Pd, ¹¹¹ Ag, ¹¹¹ In, ¹¹³ In, ¹²¹ Te, ¹²² Te, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁵ Te, ¹²⁶ I, ¹³¹ I, ¹³¹ In, ¹³³ I, ¹⁴² Pr, ¹⁴³ Pr, ¹⁵³ Pb, ¹⁵³ Sm, ¹⁶¹ Tb, ¹⁶⁵ Tm, ¹⁶⁶ Dy, ¹⁶⁶ H, ¹⁶⁷ Tm, ¹⁶⁸ Tm, ¹⁶⁹ Yb, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁸⁹ Re, ¹⁹⁷ Pt, ¹⁹⁸ Au, ¹⁹⁹ Au, ²⁰¹ Tl, ²⁰³ Hg, ²¹¹ At, ²¹² Bi, ²¹² Pb, ²¹³ Bi, ²²³ Ra, ²²⁴ Ac or ²²⁵ Ac.

In some embodiments, the agent is a therapeutic protein, including, but not limited to, a toxin, a hormone, an enzyme, and a growth factor.

Examples of toxin proteins (or polypeptides) include, but are not limited to, diphtheria toxin (e.g., diphtheria A chain), Pseudomonas exotoxin and endotoxin, ricin (e.g., ricin A chain), abrin (e.g., abrin A chain), modecin (e.g., modecin A chain), alpha-sarcin, Aleurites fordii proteins, dianthine proteins, ribonuclease (RNase), DNase I, staphylococcal enterotoxin A, pokeweed antiviral protein, gelonin, diphtheria toxin, pokeweed proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, soapwort inhibitor, mitogellin, restrictocin, phenomycin, enomycin, trichothecenes, inhibitory cystine knot (ICK) peptides (e.g., ceratotoxins) and conotoxin (eg KIIIA or SmIIIa).

In some embodiments, the agent is a biocompatible polymer. BCMA antibodies or antigen-binding fragments as described herein can be conjugated to a biocompatible polymer to increase plasma half-life and biological activity and/or to increase in vivo half-lives. Examples of biocompatible polymers include a water-soluble polymer such as polyethylene glycol (PEG) or its derivatives, and biocompatible polymers containing a zwitterion (e.g., a phosphorylcholine-containing polymer).

In some embodiments, the agent is an oligonucleotide, such as antisense oligonucleotides.

In another aspect of the invention there is provided a conjugate of an antibody or antigen-binding fragment as described herein, wherein the conjugate has the formula: antibody-(acyl donor glutamine-containing tag)-(linker)-(cytotoxic agent), wherein the acyl donor glutamine-containing tag is engineered at a specific location on the antibody or antigen-binding fragment (e.g. at the carboxyl terminus of the heavy or light chain, after residue T135 in the heavy chain of the antibody, or elsewhere), wherein the tag is conjugated to a linker (e.g. a linker comprising one or more reactive amines (e.g. a primary amine NH ₂ )), and wherein the linker is conjugated to a cytotoxic agent (e.g. MMAD or other auristatins such as 0101, 0131, or 3377).

Examples of a linker comprising one or more reactive amines include, but are not limited to, Ac-Lys-Gly (acetyl-lysine-glycine), aminocaproic acid, Ac-Lys-β-Ala (acetyl-lysine-β-alanine), amino-PEG2 (polyethylene glycol)-C2, amino-PEG3-C2, amino-PEG6-C2 (or amino PEG6-propionyl), Ac-Lys-Val-Cit-PABC (acetyl-lysine-valine-citrulline -p- aminobenzyloxycarbonyl), amino-PEG6-C2-Val-Cit-PABC, aminocaproyl-Val-Cit-PABC, [(3R,5R)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}piperidine-3,5-diyl]bis-Val-Cit-PABC, [(3S,5S)-1-{3-[2-(2-aminoethoxy)ethoxy]propanoyl}-piperidine-3,5-diyl]bis-Val-Cit-PABC, putrescine or Ac-Lys-putrescine.

In some embodiments, the conjugate is 1) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101; 2) antibody-AcLys-VC-PABC-0101 and comprises N297Q; 3) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101 and comprises N297Q; 4) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-0131 and comprises N297A; 5) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-3377 and comprises N297A; 6) antibody-GGLLQGA (SEQ ID NO: 475)-AcLys-VC-PABC-0101. In some embodiments, an acyl donor glutamine-containing tag comprising, for example, GGLLQGPP (SEQ ID NO: 474) or GGLLQGA (SEQ ID NO: 475) is engineered at the C-terminus of the light chain of the antibody. In other embodiments, an acyl donor glutamine-containing tag (for example, LLQGA (SEQ ID NO: 463) or LLQGPP (SEQ ID NO: 472)) is engineered at the C-terminus of the heavy chain of the antibody, where the lysine residue at the C-terminus is removed. In some embodiments, an acyl donor glutamine-containing tag, comprising, for example, LLQG (SEQ ID NO: 454), is designed after residue T135 in the heavy chain of the antibody or replaces amino acid residues E294-N297 in the heavy chain of the antibody. Examples of antibodies include, but are not limited to, P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ, L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA, L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT

L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ

L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6nM_C06, A02_Rd4_0.6nM_C09, A02_Rd4_6nM_C16, A02_Rd4_6nM_C03, A02_Rd4_6nM_C01, A02_Rd4_6nM_C26, A02_Rd4_6nM_C25, A02_Rd4_6nM_C22, A02_Rd4_6nM_C19, A02_Rd4_0.6nM_C03, A02_Rd4_6nM_C07, A02_Rd4_6nM_C23, A02_Rd4_0.6nM_C18, A02_Rd4_6nM_C10, A02_Rd4_6nM_C05, A02_Rd4_0.6nM_C10, A02_Rd4_6nM_C04, A02_Rd4_0.6nM_C26, A02_Rd4_0.6nM_C13, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C08, P5C1_VHVL, C01_Rd4_6nM_C24, C01_Rd4_6nM_C26, C01_Rd4_6nM_C10, C01_Rd4_0.6nM_C27, C01_Rd4_6nM_C20, C01_Rd4_6nM_C12, C01_Rd4_0.6nM_C16, C01_Rd4_0.6nM_C09, C01_Rd4_6nM_C09, C01_Rd4_0.6nM_C03, C01_Rd4_0.6nM_C06, C01_Rd4_6nM_C04, COMBO_Rd4_0.6nM_C22, COMBO_Rd4_6nM_C21, COMBO_Rd4_6nM_C10, COMBO_Rd4_0.6nM_C04, COMBO_Rd4_6nM_C25, COMBO_Rd4_0.6nM_C21, COMBO_Rd4_6nM_C11, COMBO_Rd4_0.6nM_C20, COMBO_Rd4_6nM_C09, COMBO_Rd4_6nM_C08, COMBO_Rd4_0.6nM_C19, COMBO_Rd4_0.6nM_C02, COMBO_Rd4_0.6nM_C23, COMBO_Rd4_0.6nM_C29, COMBO_Rd4_0.6nM_C09, COMBO_Rd4_6nM_C12, COMBO_Rd4_0.6nM_C30, COMBO_Rd4_0.6nM_C14, COMBO_Rd4_6nM_C07, COMBO_Rd4_6nM_C02, COMBO_Rd4_0.6nM_C05, COMBO_Rd4_0.6nM_C17, COMBO_Rd4_6nM_C22, COMBO_Rd4_0.6nM_C11, COMBO_Rd4_0.6nM_C29, P4G4 or P1A11.

In one embodiment, the conjugate further comprises an amino acid substitution of lysine to arginine at position 222. Accordingly, for example, the conjugate is 1) antibody-GGLLQGPP (SEQ ID NO: 474)- AcLys-VC-PABC-0101 and comprises K222R; 2) antibody-AcLys-VC-PABC-0101 and comprises N297Q and K222R; 3) antibody-GGLLQGPP (SEQ ID NO: 474)-AcLys-VC-PABC-0101 and comprises N297Q and K222R; 4) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-0131 and comprises N297A and K222R; 5) antibody-LLQG (SEQ ID NO: 454)-amino-PEG6-C2-3377 and comprises N297A and K222R; and 6) antibody-GGLLQGA (SEQ ID NO: 475)-AcLys-VC-PABC-0101 and comprises K222R. In some embodiments, an acyl donor glutamine-containing tag comprising, for example, GGLLQGPP (SEQ ID NO: 474) or GGLLQGA (SEQ ID NO: 475) is engineered at the C-terminus of the light chain of the antibody. In other embodiments, an acyl donor glutamine-containing tag (for example, LLQGA (SEQ ID NO: 473) or LLQGPP (SEQ ID NO: 472)) is engineered at the C-terminus of the heavy chain of the antibody, wherein the lysine residue at the C-terminus is deleted. In some embodiments, an acyl donor glutamine-containing tag, comprising, for example, LLQG (SEQ ID NO: 454), is designed after residue T135 in the heavy chain of the antibody or replaces amino acid residues E294-N297 in the heavy chain of the antibody. Examples of antibodies include, but are not limited to, P6E01/P6E01, P6E01/H3.AQ, L1.LGF/L3.KW/P6E01; L1.LGF/L3.NY/P6E01, L1.GDF/L3.NY/P6E01, L1.LGF/L3.KW/H3.AL, L1.LGF/L3.KW/H3.AP, L1.LGF/L3.KW/H3.AQ, L1.LGF/L3.PY/H3.AP, L1.LGF/L3.PY/H3.AQ, L1.LGF/L3.NY/H3.AL, L1.LGF/L3.NY/H3.AP, L1.LGF/L3.NY/H3.AQ, L1.GDF/L3.KW/H3.AL, L1.GDF/L3.KW/H3.AP, L1.GDF/L3.KW/H3.AQ, L1.GDF/L3.PY/H3.AQ, L1.GDF/L3.NY/H3.AL, L1.GDF/L3.NY/H3.AP, L1.GDF/L3.NY/H3.AQ, L3.KW/P6E01, L3.PY/P6E01, L3.NY/P6E01, L3.PY/L1.PS/P6E01, L3.PY/L1.AH/P6E01, L3.PY/L1.FF/P6E01, L3.PY/L1.PH/P6E01, L3.PY/L3.KY/P6E01, L3.PY/L3.KF/P6E01, L3.PY/H2.QR, L3.PY/H2.DY, L3.PY/H2.YQ, L3.PY/H2.LT, L3.PY/H2.HA, L3.PY/H2.QL, L3.PY/H3.YA, L3.PY/H3.AE, L3.PY/H3.AQ, L3.PY/H3.TAQ, L3.PY/P6E01, L3.PY/L1.PS/H2.QR, L3.PY/L1.PS/H2.DY, L3.PY/L1.PS/H2.YQ, L3.PY/L1.PS/H2.LT, L3.PY/L1.PS/H2.HA, L3.PY/L1.PS/H2.QL, L3.PY/L1.PS/H3.YA, L3.PY/L1.PS/H3.AE, L3.PY/L1.PS/H3.AQ, L3.PY/L1.PS/H3.TAQ, L3.PY/L1.AH/H2.QR, L3.PY/L1.AH/H2.DY, L3.PY/L1.AH/H2.YQ, L3.PY/L1.AH/H2.LT, L3.PY/L1.AH/H2.HA, L3.PY/L1.AH/H2.QL, L3.PY/L1.AH/H3.YA, L3.PY/L1.AH/H3.AE, L3.PY/L1.AH/H3.AQ, L3.PY/L1.AH/H3.TAQ, L3.PY/L1.FF/H2.QR, L3.PY/L1.FF/H2.DY, L3.PY/L1.FF/H2.YQ, L3.PY/L1.FF/H2.LT, L3.PY/L1.FF/H2.HA, L3.PY/L1.FF/H2.QL, L3.PY/L1.FF/H3.YA, L3.PY/L1.FF/H3.AE, L3.PY/L1.FF/H3.AQ, L3.PY/L1.FF/H3.TAQ, L3.PY/L1.PH/H2.QR, L3.PY/L1.PH/H2.HA, L3.PY/L1.PH/H3.AE, L3.PY/L1.PH/H3.AQ, L3.PY/L1.PH/H3.TAQ, L3.PY/L3.KY/H2.QR, L3.PY/L3.KY/H2.DY, L3.PY/L3.KY/H2.YQ, L3.PY/L3.KY/H2.LT, L3.PY/L3.KY/H2.HA, L3.PY/L3.KY/H2.QL, L3.PY/L3.KY/H3.YA, L3.PY/L3.KY/H3.TAQ, L3.PY/L3.KF/H2.DY, L3.PY/L3.KF/H2.YQ, L3.PY/L3.KF/H2.LT

L3.PY/L3.KF/H2.QL, L3.PY/L3.KF/H3.YA, L3.PY/L3.KF/H3.AE, L3.PY/L3.KF/H3.AQ

L3.PY/L3.KF/H3.TAQ, P5A2_VHVL, A02_Rd4_0.6nM_C06, A02_Rd4_0.6nM_C09

A02_Rd4_6nM_C16, A02_Rd4_6nM_C03, A02_Rd4_6nM_C01, A02_Rd4_6nM_C26, A02_Rd4_6nM_C25, A02_Rd4_6nM_C22, A02_Rd4_6nM_C19, A02_Rd4_0.6nM_C03, A02_Rd4_6nM_C07, A02_Rd4_6nM_C23, A02_Rd4_0.6nM_C18, A02_Rd4_6nM_C10, A02_Rd4_6nM_C05, A02_Rd4_0.6nM_C10, A02_Rd4_6nM_C04, A02_Rd4_0.6nM_C26, A02_Rd4_0.6nM_C13, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C08, P5C1_VHVL, C01_Rd4_6nM_C24, C01_Rd4_6nM_C26, C01_Rd4_6nM_C10, C01_Rd4_0.6nM_C27, C01_Rd4_6nM_C20, C01_Rd4_6nM_C12, C01_Rd4_0.6nM_C16, C01_Rd4_0.6nM_C09, C01_Rd4_6nM_C09, C01_Rd4_0.6nM_C03, C01_Rd4_0.6nM_C06, C01_Rd4_6nM_C04, COMBO_Rd4_0.6nM_C22, COMBO_Rd4_6nM_C21, COMBO_Rd4_6nM_C10, COMBO_Rd4_0.6nM_C04, COMBO_Rd4_6nM_C25, COMBO_Rd4_0.6nM_C21, COMBO_Rd4_6nM_C11, COMBO_Rd4_0.6nM_C20, COMBO_Rd4_6nM_C09, COMBO_Rd4_6nM_C08, COMBO_Rd4_0.6nM_C19, COMBO_Rd4_0.6nM_C02, COMBO_Rd4_0.6nM_C23, COMBO_Rd4_0.6nM_C29, COMBO_Rd4_0.6nM_C09, COMBO_Rd4_6nM_C12, COMBO_Rd4_0.6nM_C30, COMBO_Rd4_0.6nM_C14, COMBO_Rd4_6nM_C07, COMBO_Rd4_6nM_C02, COMBO_Rd4_0.6nM_C05, COMBO_Rd4_0.6nM_C17, COMBO_Rd4_6nM_C22, COMBO_Rd4_0.6nM_C11, COMBO_Rd4_0.6nM_C29, or P4G4, or P1A11.

CD3 antibodies and methods for obtaining them

The present invention further provides an antibody that binds to CD3 (e.g. human CD3 (SEQ ID NO: 502; or accession number: NM_000733.3).

In one aspect, an isolated antibody or antigen-binding fragment thereof is provided that specifically binds to CD3, wherein the antibody comprises a VH CDR1, VH CDR2 and VH CDR3 of a VH sequence set forth in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398 or 400; and/or a light chain variable region (VL) comprising the VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or 399.

In another aspect, there is provided an isolated antibody or antigen-binding fragment thereof that specifically binds to CD3, wherein the VH region comprises (1) a VH complementarity determining region one (CDR1) comprising the sequence set forth in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447, or 448, (2) a VH CDR2 comprising the sequence set forth in SEQ ID NO: 334, 336, 337, 338, 339, 404, 405, 409, 410, 411, 412, 413, 414, 417, 418, 421, 422, 427, 428, 449 or 450; and (3) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429 or 451; and/or a light chain variable region (VL) comprising (1) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435 or 440, 441; (2) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452 or 436; and (3) a VL CDR3 comprising the sequence set forth in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453.

In some embodiments, an antibody is provided having any of the partial light chain sequences set forth in Table 3 and/or any of the partial heavy chain sequences set forth in Table 3.

Table 3 mAb Light chain Heavy chain h2B4 DIVMTQSPDSLAVSLGERATINC TSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK (SEQ ID NO: 319) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNASVKG RFT ISRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS
(SEQ ID NO: 320) h2B4-
VH-wt
VL_TK DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK (SEQ ID NO: 321) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNASVKG RFT ISRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS
(SEQ ID NO: 322) h2B4-
VH-hnps
VL_TK DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGSGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK
(SEQ ID NO: 323) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNPSVKG RFTI SRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS
(SEQ ID NO: 324) h2B4-
VH-yaes
VL_TK DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGSGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK
(SEQ ID NO: 325) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDYAESVKG RFTI SRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS
(SEQ ID NO: 326) h2B4-
VH-yads
VL_TK DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGSGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK
(SEQ ID NO: 327) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDYADSVKG RFT ISRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS
(SEQ ID NO: 328) h2B4-
VH-yaps
VL_TK DIVMTQSPDSLAVSLGERATINC TSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGSGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK
(SEQ ID NO: 329) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEWVA FIRNRARGYTSDYAPSVKG RFTI SRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVT VSS
(SEQ ID NO: 330) h2B4-
VH-hnps
VL_TK
-S55Y DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIY WASTRES G VPDRFSGSGGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGSGTKLEIK (SEQ ID NO: 344) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNPSVKG RFTI SRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS (SEQ ID NO: 345) h2B4-
VH-hnps
VL_TK
-
S105Q DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGSGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGQGTKLEIK (SEQ ID NO: 346) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNPSVKG RFTI SRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS (SEQ ID NO: 347) h2B4-
VH-hnps
VL_TK
-
S55Y/
S105Q DIVMTQSPDSLAVSLGERATINC KSSQSLFNVRSRKNYLA WYQQKPGQPPKLLIY WASTRES G VPDRFSGSGGTDFTLTISSLQAEDV AVYYC KQSYDLFT FGQGTKLEIK (SEQ ID NO: 348) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNPSVKG RFTI SRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS (SEQ ID NO: 349) 2B4 DIVMSQSPPSLAVSVGDKVTMSC TSSQSLFNSRSRKNYLA WYQQKSGQSPKLLIS WASTRES G VPDRFTGSGSGTDFTLTISSVQAEDLAVYYC KQSYDLFT FGSGTKLEIK (SEQ ID NO: 350) EVKLVESGGGLVQPGGSLRLSCAT FGFTFT DYYMT WVRQPPGKALEW VA FIRNRARGYTSDHNASVKG RFT ISRDNSQNILYLQMNTLRAEDSAT YYCAR DRPSYYVLDY WGQG TTVTVSS (SEQ ID NO: 351) h2B4-11 DIVMTQSPDSLAVSLGERATINC TSSQSLFNSRSRKNYLA WYQQKPGQPPKLLIS WASTRES G VPDRFSGSGGTDFTLTISSLQAEDV AVYYC QQSYDTFT FGSGTKLEIK (SEQ ID NO: 445) EVQLVESGGGLVQPGGSLRLSCAA SGFTFS DYYMT WVRQAPGKGLEW VA FIRNRARGYTSDHNASVKG RFT ISRDNAKNSLYLQMNSLRAEDTAV YYCAR DRPSYYVLDY WGQG TTVTVSS (SEQ ID NO: 444) 1C10 DIVMSQSPSSLAVSAGEKVTMSC KSSQSLLNSRTRKNY LAWYQQKPGQSPKLLIY WASTRES G VPDRFTGSGSGTDFTLTIDSV QPEDLAVYYC TQSFILRT FGGGTKLEIK (SEQ ID NO: 352) QVQLQQPGSELVRPGASVILSCKAS GYTFT SYWMH WVRQRPGQGLEWI G NIYSGGDTINYDEKFKN KAILTVD TSSSTAYMHLSSLTSEDSAVYYCT R DATSRYFFDY WGQG TTVTVSS (SEQ ID NO: 354) 1A4 DIVMSQSPSSLAVSAGEKVTMSC KSSQSLLNSRTRKNY LAWYQQKPGQSPKLLIY WASTRAS G VPDRFTGSGSGTDFTLTISSV QAEDLAIYY CKQSFILRT FGGGTKLEIK (SEQ ID NO: 355) QVQLQQSGPDLVKPGASVEISCKA SGYSFT TYYLH WVRQRPGQGLEWI G WIFPGSDNTKYNEKFKG KATLTA DTSSSTAYMQLSSLTSEDSAVYFC AR NRDYYFDY WGQG TTVTVSS(SEQ ID NO: 356) 7A3 DIVVSQSPSSLAVSAGEKVIMSC KSSQSLLNSRTRKNY LAWYQLKPGQSPKLLIY SASTRES G VPDRFTGSGSGTDFTLTISSVQ TEDLAVYYC MQSFTLRT FGGGTKLEIK (SEQ ID NO: 443) EVQLQQSGAELVRPGALVKLSCKG SGFNIK DYYIH WVKQRPEQGLEWI G WIDPENGNNKYDPKFQG KASITA DTSSNIAYLQLSSLTSEDTAVYYCA R NDNYAFDY WGQG TTVTVSS(SEQ ID NO: 442) 25A8 QAVVTQESALTTSPGEAVTLTC RSSTGAVTTSNYAN WVQEKPDHLFTGLIG GTNTRAP G VPARFSGSLIGDKAALTITGAQTEDEAIYFC VLWYNNYWV FGG GTKLTVL (SEQ ID NO: 377) EVQLVESGGGLVRPEGSLRLSCAA SGFTFN TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFT LSRDDSLSMVYLQMNSLKNEDTA MYYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 378) 16G7 QAVVTQESALTTSPGETVTLTC RSSTGAVTTSNYAN WVQEKPDHLFTGLIG GTNNRAP G VPARFSGSLIGDKAALTITGA QTEDEAIYFC ALWYSNHWV FGGGTKLTVL (SEQ ID NO: 379) EVQLVDSGGGLVQPKGSLKLSCAA SGFTFN TYAMN WVRQAPGKGLEW VA RIRSKSNNYATYYADSVKD RFT ISRDDSQSRLYLQMNNLKTEDTAMYYCVR HETLRSGISWFAN WGQG TLVTVSS (SEQ ID NO: 380) h25A8-B5 QAVVTQEPSLTVSPGGTVTLTC RSSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTLSGA QPEDEAEYYC VLWYNNYWV FGGGTKLTVL (SEQ ID NO: 381) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 382) h25A8-B8 QAVVTQEPSLTVSPGGTVTLTC RSSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTLSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 383) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 384) h25A8-B12 QAVVTQEPSLTVSPGGTVTLTC RASTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 385) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 386) h25A8-B13 QAVVTQEPSLTVSPGGTVTLTC RTSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 387) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 388) h25A8-C5 QAVVTQEPSLTVSPGGTVTLTC RSSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTLSGA QPEDEAEYYC VLWYNNYWV FGGGTKLTVL (SEQ ID NO: 389) EVQLVESGGGLVKPGGSLRLSCAA SGFTFN TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 390) h25A8-C8 QAVVTQEPSLTVSPGGTVTLTC RSSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTLSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 391) EVQLVESGGGLVKPGGSLRLSCAA SGFTFN TYAMN WVRQAPGKGLEW VG RIRSKINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 392) h25A8-D13 QAVVTQEPSLTVSPGGTVTLTC RTSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTLSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 393) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSHINNYATYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 394) h25A8-E13 QAVVTQEPSLTVSPGGTVTLTC RTSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 395) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSKYNNYATYYAESVKG RFT ISRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 396) h25A8-F13 QAVVTQEPSLTVSPGGTVTLTC RTSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 397) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RERSKINNYATYYAESVKG RFT ISRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 398) h25A8-G13 QAVVTQEPSLTVSPGGTVTLTC RTSTGAVTTSNYAN WVQQKPGQAPRGLIG GTNTRAP G TPARFSGSLLGGKAALTSGA QPEDEAEYYC VLWYNNHWV FGGGTKLTVL (SEQ ID NO: 399) EVQLVESGGGLVKPGGSLRLSCAA SGFTFS TYAMN WVRQAPGKGLEW VG RIRSKINNYKTYYAESVKG RFTI SRDDSKNTLYLQMNSLKTEDTAV YYCVR HETLRSGISWFAS WGQG TLVTVSS (SEQ ID NO: 400)

In Table 3, the underlined sequences represent the CDR sequences according to Kabat and those in bold according to Chothia.

The invention also provides CDR regions to CD3 (including Chothia CDRs, Kabat CDRs, and CDR contact regions). The definition of CDR regions is well known in the art. It is understood that in some embodiments, the CDRs may be a combination of Kabat and Chothia CDRs (also referred to as "combined CDRs" or "extended CDRs"). In some embodiments, the CDRs are Kabat CDRs. In other embodiments, the CDRs are Chothia CDRs. In other words, in embodiments with more than one CDR, the CDRs may be any of Kabat CDRs, Chothia CDRs, combined CDRs, or a combination thereof. Table 4 provides examples of the CDR sequences provided herein.

Table 4 Heavy chain mAb CDRH1 CDRH2 CDRH3 h2B4 DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNASVKG (SEQ ID NO: 334) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-wt
VL_TK DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNASVKG (SEQ ID NO: 334) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-hnps
VL_TK DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNPSVKG
(SEQ ID NO: 336) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-yaes
VL_TK DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDYAESVKG
(SEQ ID NO: 337) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-yads
VL_TK DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDYADSVKG
(SEQ ID NO: 338) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-yaps
VL_TK DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDYAPSVKG
(SEQ ID NO: 339) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-hnps
VL_TK
-
S55Y DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNPSVKG (SEQ ID NO: 336) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-hnps
VL_TK
-
S105Q DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNPSVKG(SEQ ID NO: 336) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-
VH-hnps
VL_TK
-
S55Y/
S105Q DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNPSVKG (SEQ ID NO: 336) (Kabat) DRPSYYVLDY
(SEQ ID NO: 335) 2B4 DYYMT (SEQ ID NO: 331) (Kabat);
GFTFTDY (SEQ ID NO: 415) (Chothia);
GFTFTDYYMT (SEQ ID NO: 416) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNASVKG
(SEQ ID NO: 418) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) h2B4-11 DYYMT (SEQ ID NO: 331) (Kabat);
GFTFSDY (SEQ ID NO: 332) (Chothia);
GFTFSDYYMT (SEQ ID NO: 333) (extended) RNRARGYT
(SEQ ID NO: 417) (Chothia)
FIRNRARGYTSDHNASVKG
(SEQ ID NO: 418) (Kabat) DRPSYYVLDY (SEQ ID NO: 335) 1C10 SYWMH (SEQ ID NO: 418) (Kabat)
GYTFTSY (SEQ ID NO: 419) (Chothia)
GYTFTSYWMH (SEQ ID NO: 420) (extended) YSGGDT
(SEQ ID NO: 421) (Chothia)
NIYSGGDTINYDEKFKN (SEQ ID NO: 422) (Kabat) DATSRYFFDY (SEQ ID NO: 423) 1A4 TYYLH (SEQ ID NO: 424) (Kabat)
GYSFTTYY (SEQ ID NO: 425) (Chothia)
GYSFTTYYLH (SEQ ID NO: 426) (extended) FPGSDN (SEQ ID NO: 427) (Chothia)
WIFPGSDNTKYNEKFKG (SEQ ID NO: 428) (Kabat) NRDYYFDY
(SEQ ID NO: 429) 7A3 DYYIH (SEQ ID NO: 446) (Kabat)
GFNIKDY(SEQ ID NO: 447) (Chothia)
gfnikdyyih (SEQ ID NO: 448) (extended) DPENGN (SEQ ID NO: 449) (Chothia)
WIDPENGNNKYDPKFQG (SEQ ID NO: 450) (Kabat) NDNYAFDY
(SEQ ID NO: 451) 25A8 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFNTY (SEQ ID NO: 402) (Chothia);
GFTFNTYAMN (SEQ ID NO: 403) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) 16G7 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFNTY (SEQ ID NO: 402) (Chothia);
GFTFNTYAMN (SEQ ID NO: 403) (extended) RSKSNNYA (SEQ ID NO: 404) (Chothia)
RIRSKSNNYATYYADSVKD (SEQ ID NO: 405) (Kabat) HETLRSGISWFAN (SEQ ID NO: 406) h25A8-B5 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-B8 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-B12 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-B13 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-C5 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFNTY (SEQ ID NO: 402) (Chothia);
GFTFNTYAMN (SEQ ID NO: 403) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-C8 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFNTY (SEQ ID NO: 402) (Chothia);
GFTFNTYAMN (SEQ ID NO: 403) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYATYYAESVKG (SEQ ID NO: 405) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-D13 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSHINNYA (SEQ ID NO: 409) (Chothia)
RIRSHINNYATYYAESVKG (SEQ ID NO: 410) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-E13 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKYNNYA (SEQ ID NO: 411) (Chothia)
RIRSKYNNYATYYAESVKG (SEQ ID NO: 412) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-F13 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RERSKINNYATYYAESVKG
(SEQ ID NO: 413) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) h25A8-G13 TYAMN (SEQ ID NO: 401) (Kabat);
GFTFSTY (SEQ ID NO: 407) (Chothia);
GFTFSTYAMN (SEQ ID NO: 408) (extended) RSKINNYA (SEQ ID NO: 404) (Chothia)
RIRSKINNYKTYYAESVKG (SEQ ID NO: 414) (Kabat) HETLRSGISWFAS (SEQ ID NO: 406) Light chain mAb CDRH1 CDRH2 CDRH3 h2B4 TSSQSLFNVRSRKNYLA
(SEQ ID NO: 340) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-wt
VL_TK KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-hnps
VL_TK KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-yaes
VL_TK KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-yads
VL_TK KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-yaps
VL_TK KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) 2B4 TSSQSLFNSRSRKNYLA (SEQ ID NO: 430) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-11 TSSQSLFNSRSRKNYLA (SEQ ID NO: 430) WASTES
(SEQ ID NO: 341) QQSYDTFT (SEQ ID NO: 446) 1C10 KSSQSLLNSRTRKNY (SEQ ID NO: 431) WASTES
(SEQ ID NO: 341) TQSFILRT (SEQ ID NO: 432) 1A4 KSSQSLLNSRTRKNY (SEQ ID NO: 431) WASTRAS
(SEQ ID NO: 433) KQSFILRT (SEQ ID NO: 434) 7A3 KSSQSLLNSRTRKNY (SEQ ID NO: 431) SASTRES
(SEQ ID NO: 452) MQSFTLRT (SEQ ID NO: 453) h2B4-
VH-hnps
VL_TK
-
S55Y KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-hnps
VL_TK
-
S105Q KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) h2B4-
VH-hnps
VL_TK
-
S55Y/
S105Q KSSQSLFNVRSRKNYLA
(SEQ ID NO: 343) WASTES
(SEQ ID NO: 341) KQSYDLFT
(SEQ ID NO: 342) 25A8 RSSTGAVTTSNYAN
(SEQ ID NO: 435) GTNTRAP (SEQ ID NO: 436) VLWYNNYWV (SEQ ID NO: 437) 16G7 RSSTGAVTTSNYAN
(SEQ ID NO: 435) GTNTRAP (SEQ ID NO: 436) ALWYSNHWV (SEQ ID NO: 438) h25A8-B5 RSSTGAVTTSNYAN
(SEQ ID NO: 435) GTNTRAP (SEQ ID NO: 436) VLWYNNYWV (SEQ ID NO: 437) h25A8-B8 RSSTGAVTTSNYAN
(SEQ ID NO: 435) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-B12 RASTGAVTTSNYAN (SEQ ID NO: 440) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-B13 RTSTGAVTTSNYAN (SEQ ID NO: 441) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-C5 RSSTGAVTTSNYAN
(SEQ ID NO: 435) GTNTRAP (SEQ ID NO: 436) VLWYNNYWV (SEQ ID NO: 437) h25A8-C8 RSSTGAVTTSNYAN
(SEQ ID NO: 435) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-D13 RTSTGAVTTSNYAN (SEQ ID NO: 441) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-E13 RTSTGAVTTSNYAN (SEQ ID NO: 441) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-F13 RTSTGAVTTSNYAN (SEQ ID NO: 441) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439) h25A8-G13 RTSTGAVTTSNYAN (SEQ ID NO: 441) GTNTRAP (SEQ ID NO: 436) VLWYNNHWV (SEQ ID NO: 439)

The invention also provides isolated polynucleotides encoding the antibodies of the invention, and vectors and host cells containing the polynucleotide.

In one embodiment, the polynucleotide comprises a sequence encoding the variable regions of the heavy and/or light chain of the antibody h2B4, h2B4-VH-wt VL_TK, h2B4-VH-hnps VL_TK, h2B4-VH-yaes VL_TK, h2B4-VH-yads VL_TK, h2B4-VH-yaps VL_TK, h2B4-VH-hnps VL_TK-S55Y, h2B4-VH-hnps VL_TK-S105Q, h2B4-vH-hnps VL_TK-S55Y/S105Q, 2B4, h2B4-11, 1C10, 1A4, 7A3, 25A8, 16G7, h25A8-B5, h25A8-B8, h25A8-B12, h25A8-B13, h25A8-C5, h25A8-C8, h25A8-D13, h25A8-E13, h25A8-F13, or h25A8-G13. The sequence encoding the antibody of interest can be maintained in a vector in a host cell, and the host cell can then be expanded and frozen for later use. Vectors (including expression vectors) and host cells are described herein below.

The invention also encompasses fusion proteins comprising one or more fragments or regions of the antibodies of the invention. In one embodiment, there is provided a fusion polypeptide that comprises at least 10 contiguous amino acids of a light chain variable region as set forth in SEQ ID NOs: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 445, 352, 355, 443, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397 or 399 and/or at least 10 amino acids of a heavy chain variable region as set forth in SEQ ID NOs: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 354, 356, 444, 442, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398 or 400. In other embodiments, a fusion polypeptide is provided that comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of a light chain variable region and/or at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of a heavy chain variable region. In another embodiment, the fusion polypeptide comprises a light chain variable region and/or a heavy chain variable region shown in any pair of sequences selected from SEQ ID NOs: 319 and 320, 321 and 322, 323 and 324, 325 and 326, 327 and 328, 329 and 330, 344 and 345, 346 and 347, 348 and 349, 350 and 351, 445 and 444, 352 and 354, 355 and 356, 443 and 442, 377 and 378, 379 and 380, 381 and 382, 383 and 384, 385 and 386, 387 and 388, 389 and 390, 391 and 392, 393 and 394, 395 and 396, 397 and 398, or 399 and 400. In another embodiment, the fusion polypeptide comprises one or more CDRs. In other embodiments, the fusion polypeptide comprises CDR H3 (VH CDR3) and/or CDR L3 (VL CDR3). For purposes of the present invention, the fusion protein comprises one or more antibodies and another amino acid sequence to which it is not linked in the native molecule, such as a heterologous or homologous sequence from another region. Exemplary heterologous sequences include, but are not limited to, a "tag" such as a FLAG tag or a 6His tag. Tags are well known in the art.

The fusion polypeptide may be produced by methods well known in the art, such as synthetically or recombinantly. Typically, the fusion proteins of the present invention are produced by preparing the expression of a polynucleotide encoding them using the recombinant methods described herein, although they may also be produced by other methods known in the art, including, for example, chemical synthesis.

Representative materials of the CD3 antibody of the present invention were deposited with the American Type Culture Collection (ATCC) on September 11, 2015. The vector having ATCC accession number PTA-122513 is a polynucleotide encoding the variable region of the heavy chain of a humanized CD3 antibody, and the vector having ATCC accession number PTA-122512 is a polynucleotide encoding the variable region of the light chain of a humanized CD3 antibody. The deposits were made in accordance with the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and the Guidelines thereunder (Budapest Treaty). This ensures that the deposited culture will be maintained in viable condition for 30 years from the date of deposit. The deposit will be provided to the ATCC in accordance with the provisions of the Budapest Treaty and in agreement with Pfizer, Inc. and the ATCC, which guarantees the perpetual and unrestricted availability of the progeny of the deposited crop to the public upon the grant of a corresponding U.S. patent or upon the publication in the public domain of any U.S. or foreign patent application, whichever occurs first, and guarantees the availability of the progeny to anyone determined by the Commissioner of the United States Patent and Trademark Office to be entitled thereto pursuant to 35 U.S.C. Section 122 and the Commissioner's regulations thereunder (including 37 C.F.R. Section 1.14 with particular reference to 886 OG 638).

The patentee of this application agrees that in the event of loss, destruction or destruction of deposited materials during cultivation under suitable conditions, these materials will be promptly replaced upon notice to the other. Availability of deposited material should not be construed as a license to practice the invention in violation of rights granted under the laws of any state in accordance with its patent laws.

Bispecific antibodies and methods for obtaining them

Bispecific antibodies, monoclonal antibodies having binding specificities for at least two different antigens, can be prepared using the antibodies described herein. Methods for producing bispecific antibodies are known in the art (see, e.g., Suresh et al., Methods in Enzymology 121:210, 1986). Typically, recombinant production of bispecific antibodies is based on the coexpression of two immunoglobulin heavy chain-light chain pairs with the two heavy chains having different specificities (Millstein and Cuello, Nature 305, 537-539, 1983).

According to one approach to creating bispecific antibodies, variable domains of antibodies with the desired binding specificity (antibody-antigen binding sites) are fused to immunoglobulin constant region sequences. The fusion is preferably performed with a constant region of an immunoglobulin heavy chain comprising at least part of the hinge, CH2 and CH3 regions. It is preferred to have the first constant region (CH1) of the heavy chain, containing the site necessary for light chain binding, present in at least one of the fusions. DNAs encoding the fusions of the immunoglobulin heavy chain and, if desired, the immunoglobulin light chain are inserted into separate expression vectors and co-transfected into a suitable host organism. This provides greater flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments where unequal proportions of the three polypeptide chains used in the construct provide optimal yields. However, it is possible to insert the coding sequences of two or all three polypeptide chains into a single expression vector when expression of at least two polypeptide chains in equal ratios results in high yields, or when these ratios are not of particular importance.

In one approach, bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure, with an immunoglobulin light chain in only one half of the bispecific molecule, facilitates the separation of the desired bispecific component from unwanted immunoglobulin chain combinations. This approach is described in PCT Publication WO 94/04690.

In another approach, bispecific antibodies are created based on an amino acid modification in the first hinge region in one arm, and the substituted/replaced amino acid in the first hinge region has a charge opposite to the corresponding amino acid in the second hinge region in the other arm. This approach is described in international patent application PCT/US2011/036419 (WO2011/143545).

In another approach, the formation of a desired heteromultimeric or heterodimeric protein (e.g., a bispecific antibody) is enhanced by altering or creating a contact region between a first and second immunoglobulin-like Fc region (e.g., a hinge region and/or a CH3 region). In this approach, the bispecific antibodies may consist of a CH3 region, wherein the CH3 region comprises a first CH3 polypeptide and a second CH3 polypeptide that interact to form a CH3 contact region, wherein one or more amino acids in the CH3 contact region destabilize homodimer formation and are not electrostatically unfavorable for homodimer formation. This approach is described in International Patent Application PCT/US2011/036419 (WO2011/143545).

In another approach, bispecific antibodies can be formed using a glutamine-containing peptide tag engineered on an antibody directed to one epitope (e.g., BCMA) in one arm, and another peptide tag (e.g., a Lys-containing peptide tag or a reactive endogenous Lys) engineered on a second antibody directed to a second epitope in the other arm, in the presence of transglutaminase. This approach is described in international patent application PCT/IB2011/054899 (WO2012/059882).

In another aspect of the invention, a heterodimeric protein (e.g., a bispecific antibody) as described herein comprises a full-length human antibody, wherein a first antibody variable domain of the heterodimeric protein is capable of recruiting human immune effector cell activity by specifically binding to an effector antigen located on a human immune effector cell and wherein a second antibody variable domain of the heterodimeric protein is capable of specifically binding to a target antigen. In some embodiments, the human antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, the heterodimeric protein comprises an immunologically inert Fc region.

The human immune effector cell may be any of a variety of immune effector cells known in the art. For example, the immune effector cell may be a member of a human lymphoid cell lineage, including, but not limited to, T cells (e.g., cytotoxic T cells), B cells, and natural killer (NK) cells. The immune effector cell may also be, for example and without limitation, a member of a human myeloid cell lineage, including, but not limited to, a monocyte, a neutrophil granulocyte, and a dendritic cell. Such immune effector cells may exert either a cytotoxic or apoptotic effect on a target cell or other desired effect upon activation by binding an effector antigen.

An effector antigen is an antigen (e.g., a protein or polypeptide) that is expressed on a human immune effector cell. Examples of effector antigens that can be bound by a heterodimeric protein (e.g., a heterodimeric antibody or a bispecific antibody) include, but are not limited to, human CD3 (or CD3 (cluster of differentiation) complex), CD16, NKG2D, NKp46, CD2, CD28, CD25, CD64, and CD89.

The target cell may be a cell that is native or foreign to humans. In the case of a native target cell, the cell may be transformed into a malignant cell or pathologically modified (e.g., a native target cell infected with a virus, plasmodium, or bacterium). In the case of a foreign target cell, the cell is an invasive pathogen such as a bacterium, plasmodium, or virus.

A target antigen is expressed on a target cell in a disease (e.g., an inflammatory disease, a proliferative disease (e.g., cancer), an immunological disorder, a neurological disease, a neurodegenerative disease, an autoimmune disease, an infectious disease (e.g., a viral infection or a parasitic infection), an allergic reaction, a graft-versus-host disease, or a host-versus-graft disease). A target antigen is not an effector antigen. Examples of target antigens include, but are not limited to, BCMA, EpCAM (epithelial cell adhesion molecule), CCR5 (chemokine receptor type 5), CD19, HER (human epidermal growth factor receptor)-2/neu, HER-3, HER-4, EGFR (epidermal growth factor receptor), PSMA, CEA, MUC-1 (mucin), MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, CIhCG, Lewis-Y, CD20, CD33, CD30, ganglioside GD3, 9-O-acetyl-GD3, GM2, Globo H, fucosyl GM1, Poly SA, GD2, carbonic anhydrase IX (MN/CA IX), CD44v6, Shh (Sonic hedgehog), Wue-1, plasma cell antigen, (associated with membrane) IgE, MCSP (melanoma-associated chondroitin sulfate proteoglycan), CCR8, TNF-alpha precursor, STEAP, mesothelin, A33 antigen, PSCA (prostate stem cell antigen), Ly-6; desmoglein 4, E-cadherin neoepitope, embryonic acetylcholine receptor, CD25, CA19-9 marker, CA-125 marker and MIS (Müllerian inhibitory substance) receptor type II, sTn (sialylated Tn antigen; TAG-72), FAP (fibroblast activating antigen), endosialin, EGFRvIII, LG, SAS and CD63.

In some embodiments, a heterodimeric protein (e.g., a bispecific antibody) as described herein comprises a full-length human antibody, wherein a first variable antibody domain of the heterodimeric protein is capable of recruiting human immune effector cell activity by specifically binding to an effector antigen (e.g., a CD3 antigen) present on a human immune effector cell, wherein a second variable antibody domain of the heterodimeric protein is capable of specifically binding to a target antigen (e.g., a CD20 or EpCAM antigen), wherein the variable domain of the first and second antibodies of the heterodimeric protein comprises amino acid modifications at positions 223, 225, and 228 (e.g., (C223E or C223R), (E225R), and (P228E or P228R)) in the hinge region and at position 409 or 368 (e.g., K409R or L368E (Scheme EC numbering)) in the CH3 region of human IgG2 (SEQ ID NO: 493).

In some embodiments, the variable domains of the first and second antibody of the heterodimeric protein comprise amino acid modifications at positions 221 and 228 (e.g. (D221R or D221E) and (P228R or P228E)) in the hinge region and at position 409 or 368 (e.g. K409R or L368E (EC numbering scheme)) in the CH3 region of human IgG1 (SEQ ID NO: 494).

In some embodiments, the first and second variable domains of the antibody of the heterodimeric protein comprise amino acid modifications at positions 228 (e.g. (P228E or P228R)) in the hinge region and at position 409 or 368 (e.g. R409 or L368E (EC numbering scheme)) in the CH3 region of human IgG4 (SEQ ID NO: 495).

In another embodiment, the first antibody variable domain of the heterodimeric protein comprises a VH region comprising VH CDR1, VH CDR2 and VH CDR3 from the VH sequence shown in SEQ ID NO: 320, 322, 324, 326, 328, 330, 345, 347, 349, 351, 444, 354, 356, 378, 442, 380, 382, 384 386, 388, 390, 392, 394, 396, 398 or 400; and/or a light chain variable region (VL) comprising a VL CDR1, VL CDR2 and VL CDR3 of a VL sequence as set forth in SEQ ID NO: 319, 321, 323, 325, 327, 329, 344, 346, 348, 350, 352, 355, 377, 443, 445, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397 or 399, and the second variable antibody domain of the heterodimeric protein comprises a VH region comprising a VH sequence as set forth in SEQ ID NO: 2, 3, 7, 8, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 37, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 83, 87, 92, 95, 97, 99, 101, 104, 106, 110, 112, 114, 118, 120, 122, 125, 127, 313, 314, 363 or 365; and/or a VL region comprising VL CDR1, VL CDR2 and VL CDR3 of the VL sequence shown in SEQ ID NO: 1, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 34, 36, 38, 40, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 317, 81, 82, 84, 85, 86, 88, 89, 90, 91, 93, 94, 96, 98, 100, 102, 103, 105, 107, 108, 109, 111, 113, 115, 116, 117, 119, 121, 123, 124, 126, 128, 315 or 364.

In another embodiment, the first antibody variable domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2 and VH CDR3 from a VH sequence presented in SEQ ID NO: 324 or 388; and/or a light chain variable region (VL) comprising a VL CDR1, VL CDR2 and VL CDR3 from a VL sequence presented in SEQ ID NO: 323 or 387; and the second antibody variable domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2 and VH CDR3 from a VH sequence presented in SEQ ID NO: 112; and/or a light chain variable region (VL) comprising VL CDR1, VL CDR2 and VL CDR3 from the VL sequence set forth in SEQ ID NO: 38.

Antibodies used in the present invention may include monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g. Fab, Fab', F(ab')2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins containing an antibody portion (e.g. a domain antibody), humanized antibodies, and any other modified configuration of an immunoglobulin molecule that contains an antigen recognition site with the desired specificity, including glycosylated antibody variants, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies may be of mouse, rat, human, or any other origin (including chimeric or humanized antibodies).

In some embodiments, the BCMA or CD3 antibody as described herein is a monoclonal antibody. For example, the BCMA or CD3 antibody is a humanized monoclonal antibody or a chimeric monoclonal antibody.

In some embodiments, the antibody comprises a modified constant region, such as, for example and without limitation, a constant region that has an increased potential to induce an immune response. For example, the constant region can be modified to increase affinity for an Fc gamma receptor, such as, for example, FcγRI, FcγRIIA, or FcγIII.

In some embodiments, the antibody comprises a modified constant region, such as a constant region that is immunologically inert, i.e., has a reduced potential to induce an immune response. In some embodiments, the constant region is modified as described in Eur. J. Immunol., 29:2613-2624, 1999; in PCT/GB99/01441; and/or in UK patent application 98099518. The Fc can be human IgG1, human IgG2, human IgG3, or human IgG4. The Fc can be human IgG2 comprising the A330P331 to S330S331 mutation (IgG2Δa), wherein the amino acid residues are numbered based on the wild-type IgG2 sequence. Eur. J. Immunol., 29:2613-2624, 1999. In some embodiments, the antibody comprises an _IgG4 constant region comprising the following mutations (Armour et al., Molecular Immunology 40 585-593, 2003): E233F234L235 to P233V234A235 (IgG4Δc), wherein the numbering is based on wild-type IgG4. In another embodiment, the Fc is IgG4 E233F234L235 to P233V234A235 with deletion G236 (IgG4Δb). In another embodiment, the Fc is any human IgG4 Fc (IgG4, IgG4Δb, or IgG4Δc) containing the S228-P228 hinge stabilizing mutation (Aalberse et al., Immunology 105, 9-19, 2002). In another embodiment, the Fc may be an aglycosylated Fc.

In some embodiments, the constant region is aglycosylated by mutation of an oligosaccharide attachment residue (such as Asn297) and/or flanking residues that are part of a glycosylation recognition sequence in the constant region. In some embodiments, the constant region is aglycosylated for N-linked glycosylation enzymatically. The constant region may be aglycosylated for N-linked glycosylation enzymatically or by expression in a host cell with a glycosylation deficiency.

In some embodiments, the constant region has a modified constant region with abolished or reduced Fc-gamma receptor binding. For example, Fc can be human IgG2 containing the D265 mutation, wherein the amino acid residues are numbered based on the wild-type IgG2 sequence (SEQ ID NO: 493). Accordingly, in some embodiments, the constant region has a modified constant region having a sequence as set forth in SEQ ID NO: 496: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCRVRCPRCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In some embodiments, the constant region has a modified constant region having the sequence set forth in SEQ ID NO: 497:

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCEVECPECPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCEVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

One way to determine the binding affinity of antibodies to BCMA or CD3 is to measure the binding affinity of monofunctional Fab fragments of the antibody. To obtain monofunctional Fab fragments, the antibody (e.g. IgG) can be cleaved with papain or recombinantly expressed. The affinity of the BCMA Fab fragment of the antibody can be determined by surface plasmon resonance (Biacore™3000™ Surface Plasmon Resonance (SPR) System, Biacore™, INC, Piscataway NJ) equipped with sensor chips pre-immobilized with streptavidin (SA) or anti-mouse Fc or anti-human Fc using HBS-EP electrode buffer (0.01M HEPES, pH 7.4, 0.15 NaCl, 3 mM EDTA, 0.005% v/v P20 surfactant). Biotinylated or Fc-fused human BCMA can be diluted in HBS-EP buffer to a concentration of less than 0.5 μg/mL and injected into individual channels of the chip using variable contact times to achieve two ranges of antigen density, either 50-200 response units (RU) for detailed kinetic studies or 800-1000 RU for screening assays. Regeneration studies have shown that 25 mM NaOH in 25% v/v ethanol effectively removes bound Fab while maintaining BCMA activity on the chip for more than 200 injections. Typically, serial dilutions (concentrations spanning the range 0.1-10x predicted K _D value) of purified Fab samples are injected over 1 min at 100 μL/min and provide off-gassing times of up to 2 hours. Fab protein concentrations were determined by ELISA and/or SDS-PAGE electrophoresis using Fab of known concentration (determined by amino acid analysis) as a standard. Kinetic rates of association (k _on ) and dissociation rates (k _off ) were obtained simultaneously by fitting the data as a whole to a 1:1 Langmuir binding model (Karlsson, R. Roos, H. Fagerstam, L. Petersson, B. (1994). Methods Enzymology 6. 99-110) using the BIAevaluation program. Equilibrium dissociation constant (K _D ) values were calculated as k _off /k _on . This protocol is suitable for use in determining the binding affinity of an antibody to any BCMA, including human BCMA, other mammalian BCMA (e.g., mouse BCMA, rat BCMA, or primate BCMA), and different forms of BCMA (e.g., glycosylated BCMA). Antibody binding affinity is typically measured at 25°C, but can also be measured at 37°C.

The antibodies as described herein can be produced by any method known in the art. For the production of hybridoma cell lines, the method and schedule for immunizing the host animal generally correspond to established and conventional methods for stimulating and producing antibodies, as described further herein. General techniques for producing human and mouse antibodies are known in the art and/or described herein.

It is contemplated that any mammalian subject, including humans, or their antibody-producing cells can be manipulated as a basis for the production of mammalian cell lines, including humans, and hybridoma cell lines. Typically, the host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantarly, and/or intradermally with an amount of an immunogen, including those described herein.

Hybridomas can be generated from lymphocytes and immortalized myeloma cells using the general somatic cell hybridization technique of Kohler, B. and Milstein, C., Nature 256:495-497, 1975 or as modified by Buck, D. W., et al., In Vitro, 18:377-381, 1982. Available myeloma lines can be used for hybridization, including, but not limited to, X63-Ag8.653 and lines from the Salk Institute, Cell Distribution Center, San Diego, Calif., USA. Typically, the technique involves fusing myeloma cells and lymphoid cells using a fusogenic agent such as polyethylene glycol or electrical means well known to those skilled in the art. After fusion, the cells are separated from the fusion medium and grown in a selective growth medium, such as hypoxanthine-aminopterin-thymidine (HAT) medium, to remove unhybridized parental cells. Any medium described herein, with or without the addition of serum, can be used to culture hybridomas that secrete monoclonal antibodies. As another alternative to the cell fusion technique, EBV-immortalized B cells can be used to produce the monoclonal antibodies of the present invention. Hybridomas are expanded and subcloned if necessary, and the supernatants are analyzed for anti-immunogenic activity by conventional immunoassay techniques (e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay).

Hybridomas that can be used as a source of antibodies include all derivatives, progeny cells of parental hybridomas, that produce monoclonal antibodies specific to BCMA, CD3, or fragments thereof.

Hybridomas that produce such antibodies can be grown in vitro or in vivo using known procedures. Monoclonal antibodies can be isolated from the culture medium or body fluids using conventional immunoglobulin purification techniques such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration, if desired. Undesirable activity, if present, can be removed, for example, by passing the preparation over adsorbents formed from the immunogen attached to a solid phase and eluting or separating the desired antibodies from the immunogen. Immunization of a host animal with human BCMA or CD3, or a fragment containing the target amino acid sequence conjugated to a protein that is immunogenic in the species being immunized, such as keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, using a bifunctional or derivatizing agent, such as maleimidobenzoyl sulfosuccinimide ester (conjugation via cysteine residues), N-hydroxysuccinimide (via lysine residues), glutaraldehyde, succinic anhydride, _SOCl2 , or ^R1N =C=NR, where R and ^R1 are different alkyl groups, can yield a population of antibodies (e.g. monoclonal antibodies).

If desired, the antibody of interest (monoclonal or polyclonal) can be sequenced and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest can be maintained in a vector in a host cell and the host cell can then be propagated and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be accomplished by cloning antibody genes from B cells by methods known in the art. See, for example, Tiller et al., J. Immunol. Methods 329, 112, 2008; U.S. Patent 7,314,622.

Alternatively, the polynucleotide sequence may be genetically manipulated to "humanize" the antibody or to improve the affinity or other characteristics of the antibody. For example, the constant region may be engineered to more closely resemble human constant regions to avoid an immune response when the antibody is used in clinical trials and in human treatment. It may be desirable to genetically manipulate the antibody sequence to obtain greater affinity for BCMA or CD3 and greater potency in inhibiting BCMA.

There are four major steps in humanizing a monoclonal antibody. These are: (1) determining the nucleotide and predicted amino acid sequence of the light and heavy chain variable domains of the parent antibody; (2) engineering the humanized antibody, i.e., deciding which framework region of the antibody to use in the humanization process; (3) the actual humanization techniques/methods; and (4) transfection and expression of the humanized antibody. See, e.g., U.S. Patents 4,816,567; 5,807,715; 5,866,692; 6,331,415; 5,530,101; 5,693,761; 5,693,762; 5,585,089; and 6,180,370.

A number of "humanized" antibody molecules containing an antigen-binding site derived from a non-human immunoglobulin have been described, including chimeric antibodies having rodent V regions or modified rodent V regions and their associated CDRs fused to human constant regions. See, e.g., Winter et al. Nature 349:293-299, 1991, Lobuglio et al. Proc. Nat. Acad. Sci. USA 86:4220-4224, 1989, Shaw et al. J Immunol. 138:4534-4538, 1987, and Brown et al. Cancer Res. 47:3577-3583, 1987. Other papers describe rodent CDRs inserted into a human scaffold framework (FR) region prior to fusion with the corresponding constant region of a human antibody. See, for example, Riechmann et al. Nature 332:323-327, 1988, Verhoeyen et al. Science 239:1534-1536, 1988, and Jones et al. Nature 321:522-525, 1986. Another paper describes rodent CDRs supported by recombinantly engineered rodent framework regions. See, e.g., European Patent Publication 0519596. These "humanized" molecules are designed to minimize the undesirable immunological response to rodent anti-human antibody molecules that limits the duration and effectiveness of therapeutic use of these moieties in human recipients. For example, the constant region of the antibody can be designed to be immunologically inert (e.g., does not cause complement lysis). See, e.g., PCT Publication/GB99/01441; UK Patent Application 9809951.8. Other methods of humanizing antibodies that may also be used are disclosed in Daugherty et al., Nucl. Acids Res. 19:2471-2476, 1991, and in U.S. Patents 6,180,377; 6,054,297; 5,997,867; 5,866,692; 6210671; and 6350861; and in PCT publication WO 01/27160.

The general principles relating to humanized antibodies discussed above also apply to adapting antibodies for use in, for example, dogs, cats, primates, horses, and cows. In addition, one or more aspects of antibody humanization described herein can be combined with, for example, CDR grafting, framework mutation, and CDR mutation.

In one embodiment, fully human antibodies can be produced using commercially available mice that have been engineered to express specific human immunoglobulin proteins. Transgenic animals that are engineered to produce more desirable (e.g., fully human antibodies) or more robust immune responses can also be used to generate humanized or human antibodies. Examples of such technology include Xenomouse™ from Abgenix, Inc. (Fremont, CA) and HuMAb-Mouse® and TC Mouse™ from Medarex, Inc. (Princeton, NJ).

Alternatively, the antibodies can be produced recombinantly and expressed using any method known in the art. In another embodiment, the antibodies can be produced recombinantly using phage display technology. See, for example, U.S. Patents 5,565,332; 5,580,717; and 6,265,150; and Winter et al., Annu. Rev. Immunol. 12:433-455, 1994. Alternatively, phage display technology (McCafferty et al., Nature 348:552-553, 1990) can be used to produce human antibodies and antibody fragments in vitro from immunoglobulin variable (V) domain gene repertoires from unimmunized donors. In this technique, antibody V-domain genes are cloned in frame into a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody fragments on the surface of a phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selection based on the functional properties of the antibody also selects for a gene encoding an antibody exhibiting these properties. The phage thus mimics some of the properties of B cells. Phage display can be accomplished in a variety of formats; for a review, see, e.g., Johnson, Kevin S. and Chiswell, David J., Current Opinion in Structural Biology 3:564-571, 1993. Several sources of V gene segments can be used for phage display. Clackson et al., Nature 352:624–628, 1991 isolated a diverse array of antioxazolone antibodies from a small random combinatorial library of V genes obtained from the spleens of immunized mice. A repertoire of V genes can be generated from unimmunized human donors and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially according to the methods described in Mark et al., J. Mol. Biol. 222:581–597, 1991 or Griffith et al., EMBO J. 12:725–734, 1993. During the natural immune response, mutations in antibody genes accumulate at a high rate (somatic hypermutation). Some of the changes introduced will confer higher affinity, and during subsequent antigen stimulation, B cells displaying high-affinity surface immunoglobulin will preferentially replicate and differentiate. This natural process can be mimicked using a technique known as "chain shuffling" (Marks et al., Bio/Technol. 10:779-783, 1992). In this method, the affinity of "primary" human antibodies produced by phage display can be improved by sequentially replacing the heavy and light chain V region genes with repertoires of naturally occurring variants (repertoires) of V domain genes obtained from unimmunized donors. This technique produces antibodies and antibody fragments with affinities in the pM to nM range. A strategy for generating very large repertoires of phage antibodies (also known as "the mother-of-all libraries") is described in Waterhouse et al., Nucl. Acids Res. 21:2265-2266, 1993. Gene shuffling can also be used to produce derivatives of human antibodies from rodent antibodies, where the human antibody has affinities and specificities similar to the original rodent antibody. In this method, which is also called "epitope imprinting," a heavy or light chain V domain gene from a rodent antibody, obtained by phage display, is replaced with a repertoire of human V domain genes, creating rodent-human chimeras. Antigen selection results in the isolation of human variable regions capable of reconstituting a functional antigen-binding site, i.e., the epitope directs (imprints) partner choice. When the process is repeated to replace the remaining rodent V domain, a human antibody is obtained (see PCT Publication No. WO 93/06213). Unlike traditional humanization of rodent antibodies through CDR grafting, this method produces fully human antibodies that lack rodent-derived framework or CDR residues.

Antibodies can be produced recombinantly by first isolating antibodies and antibody-producing cells from host animals, obtaining the gene sequence, and using the gene sequence to recombinantly express the antibody in host cells (e.g., CHO cells). Another method that can be used is to express the antibody sequence in plants (e.g., tobacco) or in transgenic milk. Methods for recombinantly expressing antibodies in plants or milk have been disclosed. See, e.g., Peeters, et al. Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Pollock, et al., J Immunol Methods 231:147, 1999. Methods for producing antibody derivatives, e.g., humanized, single chain, etc., are known in the art.

Immunoassay and flow cytometric sorting methods such as fluorescence-activated cell sorting (FACS) can also be used to isolate antibodies specific to BCMA, CD3, or tumor antigens of interest.

The antibodies described herein can be linked to many different carriers. The carriers can be active and/or inert. Examples of well-known carriers include polypropylene, polystyrene, polyethylene, dextran, nylon, amylases, glass, natural and modified celluloses, polyacrylamides, agaroses and magnetite. For purposes of the invention, the carrier can be either soluble or insoluble. Those skilled in the art will know other suitable carriers for binding antibodies or will be able to ascertain them using routine experimentation. In some embodiments, the carrier comprises a moiety that targets the myocardium.

DNA encoding monoclonal antibodies is readily isolated and sequenced using conventional procedures (e.g., using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of monoclonal antibodies). Hybridoma cells are a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors (such as the expression vectors disclosed in PCT Publication No. WO 87/04462), which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to produce monoclonal antibodies in recombinant host cells. See, for example, PCT Publication No. WO 87/04462. The DNA may also be modified, for example, by substituting sequences encoding human heavy and light chain constant regions for homologous mouse sequences, see Morrison et al., Proc. Nat. Acad. Sci. 81:6851, 1984, or by covalently attaching to an immunoglobulin encoding sequence all or part of a sequence encoding a non-immunoglobulin polypeptide. In this way, "chimeric" or "hybrid" antibodies are produced, which in the present invention have the binding specificity of monoclonal antibodies.

Antibodies to BCMA or to a tumor antigen of interest as described herein can be identified or characterized using methods known in the art that detect and/or measure a decrease in expression levels of BCMA or another tumor antigen. In some embodiments, a BCMA antibody is identified by incubating a candidate agent with BCMA and observing binding and/or a concomitant decrease in BCMA expression levels. The binding assay can be performed with purified BCMA polypeptide(s) or with cells naturally expressing or transfected to express BCMA polypeptide(s). In one embodiment, the binding assay is a competitive binding assay that assesses the ability of a candidate antibody to compete with a known BCMA antibody for binding to BCMA. This assay can be performed in a variety of formats, including an ELISA format.

Following initial identification, the activity of a candidate antibody to BCMA, CD3, or another tumor antigen can be further confirmed and refined using bioassays that are known to test the target biological activities. Alternatively, bioassays can be used to directly screen candidates. Some methods for identifying and characterizing antibodies are described in detail in the Examples.

Antibodies to BCMA, CD3, or another tumor antigen can be characterized using methods well known in the art. For example, one method is to identify the epitope to which it binds, or "epitope mapping." There are many methods known in the art for mapping and characterizing the location of epitopes in proteins, including dissolution of a crystal structure of the antibody-antigen complex, competition assays, gene fragment expression assays, and synthetic peptide-based assays, as described, for example, in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999. In a further example, epitope mapping can be used to determine the sequence to which the antibody binds. Epitope mapping is commercially available from various sources, such as Pepscan Systems (Edelhertweg 15, 8219 PH Lelystad, The Netherlands). The epitope may be a linear epitope, i.e., contained within a single amino acid region, or a conformational epitope formed by a three-dimensional interaction of amino acids that may not necessarily be in the same region. Peptides of varying lengths (e.g., at least 4-6 amino acids in length) may be isolated or synthesized (e.g., recombinantly) and used for binding assays with antibodies to BCMA, CD3, or another tumor antigen. In another example, an epitope to which antibodies to BCMA, CD3, or another tumor antigen bind may be determined in a systematic screening assay using overlapping peptides derived from a BCMA, CD3, or other tumor antigen sequence and determining binding by an antibody to BCMA, CD3, or another tumor antigen. According to gene fragment expression assays, the open reading frame encoding BCMA, CD3 or another tumor antigen is fragmented either randomly or using defined genetic constructs and the reactivity of the expressed fragments of BCMA, CD3 or another tumor antigen with the test antibody is determined. The gene fragments can be produced, for example, by PCR and then transcribed and translated into protein in vitro, in the presence of radioactive amino acids. Binding of the antibody to the radiolabeled fragments of BCMA, CD3 or another tumor antigen is then determined by immunoprecipitation and gel electrophoresis. Some epitopes can also be identified using large libraries of random peptide sequences displayed on the surface of phage particles (phage libraries). Alternatively, a defined library of overlapping peptide fragments can be analyzed for binding to the test antibody in simple binding assays. In a further example, antigen-binding domain mutagenesis, domain swapping experiments, and alanine scanning mutagenesis can be performed to identify residues that are desirable, sufficient, and/or necessary for epitope binding. For example, domain swapping experiments can be performed using a mutant BCMA, CD3, or other tumor antigen in which various fragments of the BCMA, CD3, or other tumor antigen protein are replaced with BCMA sequences from another species (e.g., mouse) or a closely related but antigenically distinct protein (e.g., Trop-1). By assessing binding of the antibody to the mutant BCMA, CD3, or other tumor antigen, the importance of a particular fragment of BCMA, CD3, or other tumor antigen for binding to the antibody can be assessed.

Another method that can be used to characterize antibodies to BCMA, CD3, or another tumor antigen is to use competition assays with other antibodies that are known to bind to the same antigen, i.e., to different fragments on BCMA, CD3, or another tumor antigen, to determine whether the antibody to BCMA, CD3, or another tumor antigen binds to the same epitope as the other antibodies. Competition assays are well known to those skilled in the art.

An expression vector can be used to directly express an antibody to BCMA, CD3, or another tumor antigen. One skilled in the art is familiar with the administration of expression vectors to obtain expression of an exogenous protein in vivo. See, for example, U.S. Patents 6,436,908; 6,413,942; and 6,376,471. Administration of expression vectors includes local or systemic administration, including injection, oral administration, gene gun, or catheter administration, and topical administration. In another embodiment, the expression vector is administered directly into the sympathetic trunk or ganglion, or into the coronary artery, atrium, ventricle, or pericardium.

Targeted delivery of therapeutic compositions containing an expression vector or subgenomic polynucleotides can also be used. Methods for receptor-mediated DNA delivery are described, for example, in Findeis et al., Trends Biotechnol., 1993, 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer, J. A. Wolff, ed., 1994; Wu et al., J. Biol. Chem., 263:621, 1988; Wu et al., J. Biol. Chem., 269:542, 1994; Zenke et al., Proc. Natl. Acad. Sci. USA, 87:3655, 1990; and Wu et al., J. Biol. Chem., 266:338, 1991. Therapeutic compositions containing a polynucleotide are administered in a range of from about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. A concentration range of from about 500 ng to about 50 mg, from about 1 μg to about 2 mg, from about 5 μg to about 500 μg, and from about 20 μg to about 100 μg of DNA can also be used in a gene therapy protocol. The therapeutic polynucleotides and polypeptides can be delivered using gene delivery vehicles. The gene delivery vehicle may be of viral or nonviral origin (see generally Jolly, Cancer Gene Therapy, 1:51, 1994; Kimura, Human Gene Therapy, 5:845, 1994; Connelly, Human Gene Therapy, 1995, 1:185; and Kaplitt, Nature Genetics, 6:148, 1994). Expression of such coding sequences can be induced using endogenous mammalian promoters or heterologous promoters. Expression of the coding sequence may be constitutive or regulated.

Viral vectors for delivery of the desired polynucleotide and expression in the desired cell are well known in the art. Typical viral vectors include, but are not limited to, recombinant retroviruses (see, e.g., PCT Publications WO 90/07936; WO 94/03622; WO 93/25698; WO 93/25234; WO 93/11230; WO 93/10218; WO 91/02805; U.S. Patents 5,219,740 and 4,777,127; UK Patent 2,200,651; and EP Patent 0,345,242), alphavirus vectors (e.g., Sindbis virus, Semliki Forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246), and Venezuelan equine encephalitis (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532)), and adeno-associated virus (AAV) (see, e.g., PCT Publications WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938; WO 95/11984, and WO 95/00655). Administration of DNA linked to inactivated adenovirus may also be used, as described in Curiel, Hum. Gene Ther., 1992, 3: 147.

Non-viral delivery vehicles and methods may also be used, including, but not limited to, polycationic condensed DNA linked or unlinked to inactivated adenovirus (see, e.g., Curiel, Hum. Gene Ther., 3:147, 1992); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem., 264:16985, 1989); eukaryotic cell-based delivery vehicles (see, e.g., U.S. Patent 5,814,482; PCT Publications WO 95/07994; WO 96/17072; WO 95/30763; and WO 97/42338), and nucleic acid charge neutralization or fusion with cellular membranes. Naked DNA may also be used. Exemplary methods for introducing naked DNA are described in PCT Publication WO 90/11092 and U.S. Patent 5,580,859. Liposomes that can act as gene delivery vehicles are described in U.S. Patent 5,422,120; PCT Publications WO 95/13796; WO 94/23697; WO 91/14445; and EP 0 524968. Additional approaches are described in Philip, Mol. Cell Biol., 14:2411, 1994 and in Woffendin, Proc. Natl. Acad. Sci., 91:1581, 1994.

In some embodiments, the invention encompasses compositions comprising pharmaceutical compositions comprising antibodies described herein or produced by the methods described herein and having the characteristics described herein. As used herein, the compositions comprise one or more antibodies that bind to CD3 and a tumor antigen (e.g., BCMA), and/or one or more polynucleotides comprising sequences encoding one or more of these antibodies. These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients, including buffers, which are well known in the art.

The present invention also provides methods for producing any of these antibodies. The antibodies of the present invention can be produced by methods known in the art. The polypeptides can be produced by proteolytic or other cleavage of the antibodies, by recombinant methods (i.e., single or fusion polypeptides) as described above, or by chemical synthesis. Antibody polypeptides, especially short polypeptides of up to about 50 amino acids, are successfully made by chemical synthesis. Chemical synthesis methods are known in the art and are commercially available. For example, an antibody can be produced by an automated polypeptide synthesizer using a solid phase method. See also U.S. Pat. Nos. 5,807,715; 4,816,567 and 6,331,415.

Heteroconjugate antibodies comprising two covalently linked antibodies are also within the scope of the invention. Such antibodies are used to target immune system cells to unwanted cells (US Patent 4,676,980) and to treat HIV infection (PCT Publications WO 91/00360 and WO 92/200373; EP 03089). Heteroconjugate antibodies may be prepared using any suitable cross-linking methods. Suitable cross-linking agents and methods are well known in the art and are described in US Patent 4,676,980.

Chimeric or hybrid antibodies can also be produced in vitro using known methods of synthetic protein chemistry, including those involving cross-linking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl 4-mercaptobutyrimidate.

In recombinant humanized antibodies, the Fcγ portion may be modified to avoid interaction with the Fcγ receptor and with the complement system and the immune system. Methods for producing such antibodies are described in WO 99/58572. For example, the constant region may be engineered to more closely resemble human constant regions to avoid an immune response when the antibodies are used in clinical trials and in human treatment. See, for example, US Patents 5,997,867 and 5,866,692.

The invention encompasses modifications of the antibodies and polypeptides according to the embodiments of the invention as described herein, including functionally equivalent antibodies that do not significantly affect their properties, and variants that have increased or decreased activity and/or affinity. For example, the amino acid sequence can be mutated to produce an antibody with the desired binding affinity to BCMA and/or CD3. Modification of polypeptides is common practice in the art and does not need to be described in detail herein. Examples of modified polypeptides include polypeptides with conservative substitutions of amino acid residues, one or more deletions or additions of amino acids that do not significantly negatively affect the functional activity, or those in which the affinity of the polypeptide for its ligand is matured (increased), or the use of chemical analogs.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions that range in length from a single residue to polypeptides containing a hundred or more residues, as well as sequence insertions of one or more amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue or an antibody fused to an epitope tag. Other variants of insertion into an antibody molecule include fusion to the N- or C-termini of an antibody of an enzyme or polypeptide that increases the half-life of the antibody in the bloodstream.

Substitution variants involve the deletion of at least one amino acid residue in the antibody molecule and the insertion of another residue in its place. Sites of greatest interest for substitution mutagenesis include hypervariable regions, but FR changes are also contemplated. Conservative substitutions are shown in Table 5 under the heading "conservative substitutions". If such substitutions result in a change in biological activity, then more significant changes, termed "typical substitutions" in Table 5 or as further described below in the amino acid class reference, may be introduced and the products screened.

Table 5: Amino acid substitutions Initial balance
(natural amino acid) Conservative substitutions Typical replacements Ala (A) Val Val; Leu; Ile Arg(R) Lys Lys; Gln; Asn Asn(N) Gln Gln; His; Asp, Lys; Arg Asp(D) Glu Glu;Asn Cys(C) Ser Ser; Ala Gln(Q) Asn Asn;Glu Glu (E) Asp Asp; Gln Gly (G) Ala Ala His (H) Arg Asn; Gln; Lys; Arg Ile (1) Leu Leu; Val; Met; Ala; Phe; Norleucine Leu (L) Ile Norleucine; Ile; Val; Met; Ala; Phe Lys(K) Arg Arg; Gln; Asn Met (M) Leu Leu; Phe; Ile Phe(F) Tyr Leu; Val; Ile; Ala; Tyr Pro (P) Ala Ala Ser (S) Th Th Thr(T) Ser Ser Trp(W) Tyr Tyr; Phe Tyr (Y) Phe Trp; Phe; Thr; Ser Val (V) Leu Ile; Leu; Met; Phe; Ala; Norleucine

Substantial changes in the biological properties of an antibody are achieved by selecting substitutions that differ significantly in their effects on maintaining (a) the structure of the polypeptide backbone in the region of the substitution, such as a folded or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the size of the side chain. Natural amino acid residues are divided into groups based on common side chain properties:

(1) Non-polar: Norleucine, Met, Ala, Val, Leu, Ile;

(2) Polar without charge: Cys, Ser, Thr, Asn, Gln;

(3) Acidic (negatively charged): Asp, Glu;

(4) Alkaline (positively charged): Lys, Arg;

(5) Residues that influence chain orientation: Gly, Pro; and

(6) Aromatic: Trp, Tyr, Phe, His.

Non-conservative substitutions are carried out by replacing a representative of one of these classes with a representative of another class.

Any cysteine residue not involved in maintaining the proper conformation of the antibody may also be replaced, usually by serine, to improve the oxidative stability of the molecule and prevent aberrant cross-linking. Conversely, cysteine bond(s) may be added to an antibody to improve its stability, particularly when the antibody is an antibody fragment, such as an Fv fragment.

Amino acid modifications may range from substitution or modification of one or more amino acids to a complete reconstruction of a region, such as a variable region. Changes in the variable region may alter binding affinity and/or specificity. In some embodiments, no more than one to five conservative amino acid substitutions are made in a CDR domain. In other embodiments, no more than one to three conservative amino acid substitutions are made in a CDR domain. In other embodiments, the CDR domain is CDR H3 and/or CDR L3.

Modifications also include glycosylated and nonglycosylated polypeptides, as well as polypeptides with other posttranslational modifications such as glycosylation with various sugars, acetylation, and phosphorylation. Antibodies are glycosylated at conserved positions in their constant regions (Jefferis and Lund, Chem. Immunol. 65:111–128, 1997; Wright and Morrison, TibTECH 15:26–32, 1997). The oligosaccharide side chains of immunoglobulins influence protein function (Boyd et al., Mol. Immunol. 32:1311-1318, 1996; Wittwe and Howard, Biochem. 29:4175-4180, 1990) and intramolecular interactions between regions of the glycoprotein, which can influence the conformation and presented three-dimensional surface of the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, Current Opin. Biotech. 7:409-416, 1996). Oligosaccharides can also serve to target a given glycoprotein to specific molecules based on specific recognition structures. Glycosylation of antibodies has also been reported to influence antibody-dependent cellular cytotoxicity (ADCC). In particular, it was reported that CHO cells with tetracycline-regulated expression of β(1,4)-N-acetylglucosaminetransferase III (GnTIII), a glycosyltransferase that catalyzes the formation of GlcNAc (N-acetyl-D-glucosamine) at branch points, had improved ADCC activity (Umana et al., Mature Biotech. 17:176-180, 1999).

Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine, where X is any amino acid except proline, are the recognition sequences for the enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used.

Addition of glycosylation sites to an antibody is typically accomplished by altering the amino acid sequence so that it contains one or more of the tripeptide sequences described above (for N-linked glycosylation sites). The alteration may also be made by adding or substituting one or more serine or threonine residues in the original antibody sequence (for O-linked glycosylation sites).

The glycosylation pattern of antibodies can also be altered without changing the underlying nucleotide sequence. Glycosylation is largely dependent on the host cell used to express the antibody. Since the cell type used to express recombinant glycoproteins, such as antibodies, as potential therapeutics is rarely a native cell, altered glycosylation patterns of antibodies can be expected (see, e.g., Hse et al., J. Biol. Chem. 272:9062-9070, 1997).

In addition to the choice of host cells, factors that influence glycosylation during recombinant antibody production include growth pattern, medium composition, culture density, oxygenation, pH, purification schemes, and the like. Various methods have been proposed for altering the glycosylation pattern achieved in a particular host organism, including the introduction or overexpression of certain enzymes involved in the production of oligosaccharides (US Patents 5,047,335; 5,510,261 and 5,278,299). Glycosylation, or certain types of glycosylation, can be enzymatically removed from the glycoprotein, for example, using endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, endoglycosidase F3. In addition, the recombinant host cell can be genetically modified to be defective in the processing of certain types of polysaccharides. These and similar methods are well known in the art.

Other methods of modification include the use of coupling methods known in the art, including, but not limited to, enzymatic means, oxidative displacement, and chelation. Modifications can be used, for example, to attach labels for immunoassay. Modified polypeptides are prepared using methods generally accepted in the art and can be screened using standard assays known in the art, some of which are described below and in the Examples.

In some embodiments, the antibody comprises a modified constant region, such as a constant region that has increased affinity for the human Fc gamma receptor, is immunologically inert or partially inert, such as does not induce complement-mediated lysis, does not stimulate antibody-dependent cellular cytotoxicity (ADCC), or does not activate macrophages; or has reduced activities (relative to an unmodified antibody) in one or more of the following: inducing complement-mediated lysis, stimulating antibody-dependent cellular cytotoxicity (ADCC), or activating microglia. Different modifications of the constant region can be used to achieve an optimal level and/or combination of effector functions. See, e.g., Morgan et al., Immunology 86:319-324, 1995; Lund et al., J. Immunology 157:4963-9 157:4963-4969, 1996; Idusogie et al., J. Immunology 164:4178-4184, 2000; Tao et al., J. Immunology 143: 2595-2601, 1989; and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some embodiments, the constant region is modified as described in Eur. J. Immunol., 1999, 29:2613-2624; PCT/GB99/01441; and/or UK patent application 9809951.8. In other embodiments, the antibody comprises a human IgG2 heavy chain constant region comprising the following mutations: A330P331 - S330S331 (amino acid numbering is based on the wild-type IgG2 sequence). Eur. J. Immunol., 1999, 29:2613-2624. In other embodiments, the constant region is aglycosylated for N-linked glycosylation. In some embodiments, the constant region is aglycosylated for N-linked glycosylation by mutating the glycosylated amino acid residue or flanking residues that are part of the N-glycosylation recognition sequence in the constant region. For example, the N-glycosylation site N297 can be mutated to A, Q, K, or H. See, Tao et al., J. Immunology 143:2595-2601, 1989; and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some embodiments, the constant region is aglycosylated for N-linked glycosylation. The constant region can be aglycosylated for N-linked glycosylation enzymatically (an example is removal of the carbohydrate by the enzyme PNGase) or by expression in a glycosylation-deficient host cell.

Other modifications of antibodies include antibodies that have been modified as described in PCT Publication WO 99/58572. These antibodies comprise, in addition to a binding domain directed to a target molecule, an effector domain having an amino acid sequence substantially homologous to all or part of a constant region of a human immunoglobulin heavy chain. These antibodies are capable of binding a target molecule without causing significant complement-dependent lysis or cell-mediated destruction of the target. In some embodiments, the effector domain is capable of specifically binding to FcRn and/or FcγRIIb. They are typically based on chimeric domains derived from two or more _CH2 domains of a human immunoglobulin heavy chain. Antibodies modified in this manner are particularly suitable for use in chronic antibody therapy to avoid inflammatory and other adverse reactions to traditional antibody therapy.

The invention includes affinely mature embodiments. For example, affinity matured antibodies can be obtained by methods known in the art (Marks et al., Bio/Technology, 10:779-783, 1992; Barbas et al., Proc Nat. Acad. Sci, USA 91:3809-3813, 1994; Schier et al., Gene, 169:147-155, 1995; Yelton et al., J. Immunol., 155:1994-2004, 1995; Jackson et al., J. Immunol., 154(7):3310-9, 1995, Hawkins et al., J. Mol. Biol., 226:889-896, 1992; and PCT publication WO2004/058184).

The following methods can be used to adjust the affinity of an antibody and to characterize the CDRs. One method for characterizing the CDRs of an antibody and/or altering (e.g., improving) the binding affinity of a polypeptide, such as an antibody, is called "scanning library mutagenesis." Typically, scanning library mutagenesis is used as follows. One or more amino acid positions in a CDR are replaced with two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acids using methods recognized in the art. This creates small libraries of clones (in some embodiments, one for each amino acid position analyzed), each with a complexity of two or more representatives (if two or more amino acids are replaced at each position). Typically, the library also includes a clone containing the native (unsubstituted) amino acid. A small number of clones, such as about 20-80 clones (depending on the complexity of the library), from each library are screened for binding affinity to the target polypeptide (or other binding target) and candidates with increased, the same, decreased binding, or no binding are identified. Methods for determining binding affinity are well known in the art. Binding affinity can be determined using a Biacore™ surface plasmon resonance assay, which detects differences in binding affinity of about 2-fold or more. Biacore™ is particularly useful when the parent antibody already binds with relatively high affinity, such as a K _D of about 10 nM or less. Screening using Biacore™ surface plasmon resonance is described in the Examples herein.

Binding affinity can be determined using Kinexa Biocensor, scintillation proximity assays, ELISA, ORIGEN immunoassay (IGEN), fluorescence quenching, fluorescence transfer, and/or yeast display. Binding affinity can also be screened using a suitable bioassay.

In some embodiments, each amino acid position in the CDR is substituted (in some embodiments one at a time) with all 20 naturally occurring amino acids using art-accepted mutagenesis techniques (some of which are described herein). This creates small libraries of clones (in some embodiments, one for each amino acid position analyzed), each with a complexity of 20 members (if all 20 amino acids are substituted at each position).

In some embodiments, the library to be screened contains substitutions at two or more positions, which may be in the same CDR or in two or more CDRs. Thus, the library may contain substitutions at two or more positions in one CDR. The library may contain substitutions at two or more positions in two or more CDRs. The library may contain substitutions at 3, 4, 5 or more positions, wherein said positions are in two, three, four, five or six CDRs. The substitution may be obtained using low redundancy codons. See, for example, Table 2 in Balint et al., Gene 137(1):109-18, 1993.

The CDR may be CDRH3 and/or CDRL3. The CDR may be one or more of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and/or CDRH3. The CDR may be a Kabat CDR, a Chothia CDR, or an extended CDR.

Candidates with improved binding can be sequenced, thereby identifying a mutant with a substitution in the CDR that results in improved affinity (also called an “improved” substitution). Candidates that bind can also be sequenced, thereby identifying a substitution in the CDR that preserves binding.

Multiple rounds of screening may be performed. For example, candidates (each containing an amino acid substitution at one or more positions of one or more CDRs) with improved binding are also useful for constructing a second library containing at least the original and substituted amino acids at each improved CDR position (i.e., the amino acid position in the CDR at which the mutant with the substitution showed improved binding). The preparation and screening or selection of this library is discussed below.

Library scanning mutagenesis also provides a means of characterizing CDRs, since the frequency of clones with improved binding, the same binding, decreased binding, or no binding also provides information regarding the importance of each amino acid position for the stability of the antibody-antigen complex. For example, if a CDR position maintains binding when substituted for all 20 amino acids, that position is identified as a position that is unlikely to be required for antigen binding. In contrast, if a position in a CDR maintains binding for only a small percentage of substitutions, that position is identified as a position that is essential for CDR function. Thus, library scanning mutagenesis methods provide information about positions in CDRs that can be substituted for many different amino acids (including all 20 amino acids) and about positions in CDRs that cannot be substituted or that can be substituted for only a few amino acids.

Candidates with improved affinity can be combined in a second library that includes the improved amino acid, the original amino acid at that position, and may also include additional substitutions at that position, depending on the complexity of the library that is desired or tolerated using the desired screening or selection method. Additionally, if desired, adjacent amino acid positions can be randomized with respect to at least two or more amino acids. Randomization of adjacent amino acids can provide additional conformational flexibility in the mutant CDR, which in turn can allow or facilitate the introduction of more improving mutations. The library can also contain substitutions at positions that did not show improved affinity in the first round of screening.

The second library is screened or selected for library members with improved and/or altered binding affinity using any method known in the art, including screening using Biacore™ surface plasmon resonance assay and selection using any selection method known in the art, including phage display, yeast display, and ribosome display.

The present invention also provides compositions comprising antibodies conjugated (e.g., linked) to an agent that facilitates binding to a solid support (such as biotin or avidin). For simplicity, reference is made to antibodies in a general sense, with the understanding that these methods apply to any embodiments of a BCMA antibody described herein. Conjugation generally refers to the linking of these components as described herein. Linking (which generally involves fixing these components in close association, at least for administration) can be achieved in a variety of ways. For example, a direct reaction between the agent and the antibody is possible when each has a substituent capable of reacting with the other substituent. For example, a nucleophilic group such as an amino or sulfhydryl group on one of them may be capable of reacting with a carbonyl-containing group such as an acid anhydride or halide, or with an alkyl group containing a good leaving group (e.g., a halide) on the other.

In another aspect of the invention, a method for producing any of the polynucleotides described herein is provided.

Polynucleotides complementary to any such sequences are also within the scope of the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded and may be DNA molecules (genomic, cDNA or synthetic) or RNA. RNA molecules include HnRNA molecules (heterogeneous nuclear RNA), which contain introns and correspond one-to-one to a DNA molecule, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present in a polynucleotide of the present invention, and the polynucleotide may, but need not, be linked to other molecules and/or carriers.

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 comprise one or more substitutions, additions, deletions and/or insertions such that the immunoreactivity of the encoded polypeptide is not reduced compared to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide can generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably at least about 80% identity, even more preferably at least about 90% identity, and most preferably at least about 95% identity with a polynucleotide sequence that encodes a native antibody or a portion thereof.

Two polynucleotide or polypeptide sequences are considered "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned with best fit, as described below. Comparison of two sequences is typically accomplished by comparing the sequences in 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, typically from 30 to about 75 or from 40 to about 50, where the sequence can be compared to a reference sequence of the same number of contiguous positions after optimal alignment of the two sequences.

Optimal alignment of sequences for comparison can be performed using the Megalign program in the Lasergene bioinformatics package (DNASTAR, Inc., Madison, WI), using default parameters. This program covers 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 DC 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, CA; 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, CA; Wilbur, W.J. and Lipman, D.J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730.

Preferably, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences in a comparison window of at least 20 positions, wherein a portion of the polynucleotide or polypeptide sequence in the comparison window may contain additions or deletions (i.e., gaps) of 20 percent or less, typically 5 to 15 percent or 10 to 12 percent, compared to reference sequences (which do not contain additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which identical nucleobases or amino acid residues are present in both sequences to obtain the number of matching positions, and dividing the number of matching positions by the total number of positions in the reference sequence (i.e., the size of the window) and multiplying the results by 100 to obtain the percent sequence identity.

Variants may also, or alternatively, be substantially homologous to a native gene, or portion thereof, or set of genes. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to the native DNA sequence encoding the native antibody (or complementary sequence).

Suitable “moderately stringent conditions” include pre-washing in 5xSSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridization at 50°C-65°C, 5xSSC, overnight; followed by two washes at 65°C for 20 min each with 2X, 0.5X, and 0.2X SSC containing 0.1% SDS.

As used herein, "very stringent conditions" or "high stringency conditions" are conditions that: (1) use low ionic strength and high temperature for washing, such as 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) use a denaturing agent such as formamide during hybridization, such as 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°C; or (3) using 50% formamide, 5x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5x Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42°C with a wash at 42°C in 0.2x SSC (sodium chloride/sodium citrate) and 50% formamide at 55°C followed by a thorough wash consisting of 0.1x SSC containing EDTA at 55°C. One skilled in the art will know how to adjust the required temperature, ionic strength, etc. to suit factors such as probe length, etc.

It will be appreciated by those skilled in the art that, due to the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides have minimal homology to the nucleotide sequence of any native gene. However, polynucleotides that differ due to differences in codon usage are specifically contemplated by the present invention. In addition, alleles of genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that have been altered by 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 can be identified using standard techniques (such as hybridization, amplification, and/or sequence database comparison).

The polynucleotides of the present invention can be produced using chemical synthesis, recombinant methods, or PCR. Methods for chemically synthesizing polynucleotides are well known in the art and need not be described in detail herein. One skilled in the art can use the sequences provided herein and a commercially available DNA synthesizer to produce the desired DNA sequence.

To produce polynucleotides using recombinant techniques, a polynucleotide containing the desired sequence can be inserted into a suitable vector, and the vector can in turn be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides can be introduced 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 in 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 in the art. See, for example, Sambrook et al., 1989.

Alternatively, PCR allows DNA sequences to be reproduced. PCR technology is well known in the art and is described in US Patents 4,683,195, 4,800,159, 4,754,065, and 4,683,202, and in PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

RNA can be produced by using isolated DNA in an appropriate vector and introducing 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 skilled in the art, as discussed, for example, in Sambrook et al., 1989, supra.

Suitable cloning vectors can be constructed according to standard techniques or can be selected from a large number of cloning vectors available in the art. Although the cloning vector selected may differ depending on the host cell to be used, suitable cloning vectors typically have the ability to self-replicate, may have a single target for a particular restriction endonuclease, and/or may have marker genes that can be used in the selection of clones containing the vector. Suitable examples include plasmids and bacterial viruses, such as 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 can be purchased from commercial suppliers such as BioRad, Strategene, and Invitrogen.

Expression vectors are typically replicable polynucleotide constructs that comprise a polynucleotide of the invention. It is intended that the expression vector will replicate in host cells either as episomes or as a constituent part of chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, viral vectors including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and the expression vector(s) disclosed in PCT publication WO87/04462. Vector components may typically 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 control elements (such as promoters, enhancers, and terminators). Expression (i.e., translation) usually also requires one or more translation control elements, such as ribosome binding sites, translation initiation sites, and stop codons.

Vectors containing the polynucleotides of interest may be introduced into the host cell by any of several suitable methods, including electroporation; transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; ballistic transfection; lipofection; and infection (e.g., when the vector is an infectious agent such as vaccinia virus). The choice of vectors or polynucleotides to be introduced often depends on the characteristics of the host cell.

The invention also provides host cells comprising any of the polynucleotides described herein. Any host cell capable of overexpressing heterologous DNAs can be used for the purpose of isolating genes encoding an antibody, polypeptide, or protein of interest. Non-limiting examples of mammalian host cells include, but are not limited to, COS, HeLa, and CHO cells. See also PCT Publication WO87/04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtillis ) and yeast (such as S. cerevisae , S. pombe ; or K. lactis ). Preferably, the host cells express the cDNA at a level that is about 5-fold higher, more preferably 10-fold higher, even more preferably 20-fold higher than the corresponding endogenous antibody or protein of interest, if present, in the host cells. Screening of host cells for specific binding to BCMA or a BCMA domain (e.g. domains 1-4) is performed by immunoassay or FACS. A cell overexpressing the antibody or protein of interest can be identified.

Methods of using bispecific antibodies (therapeutic applications)

The antibodies (e.g., BCMA, CD3, or bispecific) and antibody conjugates (e.g., BCMA antibody-drug conjugates) of the present invention can be used in a variety of applications, including, but not limited to, therapeutic treatments and clinical diagnostic methods.

In one aspect, the invention provides a method of treating a condition associated with BCMA expression in a subject. In some embodiments, the method of treating a condition associated with BCMA expression in a subject comprises administering to a subject in need thereof an effective amount of a composition (e.g., a pharmaceutical composition) comprising BCMA antibodies or BCMA-antibody conjugates as described herein. Conditions associated with BCMA expression include, but are not limited to, abnormal BCMA expression, altered or aberrant BCMA expression, malignant cells expressing BCMA, a proliferative disorder (e.g., cancer), or an autoimmune disorder.

In another aspect of the invention, there is provided a method of treating B-cell cancer or malignant cells expressing a tumor antigen. In some embodiments, there is provided a method of treating B-cell cancer in a subject in need thereof, comprising a) creating a bispecific antibody as described herein and b) administering said bispecific antibody to said patient. In some embodiments, there is provided a method of treating a condition associated with malignant cells expressing a tumor antigen in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a bispecific antibody as described herein.

Accordingly, in some embodiments, a method of treating cancer in a subject is provided, comprising administering to a subject in need thereof an effective amount of a composition comprising antibodies (e.g. BCMA or CD3-BCMA bispecific antibodies) or BCMA-antibody conjugates as described herein. As used herein, cancer may be a B-cell cancer including, but not limited to, multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular Hodgkin's lymphoma with lymphocyte predominance, Kahler disease and myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosal lymphoid tissue lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, Burkitt's lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, nodular marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell/histocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV-positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8 (human herpes virus type 8)-associated multicentric Castleman disease, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell lymphomas.

In some embodiments, there is provided a method of inhibiting tumor growth or progression in a subject having malignant cells expressing BCMA, comprising administering to a subject in need thereof an effective amount of a composition comprising BCMA antibodies, CD3-BCMA bispecific antibodies, or BCMA antibody conjugates as described herein. In other embodiments, there is provided a method of inhibiting metastatic cells expressing BCMA in a subject, comprising administering to a subject in need thereof an effective amount of a composition comprising BCMA antibodies, CD3-BCMA bispecific antibodies, or BCMA antibody conjugates as described herein. In other embodiments, a method is provided for inducing tumor regression in malignant cells in a subject, comprising administering to a subject in need thereof an effective amount of a composition comprising BCMA antibodies, CD3-BCMA bispecific antibodies, or BCMA antibody conjugates as described herein.

In some embodiments, a method of treating an autoimmune disorder in a subject is provided, comprising administering to a subject in need thereof an effective amount of a composition comprising BCMA antibodies, CD3-BCMA bispecific antibodies, or BCMA antibody conjugates as described herein.

As used herein, autoimmune disorders include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, diabetes (type I), multiple sclerosis, Addison's disease, celiac disease, dermatomyositis, Graves' disease, autoimmune thyroiditis, Hashimoto's encephalopathy, myasthenia gravis, pernicious anemia, reactive arthritis, Sjogren's syndrome, acute disseminated encephalomyelitis, agammaglobulinemia, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune Pancreatitis, Autoimmune Polyendocrine Syndrome, Autoimmune Progesterone Dermatitis, Autoimmune Thrombocytopenic Purpura, Autoimmune Urticaria, Autoimmune Uveitis, Behcet's Disease, Castleman Disease, Cold Agglutinin Disease, Crohn's Disease, Dermatomyositis, Eosinophilic Fasciitis, Gastrointestinal Pemphigoid, Goodpasture's Syndrome, Guillain-Barré Syndrome, Hidradenitis Suppurativa, Idiopathic Thrombocytopenic Purpura, Narcolepsy, Pemphigus Vulgaris, Pernicious Anemia, Polymyositis, Primary Biliary Cirrhosis, Relapsing Polychondritis, Rheumatic Fever, Temporal Arteritis, Transverse Myelitis, Ulcerative Colitis, Undifferentiated Connective Tissue Disease, Vasculitis, and Wegener's Granulomatosis.

In another aspect of the invention, there is provided an effective amount of a composition (e.g., a pharmaceutical composition) comprising antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein for treating a condition (e.g., cancer or an autoimmune disorder) associated with BCMA expression in a subject in need thereof. In some embodiments, there is provided an effective amount of a composition (e.g., a pharmaceutical composition) comprising antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein for inhibiting tumor growth or progression in a subject having BCMA-expressing malignant cells. In some embodiments, there is provided an effective amount of a composition (e.g., a pharmaceutical composition) comprising antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein for inhibiting metastasis of BCMA-expressing malignant cells in a subject in need thereof. In some embodiments, there is provided an effective amount of a composition (e.g., a pharmaceutical composition) comprising antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein for inducing tumor regression in a subject having BCMA-expressing malignant cells.

In another aspect, the invention provides antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein for use in the treatment of a condition (e.g., cancer or an autoimmune disorder) associated with BCMA expression in a subject in need thereof. In some embodiments, there are provided antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein for inhibiting tumor growth or progression in a subject having BCMA-expressing malignant cells. In some embodiments, there are provided antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein for inhibiting metastasis of BCMA-expressing malignant cells in a subject in need thereof. In some embodiments, antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein are provided for inducing tumor regression in a subject having malignant cells expressing BCMA.

In another aspect of the invention there is provided the use of antibodies (e.g. BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein in the manufacture of a medicament for the treatment of a condition (e.g. cancer or an autoimmune disorder) associated with the expression of BCMA. In some embodiments there is provided the use of antibodies (e.g. BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting the growth or progression of a tumor. In some embodiments there is provided the use of antibodies (e.g. BCMA or CD3-BCMA bispecific) or BCMA antibody conjugates as described herein in the manufacture of a medicament for inhibiting the metastasis of malignant cells expressing BCMA. In some embodiments, the use of antibodies (e.g. BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein in the manufacture of a medicament for inducing tumor regression is provided.

In another aspect, a method for detecting, diagnosing and/or monitoring a condition associated with BCMA expression is provided. For example, antibodies (e.g., BCMA or CD3-BCMA bispecific) as described herein can be labeled with a detectable moiety, such as an imaging agent and an enzyme-substrate label. Antibodies as described herein can also be used for in vivo diagnostic assays, such as in vivo imaging (e.g., PET (positron emission tomography) or SPECT (single photon emission computed tomography)), or a staining reagent.

In some embodiments, the methods described herein also include the step of treating the subject with an additional form of therapy. In some embodiments, the additional form of therapy is an additional anti-cancer therapy, including, but not limited to, chemotherapy, radiation, surgery, hormonal therapy, and/or additional immunotherapy.

In some embodiments, the additional form of therapy comprises administering one or more therapeutic agents in addition to the antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein. The one or more therapeutic agents may be chemotherapeutic agents, including, but not limited to, a second antibody (e.g., an anti-VEGF (vascular endothelial growth factor) antibody (e.g., AVASTIN ^® ), an anti-HER2 antibody (e.g., HERCEPTIN ^® ), an anti-CD25 antibody, an anti-CD33 antibody, an anti-CD20 antibody (e.g., RITUXAN ^® ), an anti-mucin-like glycoprotein antibody, an anti-TNF antibody, and/or an anti-epidermal growth factor receptor (EGFR) antibody (e.g., ERBITUX ^® )), an angiogenesis inhibitor, a cytotoxic agent (e.g., anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone), a taxane (e.g., paclitaxel and docetaxel), dolastatin, duocarmycin, enediyne, geldanamycin, maytansine, puromycin, vinca alkaloid (eg, vincristine), topoisomerase inhibitor (eg, etoposide), tubulysin, pyrimidine analogue (eg, fluorouracil), platinum-containing agents (eg, cisplatin, carboplatin, and oxaliplatin), alkylating agents (eg, melphalan, cyclophosphamide, or carmustine and hemiasterlin), immunomodulatory agent (eg, prednisone and lenalidomide (REVLIMID ^® )), anti-inflammatory agent (eg, dexamethasone), aromatase inhibitor (eg, anastrozole, exemestane, letrozole, vorozole, formatane, or testolactone), proteasome inhibitor (eg, bortezomib such as VELCADE ^® ([(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid or carfilzomib) and other agents such as tamoxifen.

For example, in some embodiments, there is provided a method of treating multiple myeloma comprising administering to a patient in need thereof an effective amount of a composition comprising antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein and one or more other therapeutic agents, such as a chemotherapeutic agent (e.g., doxorubicin or carfilzomib) or thalidomide or derivatives thereof (e.g., lenalidomide ( ^REVLIMID® )). In some embodiments, the one or more other therapeutic agents are selected from the group consisting of bortezomib (e.g., ^VELCADE® ), melphalan, prednisone, doxorubicin, lenalidomide, thalidomide, prednisone, carmustine, etoposide, cisplatin, cyclophosphamide, carfilzomib, and vincristine. In some embodiments, the other therapeutic agent is bortezomib (e.g., ^VELCADE® ), melphalan, lenalidomide ( ^REVLIMID® ), carfilzomib, doxorubicin, or prednisone. Accordingly, there is provided a method of treating multiple myeloma comprising administering to a patient in need thereof, an effective amount of a composition comprising antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates as described herein and one or more other therapeutic agents selected from the group consisting of bortezomib, lenalidomide, carfilzomib, and doxorubicin. In some embodiments, the patient has relapsed or is refractory to prior treatment for multiple myeloma.

The antibodies (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates can be administered to the subject by any suitable route. Those skilled in the art will appreciate that the examples described herein are not intended to be limiting, but are illustrative of available techniques. Accordingly, in some embodiments, the antibody (e.g., BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugates are administered to the subject according to known methods, such as intravenous administration, such as a bolus or by continuous infusion over a period of time, intramuscular, intraperitoneal, cerebrospinal, intracranial, transdermal, subcutaneous, intra-articular, sublingual, intra-articular, via an insufflator, intrathecal, oral, inhalation, or topical. The administration can be systemic, such as intravenous, or local. Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers, are suitable for administration. Liquid formulations can be directly nebulized, and lyophilized powder can be nebulized after reconstitution. Alternatively, the antibody (e.g. BCMA or CD3-BCMA bispecific) or BCMA-antibody conjugate can be aerosolized using a fluorocarbon formulation and a metered dose inhaler, or administered by inhalation as a lyophilized or milled powder.

In one embodiment, the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugates are administered via site-specific or targeted local delivery methods. Examples of site-specific or targeted local delivery methods include various implantable depot sources of the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate or local delivery catheters such as infusion catheters, indwelling catheters or needle catheters, synthetic grafts, adventitial dressings, shunts and stents or other implantable devices, site-specific carriers, direct injection or direct application. See, for example, PCT Publication WO 00/53211 and US Patent 5,981,568.

Various compositions of the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugates can be used for administration. In some embodiments, the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate can be administered alone. In some embodiments, the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate and the pharmaceutically acceptable excipient can be in various compositions. Pharmaceutically acceptable excipients are known in the art and are relatively inert substances that facilitate administration of the pharmacologically effective substance. For example, the excipient can impart shape or consistency, or act as a diluent. Suitable excipients include, but are not limited to, stabilizers, wetting and emulsifying agents, salts for altering osmolarity, encapsulating agents, buffers, and skin penetration enhancers. Excipients and compositions for parenteral and non-parenteral administration of the drug are described in Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005.

In some embodiments, these agents are designed for administration by injection (e.g., intraperitoneal, intravenous, subcutaneous, intramuscular, etc.). Accordingly, these agents can be combined with pharmaceutically acceptable carriers such as saline, Ringer's solution, dextrose solution, and the like. The specific treatment regimen, i.e., dose, timing, and repetitions, depend on the specific subject and the subject's medical history.

The antibodies (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugates as described herein may be administered using any suitable route, including by injection (e.g., intraperitoneal, intravenous, subcutaneous, intramuscular, etc.). The antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate may also be administered by inhalation as described herein. Typically, for administration of the antibody (e.g., BCMA or bispecific CD3-BCMA) and BCMA-antibody conjugate, an initial potential dose may be about 2 mg/kg. For purposes of the present invention, a typical daily dose may range from any of about 3 mcg/kg to 30 mcg/kg, to 300 mcg/kg, to 3 mg/kg, to 30 mg/kg, to 100 mg/kg or more, depending on the factors mentioned above. For example, a dosage of about 1 mg/kg, about 2.5 mg/kg, about 5 mg/kg, about 10 mg/kg and about 25 mg/kg may be used. With repeated administrations over several days or longer, depending on the condition, treatment is continued until the desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved, such as inhibition or slowing of tumor growth/progression or metastasis of cancer cells. A typical treatment regimen includes administering an initial dose of about 2 mg/kg followed by a weekly maintenance dose of about 1 mg/kg of antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate, or followed by a maintenance dose of about 1 mg/kg every two weeks. Another typical treatment regimen includes administering escalating doses (e.g., with an initial dose of 1 mg/kg and gradually increasing to one or more higher doses every week or over a longer period of time). Other dosing regimens may also be used depending on the pharmacokinetic degradation pattern desired by the practitioner. For example, in some embodiments, dosing is from one to four times per week. In other embodiments, dosing is once per month, or once every two months, or once every three months. The effectiveness of this therapy is readily monitored using routine methods and assays. The treatment regimen (including the antibody (eg, BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate) used may change over time.

For the purposes of the present invention, the appropriate dose of the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate will depend on the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate (or composition thereof) used, the type and severity of the symptoms being treated, whether the agent is being administered for therapeutic purposes, previous therapy, the patient's medical history and response to the agent, the rate of clearance of the administered agent from the patient's body, and the judgment of the treating physician. Typically, the clinician will administer the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate to a dose that achieves the desired result. The dose and/or frequency may vary during the course of treatment. Practical factors, such as half-life, typically influence dose determination. For example, antibodies that are compatible with the human immune system, such as humanized antibodies or fully human antibodies, can be used to increase the half-life of the antibody and prevent attack on the antibody by the host immune system. The frequency of administration can be determined and adjusted during the course of therapy and is usually, but not necessarily, based on the treatment and/or suppression and/or improvement and/or delay of symptoms, such as inhibition or delay of tumor growth, etc. Alternatively, sustained continuous release antibody (e.g. BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate formulations may be suitable. Various formulations and devices for achieving sustained release are known in the art.

In one embodiment, the doses of the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate can be determined empirically in subjects who have received one or more administrations of the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate. The subjects are administered escalating doses of the antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate. Disease symptom can be monitored to assess efficacy.

Administration of the antibody (e.g. BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate according to the method of the present invention may be continuous or intermittent depending on, for example, the physiological state of the recipient, whether the purpose of administration is therapeutic or prophylactic, and other factors known to those skilled in the art. Administration of the antibody (e.g. BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate may be substantially continuous over a preselected period of time or may be a series of doses administered at intervals.

In some embodiments, more than one antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate may be present. At least one, at least two, at least three, at least four, at least five or more different antibodies (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugates may be present. Typically, these antibodies (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugates may have complementary activities that do not adversely affect each other. For example, one or more of the following antibodies may be used: a first BCMA or CD3 antibody directed to one epitope on BCMA or CD3, and a second BCMA or CD3 antibody directed to another epitope on BCMA or CD3.

Therapeutic compositions of the antibody (e.g. BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate used in accordance with the present invention are prepared for storage by mixing the antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005) in the form of lyophilized compositions or aqueous solutions. Suitable carriers, excipients or stabilizers are non-toxic to recipients at the dosages and concentrations used and may contain buffers such as phosphate, citrate and other organic acids; salts such as sodium chloride; 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; catechin; 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

Liposomes containing an antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate are prepared by methods known in the art, such as those described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030, 1980; and in U.S. Patents 4,485,045 and 4,544,545. Liposomes with increased circulation time in the bloodstream are disclosed in U.S. Patent 5,013,556. Particularly useful liposomes can be prepared by reverse phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters with a defined pore size to obtain liposomes with the desired diameter.

The active ingredients can also be incorporated into microcapsules obtained, for example, by coacervation or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g. liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such methods are disclosed in Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005.

Sustained release preparations may be prepared. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, such matrices being in the form of shaped articles such as films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g. poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (US Patent 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable copolymers of lactic acid and glycolic acid such as LUPRON DEPOT™ (injectable microspheres consisting of a copolymer of lactic acid and glycolic acid and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

Compositions to be used for in vivo administration must be sterile. This can be easily accomplished, for example, by filtration through sterile filter membranes. Compositions of the therapeutic antibody (e.g. BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate are typically placed in a container having a sterile access port, such as an intravenous solution bag or a vial having a stopper pierced by a hypodermic needle.

The compositions of the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

For the preparation of solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, for example, conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and with other pharmaceutical diluents, for example, water, to form a solid preformulation containing a homogeneous mixture of a compound of the present invention or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulations as homogeneous, it is meant that the active ingredient is distributed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition may be coated or otherwise formulated to provide a dosage form that provides the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a shell over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to delay its release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Suitable surface-active agents include, in particular, nonionic agents such as polyoxyethylene sorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Surface-active agent compositions typically contain from 0.05 to 5% surface-active agent and may contain from 0.1 to 2.5%. It is understood that other ingredients, e.g. mannitol or other pharmaceutically acceptable carriers, may be added if desired.

Suitable emulsions may be prepared using commercially available fat emulsions such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may either be dissolved in a pre-mixed emulsion composition or, alternatively, it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and the emulsion prepared by mixing with phospholipids (e.g. egg phospholipids, soy phospholipids or soy lecithin) and water. It will be appreciated that other ingredients, e.g. glycerol or glucose, may be added to adjust the tonicity of the emulsion. Suitable emulsions typically contain up to 20% oil, e.g. from 5 to 20%. The fat emulsion may contain fat droplets from 0.1 to 1.0 µm, in particular from 0.1 to 0.5 µm, and have a pH in the range from 5.5 to 8.0.

Emulsion compositions can be prepared by mixing an antibody (e.g. BCMA or bispecific CD3-BCMA) or a BCMA-antibody conjugate with Intralipid™ or its components (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as indicated above. In some embodiments, the compositions are administered orally or intranasally by the respiratory route to produce a local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents can be nebulized using gases. Aerosol solutions can be inhaled directly from a nebulizer device or the nebulizer device can be attached to a face mask, tent or intermittent positive pressure breathing apparatus. Solution, suspension or powder compositions can be administered, preferably orally or nasally, from devices that deliver the drug in an appropriate manner.

Compositions

The compositions used in the methods of the present invention comprise an effective amount of an antibody (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugate as described herein. Examples of such compositions and their preparation are also described in the section above and below. In some embodiments, the composition comprises one or more antibodies (e.g., BCMA or bispecific CD3-BCMA) or BCMA-antibody conjugates. For example, the BCMA antibody or CD3-BCMA bispecific antibody recognizes human BCMA or CD3-BCMA. In some embodiments, the BCMA or CD3-BCMA antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the BCMA antibody or CD3-BCMA antibody comprises a constant region that is capable of initiating a desired immune response, such as antibody-mediated lysis or ADCC. In other embodiments, the BCMA antibody or CD3-BCMA antibody comprises a constant region that does not elicit an unwanted or unnecessary immune response, such as antibody-mediated lysis or ADCC.

It is understood that the compositions may comprise more than one antibody (e.g. BCMA or CD3-BCMA bispecific antibody) or BCMA-antibody conjugate (e.g. a mixture of BCMA antibodies or CD3-BCMA bispecific antibodies that recognize different epitopes of BCMA or CD3 and BCMA). Other exemplary compositions comprise more than one BCMA antibody, CD3-BCMA antibody, or BCMA-antibody conjugate that recognize the same epitope(s), or other types of BCMA antibodies, CD3-BCMA bispecific antibodies, or BCMA-antibody conjugate that bind to different epitopes of BCMA (e.g. human BCMA) or CD3 and BCMA (human CD3 and BCMA).

The composition of the present invention may also contain pharmaceutically acceptable carriers, excipients, or stabilizers (Remington: The Science and practice of Pharmacy 21st Ed., 2005, Lippincott Williams and Wilkins, Ed. KE Hoover) in the form of lyophilized compositions or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at these doses and concentrations and may include 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; catechin; 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 counterions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Pharmaceutically acceptable excipients are also described herein.

Sets

The invention also provides kits for use in rapid methods. The kits of the invention include one or more containers containing a BCMA antibody, a CD3-BCMA bispecific antibody or a BCMA antibody conjugate as described herein and instructions for use in accordance with any of the methods of the invention described herein. Typically, these instructions describe the administration of the BCMA antibody, the CD3-BCMA bispecific antibody or the BCMA antibody conjugate for the above-described therapy.

Instructions for use of the BCMA antibodies, CD3-BCMA bispecific antibodies or BCMA antibody conjugates as described herein typically include dosage, administration schedule and route of administration information for the intended treatment. Containers may be single doses, multi-dose packages (e.g. multi-dose packages) or sub-unit doses. Instructions provided in kits of the invention typically are instructions written on a label or package insert (e.g. on a piece of paper included in the kit), but machine-readable instructions (e.g. instructions on a magnetic or optical storage disk) are also acceptable.

The kits of the present 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, a nasal administration device (e.g., a nebulizer), or an infusion device, such as a minipump. The kit may have a sterile entry port (e.g., the container may be a bag of intravenous solution or a vial having a stopper pierced by a hypodermic needle). The container may also have a sterile entry port (e.g., the container may be a bag of intravenous solution or a vial having a stopper pierced by a hypodermic needle). At least one active agent in the composition is a BCMA antibody, a bispecific CD3-BCMA antibody, or a BCMA-antibody conjugate. The container may further contain a second pharmaceutically active agent.

Kits may include additional components such as buffers and explanatory information. Typically, a kit will contain a container and a label or package insert(s) on or with the container.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description and are within the scope of the appended claims.

Examples

Example 1: Determination of the kinetics and affinity of hBCMA/human IgG interactions at 25°C and/or 37°C

In this example, the kinetics and affinity of various anti-BCMA antibodies are determined at 25°C and 37°C.

All experiments were performed on a Bio-Rad Proteon XPR36 surface plasmon resonance biosensor (Bio-Rad, Hercules, CA). Anti-BCMA antibody repertoires were generated using an amine coupling method on a Bio-Rad GLC sensor chip similar to that described in Abdiche, et al., Anal. Biochem. 411, 139–151 (2011). The assay temperature for immobilization was 25°C and the electrode buffer was HBS-T+ (10 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.4). Channels were activated in the analyte (horizontal) direction by injecting a mixture of 1 mM ECD and 0.25 mM NHS for 3 min at a flow rate of 30 μL/min. IgG were immobilized on activated sites by injecting them in the ligand direction (vertical) at 20 μg/ml in 10 mM acetate buffer, pH 4.5, for 1.5 min at 30 μg/ml. Activated surfaces were blocked by injecting 1 M ethanolamine, pH 8.5, in the analyte direction for 3 min at 30 μl/min.

The temperature in the hBCMA binding assay was 37°C or 25°C in HBS-T+ electrode buffer supplemented with 1 mg/mL BSA. A kinetic titration method was used for the interaction assay as described by Abdiche, et al. The hBCMA analyte (human BCMA) was injected towards the analyte using a series of injections from low to high concentration. The concentrations used were 0.08 nM, 0.4 nM, 2 nM, 10 nM, and 50 nM (5-term series with a 5-fold dilution factor and an upper concentration of 50 nM). The association time for a given analyte dilution was two minutes. Immediately after the injection of 50 nM hBCMA, dissociation was monitored for 2 hours. Before the hBCMA analyte injections, buffer was injected 5 times using the same association and dissociation times as in the hBCMA analyte cycles to obtain a control sensorgram for the buffer to obtain a double standard (the double standard described in Myszka, J. Mol. Recognit. 12, 279-284 (1999)).

Sensorgrams were generated with a dual standard and fitted to a 1:1 Langmuir mass transfer titration kinetic model in BIAevaluation version 4.1.1 (GE Lifesciences, Piscataway, NJ). The sensorgrams and fits are shown in Fig. 1, and the kinetic and affinity parameters for the various anti-BCMA antibodies of the present invention are presented in Tables 6A-6C.

Table 6A Sample k _a (1/Mc) k _d (1/c) t _1/2 (min) K _D (pM) A02_Rd4_6nM_C01 1,2E+06 2,8E-05 411 24 A02_Rd4_6nM_C16 1,1E+06 6.2E-05 187 59 Combo_Rd4_06nM_C29 6.6E+06 1,4E-04 83 21 L3PY/H3TAQ 2.6E+06 1,4E-04 84 53

Table 6B Antibody ka (1/Mc) huBCMA at 25°C kd (1/c) huBCMA at 25°C T ½ (min) with huBCMA at 25°C KD (nM) with huBCMA at 25°C P6E01/P6E01 1.04E+06 4,15E-03 2.8 4.0 P6E01/H3.AQ 8.35E+05 3.45E-04 33.53 0.41 L1.LGF/L3.KW/P6E01 8.31E+05 7.55E-03 1.53 9.08 L1.LGF/L3.NY/P6E01 1.33E+06 4,40E-03 2.63 3.32 L1.GDF/L3.NY/P6E01 1.60E+06 5.92E-03 1.95 3.70 L1.LGF/L3.KW/H3.AL 4.28E+05 1,23E-03 9.40 2.87 L1.LGF/L3.KW/H3.AP 9.28E+05 2,27E-03 5.10 2.44 L1.LGF/L3.KW/H3.AQ 5.24E+05 9,56E-04 12.09 1.82 L1.LGF/L3.PY/H3.AP 4.57E+05 9,69E-04 11.92 2.12 L1.LGF/L3.PY/H3.AQ 9.31E+05 8,86E-04 13.04 0.95 L1.LGF/L3.NY/H3.AL 7.63E+05 9,70E-04 11.91 1.27 L1.LGF/L3.NY/H3.AP 9.36E+05 5,33E-04 21.67 0.57 L1.LGF/L3.NY/H3.AQ 6.66E+05 2.99E-04 38.61 0.45 L1.GDF/L3.KW/H3.AL 4.45E+05 3.90E-03 2.96 8.76 L1.GDF/L3.KW/H3.AP 1.17E+06 4,61E-03 2.51 3.93 L1.GDF/L3.KW/H3.AQ 7.97E+05 3.48E-03 3.32 4.37 L1.GDF/L3.PY/H3.AQ 1.42E+06 1,35E-02 0.86 9.49 L1.GDF/L3.NY/H3.AL 9.07E+05 4.03E-03 2.87 4.44 L1.GDF/L3.NY/H3.AP 1.41E+06 1,41E-03 8.21 1.00 L1.GDF/L3.NY/H3.AQ 9.84E+05 7.22E-04 16.00 0.73 L3.KW/P6E01 7.40E+05 3,15E-04 36.66 0.43 L3.PY/P6E01 7.12E+05 2,28E-04 50.74 0.32 L3.NY/P6E01 8.76E+05 3.84E-04 30.08 0.44 Antibody ka (1/Mc) huBCMA at 37°C kd (1/c) huBCMA at 37°C T ½ (min) with huBCMA at 37°C KD (nM) with huBCMA at 37°C L3.PY/L1.PS/P6E01 2.49E+06 1,13E-03 10.21 0.45 L3.PY/L1.AH/P6E01 2.55E+06 1,26E-03 9.19 0.49 L3.PY/L1.FF/P6E01 2.39E+06 1,41E-03 8.18 0.59 L3.PY/L1.PH/P6E01 2.81E+06 9,13E-04 12.65 0.32 L3.PY/L3.KY/P6E01 3.18E+06 1,09E-03 10.65 0.34 L3.PY/L3.KF/P6E01 2.88E+06 2.08E-03 5.56 0.72 L3.PY/H2.QR 2.56E+06 1,19E-03 9.75 0.46 L3.PY/H2.DY 2.60E+06 1,38E-03 8.37 0.53 L3.PY/H2.YQ 2.58E+06 1,56E-03 7.41 0.60 L3.PY/H2.LT 2.40E+06 1,29E-03 8.95 0.54 L3.PY/H2.HA 2.43E+06 1,47E-03 7.89 0.60 L3.PY/H2.QL 2.64E+06 2,18E-03 5.31 0.82 L3.PY/H3.YA 3.15E+06 1,18E-03 9.82 0.37 L3.PY/H3.AE 3.29E+06 1,39E-03 8.32 0.42 L3.PY/H3.AQ 3.08E+06 1,73E-03 6.69 0.56 L3.PY/H3.TAQ 3.08E+06 1,14E-03 10.13 0.37 L3.PY/P6E01 2.65E+06 1,96E-03 5.91 0.74 L3.PY/L1.PS/H2.QR 3.97E+06 1,03E-01 0.11 25.85 L3.PY/L1.PS/H2.DY 3.22E+06 3,61E-03 3.20 1,12 L3.PY/L1.PS/H2.YQ 3.35E+06 4.30E-03 2.69 1.28 L3.PY/L1.PS/H2.LT 3.40E+06 4,65E-03 2.49 1.37 L3.PY/L1.PS/H2.HA 3.30E+06 1,06E-02 1.09 3.21 L3.PY/L1.PS/H2.QL 1.52E+07 3.14E-01 0.04 20.64 L3.PY/L1.PS/H3.YA 3.07E+06 9.05E-03 1.28 2.95 L3.PY/L1.PS/H3.AE 3.14E+06 1,46E-03 7.93 0.46 L3.PY/L1.PS/H3.AQ 3.26E+06 1,79E-03 6.46 0.55 L3.PY/L1.PS/H3.TAQ 3.25E+06 2,46E-03 4.70 0.76 L3.PY/L1.AH/H2.QR 3.13E+06 1,81E-03 6.39 0.58 L3.PY/L1.AH/H2.DY 3.05E+06 1,52E-03 7.62 0.50 L3.PY/L1.AH/H2.YQ 2.42E+06 1,93E-03 6.00 0.80 L3.PY/L1.AH/H2.LT 3.16E+06 1,23E-03 9.38 0.39 L3.PY/L1.AH/H2.HA 3.33E+06 1,81E-03 6.37 0.54 L3.PY/L1.AH/H2.QL 3.04E+06 1,60E-03 7.22 0.53 L3.PY/L1.AH/H3.YA 3.00E+06 1,50E-03 7.73 0.50 L3.PY/L1.AH/H3.AE 3.32E+06 1,73E-03 6.70 0.52 L3.PY/L1.AH/H3.AQ 3.03E+06 1,97E-03 5.85 0.65 L3.PY/L1.AH/H3.TAQ 3.27E+06 1,19E-03 9.68 0.37 L3.PY/L1.FF/H2.QR 3.47E+06 1,77E-03 6.54 0.51 L3.PY/L1.FF/H2.DY 4.14E+06 2.71E-03 4.27 0.65 L3.PY/L1.FF/H2.YQ 3.32E+06 1,52E-03 7.61 0.46 L3.PY/L1.FF/H2.LT 3.30E+06 1,67E-03 6.92 0.51 L3.PY/L1.FF/H2.HA 3.49E+06 2,19E-03 5.29 0.63 L3.PY/L1.FF/H2.QL 3.48E+06 1,40E-03 8.28 0.40 L3.PY/L1.FF/H3.YA 3.50E+06 1,80E-03 6.41 0.51 L3.PY/L1.FF/H3.AE 3.82E+06 2,63E-03 4.39 0.69 L3.PY/L1.FF/H3.AQ 3.32E+06 1,54E-03 7.51 0.46 L3.PY/L1.FF/H3.TAQ 3.52E+06 1,89E-03 6.12 0.54 L3.PY/L1.PH/H2.QR 3.69E+06 2,36E-03 4.89 0.64 L3.PY/L1.PH/H2.HA 2.37E+06 1,16E-03 9.99 0.49 L3.PY/L1.PH/H3.AE 3.68E+06 1,34E-03 8.61 0.36 L3.PY/L1.PH/H3.AQ 3.08E+06 1,59E-03 7.27 0.52 L3.PY/L1.PH/H3.TAQ 3.58E+06 2,13E-03 5.43 0.59 L3.PY/L3.KY/H2.QR 2.95E+06 9,90E-04 11.67 0.34 L3.PY/L3.KY/H2.DY 3.19E+06 6.42E-04 18:00 0.20 L3.PY/L3.KY/H2.YQ 2.14E+06 1,65E-03 7.02 0.77 L3.PY/L3.KY/H2.LT 2.92E+06 9.06E-04 12.75 0.31 L3.PY/L3.KY/H2.HA 3.29E+06 1,63E-03 7.10 0.49 L3.PY/L3.KY/H2.QL 3.65E+06 2.08E-03 5.56 0.57 L3.PY/L3.KY/H3.YA 3.30E+06 9,12E-04 12.67 0.28 L3.PY/L3.KY/H3.TAQ 2.79E+06 6.49E-04 17.79 0.23 L3.PY/L3.KF/H2.DY 2.74E+06 1,82E-03 6.35 0.67 L3.PY/L3.KF/H2.YQ 1.96E+06 2,23E-03 5.18 1.14 L3.PY/L3.KF/H2.LT 2.75E+06 1,91E-03 6.05 0.69 L3.PY/L3.KF/H2.QL 2.07E+06 1,25E-03 9.26 0.60 L3.PY/L3.KF/H3.YA 3.12E+06 1,47E-03 7.85 0.47 L3.PY/L3.KF/H3.AE 3.07E+06 1,55E-03 7.44 0.51 L3.PY/L3.KF/H3.AQ 3.48E+06 2,27E-03 5.09 0.65 L3.PY/L3.KF/H3.TAQ 2.82E+06 1,62E-03 7.12 0.58 Antibody ka (1/Mc) cyBCMA at 25°C kd (1/c) cyBCMA at 25°C T ½ (min) with cyBCMA at 25°C KD (nM) with cyBCMA at 25°C P6E01/P6E01 7.02E-02 0.16 115.4 P6E01/H3.AQ 1.08E+06 7.40E-03 1.6 6.9 L1.LGF/L3.KW/P6E01 4.55E+05 1,95E-02 0.6 42.8 L1.LGF/L3.NY/P6E01 9.20E+05 1,05E-02 1,1 11.4 L1.GDF/L3.NY/P6E01 1.20E+06 7,67E-03 1.5 6.4 L1.LGF/L3.KW/H3.AL 2.90E+05 1,21E-02 1.0 41.8 L1.LGF/L3.KW/H3.AP 5.54E+05 1,54E-02 0.7 27.8 L1.LGF/L3.KW/H3.AQ 5.27E+05 3.55E-03 3.3 6.7 L1.LGF/L3.PY/H3.AP 3.64E+05 1,30E-02 0.9 35.8 L1.LGF/L3.PY/H3.AQ 1.00E+06 4.77E-03 2.4 4.8 L1.LGF/L3.NY/H3.AL 6.35E+05 1,48E-02 0.8 23.2 L1.LGF/L3.NY/H3.AP 8.30E+05 5,57E-03 2.1 6.7 L1.LGF/L3.NY/H3.AQ 7.51E+05 1,48E-03 7.8 2.0 L1.GDF/L3.KW/H3.AL 3.18E+05 1,80E-02 0.6 56.7 L1.GDF/L3.KW/H3.AP 8.14E+05 2.03E-02 0.6 24.9 L1.GDF/L3.KW/H3.AQ 8.02E+05 5,65E-03 2.0 7.0 L1.GDF/L3.PY/H3.AQ 1.55E+06 1,66E-02 0.7 10.7 L1.GDF/L3.NY/H3.AL 9.00E+05 2,19E-02 0.5 24.3 L1.GDF/L3.NY/H3.AP 1.36E+06 7.02E-03 1.6 5.2 L1.GDF/L3.NY/H3.AQ 1.18E+06 1,36E-03 8.5 1,2 L3.KW/P6E01 7.63E+05 2,57E-03 4.5 3.4 L3.PY/P6E01 8.55E+05 2.93E-03 3.9 3.4 L3.NY/P6E01 1.01E+06 2,87E-03 4.0 2.8 Antibody ka (1/Mc) cyBCMA at 37°C kd (1/c) cyBCMA at 37°C T ½ (min) with cyBCMA at 37°C KD (nM) with cyBCMA at 37°C L3.PY/L1.PS/P6E01 2.17E+06 6.06E-03 1.91 2.79 L3.PY/L1.AH/P6E01 2.16E+06 5,72E-03 2.02 2.65 L3.PY/L1.FF/P6E01 2.45E+06 5.91E-03 1.96 2.41 L3.PY/L1.PH/P6E01 2.17E+06 7,89E-03 1.46 3.63 L3.PY/L3.KY/P6E01 2.27E+06 5.02E-03 2.30 2.21 L3.PY/L3.KF/P6E01 2.39E+06 8.30E-03 1.39 3.48 L3.PY/H2.QR 2.18E+06 6.58E-03 1.76 3.02 L3.PY/H2.DY 2.24E+06 6,18E-03 1.87 2.76 L3.PY/H2.YQ 2.46E+06 6.21E-03 1.86 2.53 L3.PY/H2.LT 2.09E+06 7,57E-03 1.53 3.63 L3.PY/H2.HA 1.99E+06 7.55E-03 1.53 3.79 L3.PY/H2.QL 2.05E+06 1,26E-02 0.91 6.16 L3.PY/H3.YA 2.87E+06 5,40E-03 2.14 1.88 L3.PY/H3.AE 2.82E+06 5.04E-03 2.29 1.79 L3.PY/H3.AQ 2.77E+06 5.39E-03 2.14 1.94 L3.PY/H3.TAQ 2.57E+06 4.37E-03 2.64 1.70 L3.PY/P6E01 2.20E+06 1,31E-02 0.88 5.96 L3.PY/L1.PS/H2.QR 5.25E+05 6,70E-04 17.23 1.28 L3.PY/L1.PS/H2.DY 1.90E+06 3.78E-03 3.06 1.99 L3.PY/L1.PS/H2.YQ 2.00E+06 3.74E-03 3.09 1.87 L3.PY/L1.PS/H2.LT 2.17E+06 4.11E-03 2.81 1.89 L3.PY/L1.PS/H2.HA 1.45E+06 2,69E-03 4.30 1.86 L3.PY/L1.PS/H2.QL 6.57E+05 6,36E-04 18,17 0.97 L3.PY/L1.PS/H3.YA 1.77E+06 9.98E-03 1.16 5.65 L3.PY/L1.PS/H3.AE 2.46E+06 4,13E-03 2.80 1.68 L3.PY/L1.PS/H3.AQ 2.52E+06 4.33E-03 2.67 1.72 L3.PY/L1.PS/H3.TAQ 2.58E+06 5.52E-03 2.09 2.14 L3.PY/L1.AH/H2.QR 2.20E+06 4.91E-03 2.35 2.23 L3.PY/L1.AH/H2.DY 2.32E+06 4.51E-03 2.56 1.95 L3.PY/L1.AH/H2.YQ 1.58E+06 4.31E-03 2.68 2.74 L3.PY/L1.AH/H2.LT 2.19E+06 2,96E-03 3.91 1.35 L3.PY/L1.AH/H2.HA 2.58E+06 4.39E-03 2.63 1.70 L3.PY/L1.AH/H2.QL 2.62E+06 9,55E-03 1.21 3.65 L3.PY/L1.AH/H3.YA 2.37E+06 5.26E-03 2.20 2.22 L3.PY/L1.AH/H3.AE 2.25E+06 3.56E-03 3.25 1.58 L3.PY/L1.AH/H3.AQ 2.24E+06 3.99E-03 2.90 1.78 L3.PY/L1.AH/H3.TAQ 2.28E+06 3.02E-03 3.83 1.32 L3.PY/L1.FF/H2.QR 2.55E+06 4.21E-03 2.75 1.65 L3.PY/L1.FF/H2.DY 2.66E+06 5.00E-03 2.31 1.88 L3.PY/L1.FF/H2.YQ 2.19E+06 3.26E-03 3.55 1.49 L3.PY/L1.FF/H2.LT 2.19E+06 3.41E-03 3.38 1.56 L3.PY/L1.FF/H2.HA 2.33E+06 4,17E-03 2.77 1.79 L3.PY/L1.FF/H2.QL 2.36E+06 4,49E-03 2.57 1.91 L3.PY/L1.FF/H3.YA 2.46E+06 4,16E-03 2.77 1.69 L3.PY/L1.FF/H3.AE 2.85E+06 5.01E-03 2.31 1.76 L3.PY/L1.FF/H3.AQ 2.18E+06 3.29E-03 3.51 1.51 L3.PY/L1.FF/H3.TAQ 2.32E+06 3.76E-03 3.07 1.62 L3.PY/L1.PH/H2.QR 2.42E+06 4.36E-03 2.65 1.80 L3.PY/L1.PH/H2.HA 1.61E+06 5,53E-03 2.09 3.44 L3.PY/L1.PH/H3.AE 2.61E+06 2.02E-03 5.72 0.77 L3.PY/L1.PH/H3.AQ 2.28E+06 3.41E-03 3.39 1.50 L3.PY/L1.PH/H3.TAQ 2.51E+06 3.20E-03 3.61 1.28 L3.PY/L3.KY/H2.QR 2.05E+06 7.74E-03 1.49 3.78 L3.PY/L3.KY/H2.DY 1.96E+06 2,43E-03 4.75 1.24 L3.PY/L3.KY/H2.YQ 1.27E+06 2,58E-03 4.47 2.04 L3.PY/L3.KY/H2.LT 1.82E+06 2,32E-03 4.98 1.27 L3.PY/L3.KY/H2.HA 2.28E+06 3.18E-03 3.63 1.40 L3.PY/L3.KY/H2.QL 2.75E+06 4.09E-03 2.83 1.49 L3.PY/L3.KY/H3.YA 1.84E+06 4.28E-03 2.70 2.33 L3.PY/L3.KY/H3.TAQ 1.81E+06 1,92E-03 6.03 1.06 L3.PY/L3.KF/H2.DY 2.08E+06 3,68E-03 3.14 1.77 L3.PY/L3.KF/H2.YQ 1.41E+06 5.01E-03 2.30 3.55 L3.PY/L3.KF/H2.LT 1.91E+06 4,13E-03 2.80 2.16 L3.PY/L3.KF/H2.QL 1.42E+06 3,10E-03 3.73 2.18 L3.PY/L3.KF/H3.YA 2,10E+06 7.96E-03 1.45 3.78 L3.PY/L3.KF/H3.AE 1.85E+06 5,64E-03 2.05 3.05 L3.PY/L3.KF/H3.AQ 2.55E+06 2,38E-03 4.85 0.93 L3.PY/L3.KF/H3.TAQ 2.01E+06 1,91E-03 6.05 0.95

Table 6C* Antibody Human Javan macaque ka (1/Mc) kd (1/c) KD (pM) ka (1/Mc) kd (1/c) KD (pM) P5A2_VHVL 6.96E+06 3.87E-02 5567 1.61E+06 1,64E-02 10230 A02_Rd4_0.6nM_C06 3.49E+06 7.37E-05 21 1.81E+06 1.05E-04 58 A02_Rd4_0.6nM_C09 5.50E+06 9.75E-05 18 2.13E+06 1,74E-04 82 A02_Rd4_6nM_C16 1.56E+06 1,41E-04 90 1.34E+06 1,58E-04 118 A02_Rd4_6nM_C03 1.69E+06 1,26E-04 75 1.17E+06 1,85E-04 158 A02_Rd4_6nM_C01 3.11E+06 9,20E-05 30 1.45E+06 5,83E-04 401 A02_Rd4_6nM_C26 4.26E+06 1,39E-04 33 2.21E+06 4,48E-04 203 A02_Rd4_6nM_C25 2.75E+06 1,80E-04 65 1.50E+06 3.30E-04 220 A02_Rd4_6nM_C22 3.38E+06 1,82E-04 54 1.84E+06 3.24E-04 176 A02_Rd4_6nM_C19 3.00E+06 1,48E-04 49 2.54E+06 6,61E-04 260 A02_Rd4_0.6nM_C03 4.27E+06 1,82E-04 43 2,12E+06 4,26E-04 201 A02_Rd4_6nM_C07 1.48E+06 1,89E-04 128 6.91E+05 7,86E-04 1138 A02_Rd4_6nM_C23 1.22E+07 2,55E-04 21 2.63E+06 4,14E-04 157 A02_Rd4_0.6nM_C18 4.73E+06 2,29E-04 48 3.24E+06 6,39E-04 197 A02_Rd4_6nM_C10 4.51E+06 3,15E-04 70 1.90E+06 8.98E-04 472 A02_Rd4_6nM_C05 3.10E+06 3.08E-04 99 1.36E+06 1,29E-03 950 A02_Rd4_0.6nM_C10 2.30E+06 2,96E-04 129 8.83E+05 1,63E-03 1842 A02_Rd4_6nM_C04 4.47E+06 6.03E-04 135 2.18E+06 8.31E-04 381 A02_Rd4_0.6nM_C26 7.26E+06 4,43E-04 61 2.71E+06 2,56E-03 941 A02_Rd4_0.6nM_C13 8.53E+06 5,66E-04 66 2.29E+06 1,28E-03 560 A02_Rd4_0.6nM_C01 4.74E+06 9,15E-04 193 2.39E+06 1,57E-03 655 A02_Rd4_6nM_C08 3.92E+06 7.38E-04 188 2.23E+06 1,13E-02 5072 P5C1_VHVL 1.16E+07 6.92E-02 5986 3.53E+06 5.38E-02 15231 C01_Rd4_6nM_C24 7.47E+06 3.48E-03 467 3.17E+06 8,91E-04 281 C01_Rd4_6nM_C26 1.50E+07 1,36E-03 90 4.75E+06 1,99E-03 419 C01_Rd4_6nM_C02 1.61E+07 1,44E-03 89 5.12E+06 2,18E-03 426 C01_Rd4_6nM_C10 1.31E+07 2,12E-03 162 4.44E+06 2,19E-03 493 C01_Rd4_0.6nM_C27 1.23E+07 3.74E-03 303 3.34E+06 2,85E-03 852 C01_Rd4_6nM_C20 6.02E+06 2,76E-03 459 3.60E+06 6.25E-03 1737 C01_Rd4_6nM_C12 1.21E+07 6,49E-03 535 4.51E+06 3.70E-03 820 C01_Rd4_0.6nM_C16 1.55E+07 6.30E-03 407 4.95E+06 4,64E-03 939 C01_Rd4_0.6nM_C09 1.51E+07 8,25E-03 545 5.28E+06 9,36E-03 1773 C01_Rd4_6nM_C09 1.58E+07 1,28E-02 811 3.73E+06 8,68E-03 2328 C01_Rd4_0.6nM_C03 1.55E+07 1,50E-02 964 4.72E+06 1,19E-02 2528 C01_Rd4_0.6nM_C06 1.82E+07 1.54E-02 847 6.22E+06 1.21E-02 1948 C01_Rd4_6nM_C04 2.33E+07 4.97E-02 2134 6.34E+06 3.27E-02 5156 COMBO_Rd4_0.6nM_C22 1.97E+06 7,15E-05 36 1.34E+06 6,66E-05 50 COMBO_Rd4_6nM_C21 1.17E+07 7.34E-05 6 3.17E+06 2,48E-04 78 COMBO_Rd4_6nM_C10 5.47E+06 9,72E-05 18 1.52E+06 1,60E-04 105 COMBO_Rd4_0.6nM_C04 1.07E+07 1,58E-04 15 3.52E+06 1,37E-04 39 COMBO_Rd4_6nM_C25 7.98E+06 1,13E-04 14 2.85E+06 2,26E-04 79 COMBO_Rd4_0.6nM_C21 1.34E+07 1,15E-04 9 3.63E+06 3.04E-04 84 COMBO_Rd4_6nM_C11 6.74E+06 1,24E-04 18 2.64E+06 4,12E-04 156 COMBO_Rd4_0.6nM_C20 7.65E+06 1,46E-04 19 3.09E+06 2,84E-04 92 COMBO_Rd4_6nM_C09 8.85E+06 1,43E-04 16 2.37E+06 3.18E-04 134 COMBO_Rd4_6nM_C08 8.99E+06 1,69E-04 19 3.06E+06 4.28E-04 140 COMBO_Rd4_0.6nM_C19 7.86E+06 1,55E-04 20 2.92E+06 9.79E-04 336 COMBO_Rd4_0.6nM_C02 8.57E+06 1,85E-04 22 3.01E+06 4.94E-04 164 COMBO_Rd4_0.6nM_C23 7.39E+06 2,10E-04 28 2.81E+06 5.31E-04 189 COMBO_Rd4_0.6nM_C29 1.47E+07 2,77E-04 19 4.00E+06 3.36E-04 84 COMBO_Rd4_0.6nM_C09 1.04E+07 3.19E-04 31 3.77E+06 3.46E-04 92 COMBO_Rd4_6nM_C12 1.38E+07 2,70E-04 20 3.29E+06 4,86E-04 148 COMBO_Rd4_0.6nM_C30 4.35E+06 2,82E-04 65 1.68E+06 8.08E-04 481 COMBO_Rd4_0.6nM_C14 8.66E+06 3.28E-04 38 3.48E+06 6.45E-04 185 COMBO_Rd4_6nM_C07 1.05E+07 3.71E-04 35 3.94E+06 9.34E-04 237 COMBO_Rd4_6nM_C02 1.05E+06 4,43E-04 422 7.95E+05 1,36E-03 1714 COMBO_Rd4_0.6nM_C05 4.32E+06 4.97E-04 115 1.94E+06 1,72E-03 886 COMBO_Rd4_0.6nM_C17 8.68E+06 8.01E-04 92 3.06E+06 1.01E-03 330 COMBO_Rd4_6nM_C22 3.03E+06 7.75E-04 256 1.70E+06 1,65E-03 972 COMBO_Rd4_0.6nM_C11 5.11E+06 1,06E-03 207 2.20E+06 4.23E-03 1924 *Binding assays were performed at 37°C.

Example 2: Flow cytometry of human anti-BCMA antibodies on BCMA-positive tumor cells

This example demonstrates the binding of BCMA-positive tumor cells to various BCMA antibodies of the present invention.

Binding of human anti-hBCMA expressed in mouse IgG2a was assessed on BCMA-expressing cells (KMS12BM, L363, MM1S and KMS12PE) by flow cytometry. 250,000 cells were incubated with 0.5 μg antibody in 100 μl binding buffer (PBS (phosphate buffered saline) + 0.2% BSA (bovine serum albumin)), followed by incubation with Alex Fluor 647-conjugated anti-mouse IgG (Biolegend). Table 7 shows the MFI (mean fluorescence intensity) on BCMA-positive tumor cells with different BCMA antibodies (e.g. Combo_Rd4_0.6nM_C29, A02_Rd4_6nM_C01, A02_Rd4_6nM_C16 and P6E01/H3TAQ)

Example 3: Cytotoxicity of anti-BCMA ADC in BCMA-positive cells

This example demonstrates the efficacy of anti-BCMA ADC in BCMA-positive cells.

Human anti-BCMA (L3.PY/P6E01, L3.PY/H3.TAQ, Combo_Rd4_0.6nM_C29, A02_Rd4_6nM_C01, and A02_Rd4_6nM_C16) antibodies were expressed as human IgG1 subtypes engineered with glutamine-containing transglutaminase (“Q”) tags (e.g., LCQ05, H7c, N297A, N297Q, N297A/H7c, N297Q/LCQ05) for drug-to-antibody ratios (DAR) 2, 4, and 6. TG17 corresponds to SEQ ID NO: 472 (LLQGPP); LCQ05 corresponds to SEQ ID NO: 474 (GGLLQGPP), H7c corresponds to SEQ ID NO: 454 (LLQG), respectively, and is conjugated with AcLys-Val-Cit-PABC-Aur0101 (Acetyl-Lysine-Valine-Citrulline- p -aminobenzyloxycarbonyl), amino-PEG6-C2-Aur3377 or amino-PEG6-C2-Aur0131, as indicated in Table 8. In one case, the transglutaminase tags can be designed on the light chain, the heavy chain or a combination of light and heavy chains. In another case, the transglutaminase tag (e.g. Q) is designed at a site of the antibody, for example at position 297 of human IgG (EU numbering scheme). For example, the wild-type amino acid asparagine (N) is substituted with glutamine or alanine at position 297 of the BCMA antibody (N297Q or N297A) of the present invention. Conjugation of the anti-BCMA antibody to Aur0101, Aur3377 and Aur0131 is then achieved by a transamidation reaction catalyzed by microbial transglutaminase between the anti-BCMA antibody bearing the target glutamine or glutamine tag at a specific site (e.g., the carboxyl terminus or the amino terminus of the heavy chain or light chain, at position 297 or at another site of the antibody) and an amino-containing derivative of the payload (e.g., MMAD, Aur0101, Aur3377 or Aur0131). In some cases, the wild-type amino acid lysine at position 222, 340, or 370 (according to the EU numbering scheme) was replaced by the amino acid arginine ("K222R", "K340R", or "K370R"). For example, the K222R substitution was found to have the unusual effect of resulting in a more homogeneous antibody and payload conjugate, better intermolecular cross-linking of the antibody and payload, and/or a significant reduction in interchain cross-linking with the glutamine tag at the C-terminus of the antibody light chain.

In the transamidation reaction, glutamine on the antibody acted as an acyl donor and the amine-containing compound acted as an acyl acceptor (amine donor). Purified anti-BCMA antibody at a concentration of 1-150 μM was incubated with 5-100 molar excess of the acyl acceptor, in the range of 5 μM-15 mM, in the presence of 0.23-0.55% (w/v) Streptoverticillium mobaraense transglutaminase (ACTIVA™, Ajinomoto, Japan) in 10-1000 mM NaCl and 25 mM MES, HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid] or Tris HCl buffer in the pH range of 6.2-8.8. Reaction conditions were adjusted for individual acyl acceptor derivatives and optimal efficiency and specificity were typically observed with 33 μM antibody, 0.67 mM derivative and 0.378% (w/v) transglutaminase in 75 mM NaCl, 25 mM Tris HCl, pH 8.5. After incubation at 20-37°C for 1-24 hours, the antibody was purified by high performance chromatography on butyl sepharose high performance (Butyl HP) resin (GE Healthcare, Waukesha, WI) using standard chromatographic methods known to those skilled in the art, such as the commercial hydrophobic interaction chromatography from GE Healthcare.

The target expressing cells (MM1.S, KMS12BM and L363) were then seeded on clear plates at 3000 cells/well. The cells were treated with 4-fold serially diluted antibody-drug conjugates in triplicate. Cell viability was determined using CellTiter- ^Glo® Luminescent Cell Viability Assay 96 (Promega, Madison WI) 96 hours after treatment. Relative cell viability was determined as a percentage of the untreated control. EC50 was calculated using Prism software. Table 8 shows that all human anti-BCMA antibodies of the present invention conjugated to cytotoxic agent 0101, 3377 and 0131 via transglutaminase tags and linkers exhibit potent cell killing activity in BCMA expressing cells.

Table 8 EC50 MM1.S LUCGFP (BCMA++) KMS12BM LUCGFP (+) L363 LUCGFP (+) ANTIBODY DAR nM mcg/ml nM mcg/ml nM mcg/ml L3.PY/P6E01 N297Q/K222R AcLys vc0101 4 0.42 0.06 31.79 4.77 7.34 1.10 L3PY/H3.TAQ
N297Q/K222R Aclys vc0101 4 0.12 0.02 3.94 0.59 0.60 0.09 A02_Rd4_6nM_C01 N297Q/K222R Aclys vc0101 3.91 0.26 0.04 18.67 2.80 2.53 0.38 A02_Rd4_6nM_C16
N297Q/K222R Aclys vc0101 3.92 0.80 0.12 38.73 5.81 9.68 1.45 Combo_Rd4_0.6nM_C29 LCQ05/K222R Aclys vc0101 2 0.13 0.02 10.91 1.64 1.67 0.25 Combo_Rd4_0.6nM_C29 N297Q/K222R Aclys vc0101 3.9 0.11 0.02 0.99 0.15 0.66 0.10 Combo_Rd4_0.6nM_C29 LCQ05/N297Q/K222R Aclys vc0101 5.98 0.34 0.05 1.19 0.18 1.05 0.16 Combo_Rd4_0.6nM_C29 H7c/N297A/K222R AmPEG6 Aur0131 3.81 0.23 0.03 0.85 0.13 0.81 0.12 Combo_Rd4_0.6nM_C29 H7c/N297A/K222R AmPEG6 Aur3377 3.88 0.30 0.05 5.01 0.75 1.36 0.20

Example 4: Anti-BCMA ADCs induce tumor regression in an orthotopic multiple myeloma model

This example illustrates the in vivo efficacy of anti-BCMA ADC in the MM1S orthotopic multiple myeloma model.

An in vivo study of the efficacy of BCMA ADC was performed in the MM1.S multiple myeloma cell line expressing luciferase and GFP (green fluorescent protein) in an orthotopic model. Ten million MM1.S LucGFP cells were injected intravenously via the tail vein into 6-8-week-old CB17/SCID females. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μL per animal at 15 mg/mL), followed by isoflurane anesthesia and subsequent whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted by the interaction between tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). When the total flux reached an average of 1-3E6 for all animals, animals were randomized to groups and a single dose of human anti-BCMA antibody conjugated to 1) LCQ05/K222R-vc0101 at the C-terminus of the antibody light chain and control conjugates were administered by bolus injection into the tail vein. Animal studies were terminated when they developed limb paralysis, the endpoint of the MM1.S orthotopic models. In Fig. 2 showed that a single dose of 3 mg/kg of various human anti-BCMA ADCs inhibited tumor progression compared with the negative control (NNC), including P6E01/P6E01-AcLys-Val-Cit-PABC-Aur0101; P5A2_VHVL-AcLys-Val-Cit-PABC-Aur0101; P5C1_VHVL-AcLys-Val-Cit-PABC-Aur0101; P4G4-AcLys-Val-Cit-PABC-Aur0101; and P1A11-AcLys-Val-Cit-PABC-Aur0101.

This study demonstrates that BCMA-ADC treatment inhibits the progression of multiple myeloma.

Example 5: Anti-BCMA ADC Induces Tumor Regression and Inhibition in an Orthotopic Model of Multiple Myeloma

This example also illustrates the in vivo efficacy of anti-BCMA ADC in orthotopic multiple myeloma MM1.S models.

An in vivo study of the efficacy of BCMA ADC was performed in the MM1.S multiple myeloma cell line expressing luciferase and GFP in an orthotopic model. Ten million MM1.S LucGFP cells were injected intravenously into the tail vein of 6-8-week-old CB17/SCID females. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μL per animal at a concentration of 15 mg/mL), followed by isoflurane anesthesia and subsequent whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted by the interaction of tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). When the total flux reached an average of 1-3E6 for all animals, animals were randomized into groups; 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101 and 6) control conjugate LCQ04/K222R-AcLys-Val-Cit-PABC-Aur0101. A single dose of human anti-BCMA ADC and control conjugate were administered by bolus injection into the tail vein. Animal studies were terminated when limb paralysis, the endpoint of the MM1.S orthotopic model, was observed. Figure 3 shows that a single dose of human anti-BCMA L3.PY/P6E01 antibody conjugated to 1) H7c/N297A/K222R-amino-PEG6-C2-0131 and 2) H7c/N297A/K222R-amino-PEG6-C2-3377 resulted in tumor regression. A single dose of human anti-BCMA L3.PY/P6E01 antibody conjugated with 1) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 2) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101 and 3) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101 results in tumor inhibition.

Accordingly, this study demonstrates that BCMA-ADC treatment induces regression and inhibits progression of multiple myeloma.

Example 6: Anti-BCMA ADCs induce tumor inhibition in an orthotopic model of multiple myeloma

This example also illustrates the in vivo efficacy of anti-BCMA ADC in orthotopic models of KMS12BM multiple myeloma.

An in vivo study of the efficacy of BCMA ADC was performed using the KMS12BM multiple myeloma cell line expressing luciferase and GFP in an orthotopic model. Six- to eight-week-old NSG females were irradiated with 100 cGy and 24 hours after irradiation, ten million KMS12BM LucGFP cells were injected intravenously into the tail vein. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μL per animal at a concentration of 15 mg/mL), followed by isoflurane anesthesia and subsequent whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted by the interaction of tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). When the total flux reached an average of 5E6 across all animals, animals were randomized into groups; 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur010, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131, 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101, and 6) control conjugate LCQ04/K222R-AcLys-Val-Cit-PABC-Aur0101. A single dose of anti-BCMA-ADC and control conjugate was administered by bolus injection into the tail vein. Animal studies were terminated when animals lost more than 15% of total body weight, the endpoint for orthotopic KMS12BM models. In Fig. 4 It is shown that a single dose of human anti-BCMA L3.PY/P6E01 antibody conjugated with 1) H7c/N297A/K222R-amino-PEG6-C2-3377, 2) N297Q/K222R-AcLys-Val-Cit-PABC-Aur0101, 3) LCQ05/K222R-AcLys-Val-Cit-PABC-Aur0101, 4) H7c/N297A/K222R-amino-PEG6-C2-0131 and 5) N297Q/K222R/LCQ05-AcLys-Val-Cit-PABC-Aur0101 results in tumor suppression.

Accordingly, this study also demonstrates that treatment with BCMA-ADC induces regression and inhibits progression of multiple myeloma.

Example 7: Dose-response curve for anti-BCMA ADC in the orthotopic MM1S model

This example also illustrates the in vivo efficacy of anti-BCMA ADC in the orthotopic MM1S multiple myeloma model .

An in vivo study of BCMA ADC efficacy was performed in the MM1.S luciferase- and GFP-expressing multiple myeloma cell line in an orthotopic model. Ten million MM1.S LucGFP cells were injected intravenously via the tail vein into 6- to 8-week-old CB17/SCID females. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μL per animal at a concentration of 15 mg/mL), followed by isoflurane anesthesia and whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted by the interaction of tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). When the total flux reached an average of 1.2E6 across all animals, animals were randomized into groups; 1) 0.1 mg/kg H7c/N297A/K222R-amino-PEG6-C2-0131, 2) 0.38 mg/kg H7c/N297A/K222R-amino-PEG6-C2-0131, 3) 0.75 mg/kg H7c/N297A/K222-amino-PEG6-C2-0131, 4) 1.5 mg/kg H7c/N297A/K222R-amino-PEG6-C2-0131, and 5) 3 mg/kg control conjugate N297Q/K222R-AcLys-VC-0101. A single dose of human anti-BCMA ADC and control conjugate were administered by bolus injection via the tail vein. The animal study was terminated when hindlimb paralysis, the endpoint for the orthotopic MM1.S model, was detected. Figure 5 shows that a single dose of human anti-BCMA COMBO_Rd4_0.6nM_C29 antibody conjugated to groups (1)-(4) above results in tumor regression starting at 0.1 mg/kg and tumor inhibition for up to 100 days starting at 0.75 mg/kg.

Accordingly, this study demonstrates that BCMA-ADC treatment induces tumor regression and tumor inhibition in multiple myeloma.

Example 8: Production and purification of heterodimeric antibodies

This example describes the production and purification of heterodimeric antibodies of the present invention.

The variable region of human specific anti-CD3 antibody was cloned into human IgG1 or IgG2ΔA containing the following mutations: 221R, 228R, and K409R; or 223R, 225R, 228R, and K409R, respectively, and designated as hIgG1 RRR or IgG2ΔA-RRRR.

The variable region of the anti-target antibody was cloned into human IgG1 or IgG2ΔA containing the following mutations: 221E, 228E, L368E or 223E, 225E, 228E and L368E, respectively, and designated as hIgG1EEE or hIgG2ΔA-EEEE.

Heterodimers were prepared by incubating anti-CD3 IgG1 or IgG2ΔA having the hIgG1 RRR or IgG2ΔA-RRRR mutations with the anti-target antibody having the hIgG1EEE or hIgG2ΔA-EEEE mutations in PBS with 1 mM or 2 mM GSH for 24 hours at 37°C as described in International Patent Application PCT/US2011/036419 (WO2011/143545). The heterodimer was purified by ion exchange chromatography as described below.

All heterodimers were purified by ion exchange chromatography. Briefly, analytical ion exchange separation of Fc hetero- and Fc homodimers was performed on an Agilent 1100 Quaternary Pump LC System (Agilent Inc, Santa Clara, CA, USA) equipped with a DIONEX Propac WCX-10G weak cation exchange column (4x50 mm). Proteins were injected in 5% buffer A (20 mM MES pH 5.4) and eluted with a gradient of 25% to 75% buffer B (20 mM MES pH 5.4 and 500 mM NaCl) over a 20-min period at a flow rate of 1 ml/min. Larger scale purification of the Fc heterodimer was performed on an Akta Explorer (GE) equipped with a DIONEX Propac WCX-10G weak cation exchange column (4x250 mm). Proteins were injected in 5% buffer A (20 mM MES pH 5.4) and eluted with a gradient of 15% to 75% buffer B (20 mM MES pH 5.4 and 500 mM NaCl) over a 60 min period at a flow rate of 1 ml/min.

Example 9: Determination of the kinetics and affinity of hCD3/human IgG interactions at 25°C and/or 37°C

In this example, the kinetics and affinity of different anti-CD3 antibodies are determined at 25°C and 37°C.

All experiments were performed on a Bio-Rad Proteon XPR36 surface plasmon resonance biosensor (Bio-Rad, Hercules, CA). Anti-CD3 antibody pools were prepared using an amine coupling method on a Bio-Rad GLC sensor chip similar to that described in Abdiche, et al., Anal. Biochem. 411, 139–151 (2011). The assay temperature for immobilization was 25°C and the electrode buffer was HBS-T+ (10 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.4). Channels were activated in the analyte (horizontal) direction by injecting a mixture of 1 mM ECD and 0.25 mM NHS for 3 min at a flow rate of 30 μL/min. IgG were immobilized on the activated sites by introducing them in the ligand direction (vertical) at 20 μg/ml in 10 mM acetate buffer, pH 4.5, for 1.5 min at 30 μg/ml. The activated surfaces were blocked by introducing 1 M ethanolamine, pH 8.5, in the analyte direction for 3 min at 30 μl/min.

The assay temperature for the hCD3 binding assay was 37°C or 25°C in HBS-T+ electrode buffer supplemented with 1 mg/ml BSA. A kinetic titration method was used for the interaction assay as described by Abdiche, et al. The hCD3 analyte (human CD3) was injected towards the analyte using a series of injections from low to high concentration. The concentrations used were 0.08 nM, 0.4 nM, 2 nM, 10 nM, and 50 nM (5-term series, with a 5-fold dilution factor and an upper concentration of 50 nM). The association time for a given analyte dilution was two minutes. Immediately after injection of 50 nM hCD3, dissociation was monitored for 2 hours. Before the hCD3 analyte injections, buffer was injected 5 times using the same association and dissociation times as in the hCD3 analyte cycles to obtain a control buffer sensorgram for the double standard (double standard as described in Myszka, J. Mol. Recognit. 12, 279-284 (1999)).

Sensorgrams were generated with a double standard and fitted to a 1:1 Langmuir mass transfer titration kinetic model in BIAevaluation version 4.1.1 (GE Lifesciences, Piscataway, NJ). The kinetic parameters and affinities of the various anti-CD3 antibodies of the present invention are presented in Table 9.

Table 9 Antibody ka (1/Mc) huCD3ed at 25°C kd (1/c) huCD3ed at 25°C T ½ (min) with huCD3ed at 25°C KD (nM) with huCD3ed at 25°C H2B4 3.7E+05 2.0E-03 5.8 5.3 Antibody ka (1/Mc) huCD3ed at 37°C kd (1/s) huCD3ed at 37°C T ½ (min) with huCD3ed at 37°C KD (nM) with huCD3ed at 37°C H2B4 4.37E+05 0,01369 0.84 3.14E-08 h2B4-VH-wt VL_TK 3.80E+05 1,40E-02 0.83 3.80E-08 h2B4-VH-Hnps VL_TK 3.90E+05 1,60E-02 0.72 4,10E-08 h2B4-VH-yads VL_TK 2.40E+05 2,10E-02 0.79 8,60E-08 h2B4-VH-yaes VL_TK 2.30E+05 2,30E-02 0.50 1,00E-07 h2B4-VH-yaps VL_TK 2.50E+05 2,30E-02 0.50 9,20E-08 Antibody ka (1/Mc) cyCD3ed at 25°C kd (1/c) cyCD3ed at 25°C T ½ (min) with cyCD3ed at 25°C KD (nM) to cyCD3ed at 25°C H2B4 3.9E+05 1,5E-03 7.7 3.8

Example 10: Flow cytometry of human anti-CD3 bispecific antibodies on B cells and CD8+ T cells

This example demonstrates the efficacy of anti-CD3-anti-CD20 bispecific antibodies in CD20+ cells.

Cynomolgus macaque studies were performed at the Charles River Laboratory, Nevada Preclinical Facilities, in accordance with the Institutional Animal Care and Use Committee. Animals (n=2) were treated by intravenous bolus injection with the bispecific anti-CD20/h2B4 antibody at doses of 500 μg/kg, 100 μg/kg, 20 μg/kg, 2 μg/kg, 0.2 μg/kg, or 0.02 μg/kg. Animals were observed twice daily and at each blood draw. Blood for flow cytometry and cytokine analysis was collected in K2EDTA tubes from a peripheral vessel not used for intravenous administration.

Efficacy was determined by measuring B cells and T cells in peripheral blood by flow cytometry. Whole blood was collected at the indicated time points and maintained at 4°C until analysis. Red blood cells were lysed with ACK buffer (Gibco) for 5 min at room temperature and leukocytes were pelleted by centrifugation. Cells were stained for 1 h at 4°C with a cocktail containing fluorescently labeled antibodies recognizing cyno CD19 (Beckman Coulter), CD45, CD4, CD8, Ki67 (BD Biosciences) in PBS + 2% FBS. For Ki67 analysis, cells were first stained with CD4 and CD8, then fixed/permeabilized with BD cyotfix/cytoperm kit (BD Biosciences) according to the manufacturer's instructions prior to intracellular Ki67 staining. Cells were isolated on a BD LSRII flow cytometer immediately after staining.

The resulting B cell counts were plotted as a percentage of pre-assay B cell counts in Figs. 6A-6F. Prolonged B cell depletion after a single dose was achieved at doses as low as 2 μg/kg. B cell depletion was observed at all doses. The duration of the depletion effect was dose-dependent.

The resulting CD8+ T cell counts were plotted as a percentage of pre-study CD8+ T cell counts in Figs. 7A-7F. Following initial translocation, T cell levels were restored to baseline levels or higher during the course of this study.

Example 11: Flow cytometry of human bispecific anti-CD3 antibodies on CD8+ T cells

This example demonstrates the efficacy of a monovalent anti-CD3 antibody on T cell kinetics and activation.

Studies were conducted in cynomolgus macaques and efficacy was determined by measuring T cells in peripheral blood by flow cytometry as described in Example 3. Cynomolgus macaques (n=2) were injected weekly intravenously with 0.2 μg/kg anti-CD20/h2B4 or NNC (non-specific antibody)/h2B4. In contrast to the CD20-targeted bispecific antibody, NNC/h2B4 had little or no effect on blood CD8+ T cell kinetics as measured by flow cytometry. Ki67 was used as a marker of T cell activation.

The resulting T cell counts were plotted as a percentage of pre-assay CD8+ T cell counts in Fig. 8A and 8B. In CD20/h2B4 bispecific antibody-treated cynomolgus monkeys, Ki67+ T cell levels increased and peaked between days 3 and 7 post-treatment, indicating T cell activation. However, there was no increase in Ki67+ T cell levels in NNC/h2B4-treated cynomolgus monkeys.

Example 12: Flow cytometry of human anti-CD3 bispecific antibodies on B cells

This example demonstrates the impact of anti-CD3 arm affinity on B cell depletion.

Studies were performed in cynomolgus monkeys and efficacy was determined by measuring T cells in peripheral blood by flow cytometry as described in Example 10. Bispecific antibodies were generated with an anti-CD20 arm paired with four arms of an anti-CD3 antibody with different affinities. Following a single intravenous dose of 0.2 μg/kg, efficacy was determined by measuring B cells in peripheral blood by flow cytometry.

In Fig. 9A-9D, the resulting B cell counts were plotted as a percentage of the pre-assay B cell counts. The efficiency of B cell depletion correlates with the affinity of the anti-CD3 arm.

Example 13: In vitro study of a bispecific antibody against T-cell-mediated killing of BCMA-positive cells

This example illustrates the in vitro cytotoxicity of bispecific anti-BCMA/CD3 hIgG2ΔA in BCMA-positive cells.

Human anti-BCMA (P5A2, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C16, P5C1, C01_Rd4_6nM_C12, COMBO_Rd4_0.6nM_C22, Combo_Rd4_0.6nM_C29, L3PY/H3TAQ, and A02_Rd4_6nM_C01) and human anti-CD3 (H2B4) antibodies were expressed as human IgG2dA engineered with EEEE for bispecific exchange as described in Example 8.

CD3+ T cells from PBMCs were negatively selected using a human pan T cell isolation kit (Miltenyi, San Diego CA). Target (KMS12PE, L363, and Molp8) expressing cells and CD3+ T cells were seeded on clear U-bottom plates at 20,000 and 100,000 cells/well, respectively. Cells were treated with 10-fold serially diluted bispecific antibody in triplicate. Cell killing was determined by the CytoTox ^96® non-radioactive cytotoxicity assay (Promega, Madison WI) 20 hours after treatment. Cellular cytotoxicity was determined as a percentage of the sum of untreated effector and target control wells. EC50 was calculated using Prism software. Table 10 shows that all human anti-BCMA_H2B4 bispecific antibodies exhibit cell killing activity in BCMA-expressing cells.

Table 10 Anti-BCMA bispecific KMS12PE (BCMA+++) KMS12BM (BCMA+) MOLP8 (MOLP8+) P5A2 0.371 1,509 5,231 A02_Rd4_0.6nM_C01 0.073 0.078 0,550 A02_Rd4_6nM_C16 0.186 0.052 0.315 P5C1 0.581 4,117 N/A C01_Rd4_6nM_C12 0.189 0.415 0,850 COMBO_Rd4_0.6nM_C22 0.115 0.049 0.065 Combo_Rd4_0.6nM_C29 0.175 0.049 0.201 L3PY/H3TAQ 0,070 0.055 0.337 A02_Rd4_6nM_C01 UND 0.057 0,060

UND - not determined; N/A means that EC50 cannot be determined

Example 14: In vitro characterization of a cloned anti-CD3 antibody from a mouse hybridoma

This example illustrates in vitro T cell activation/proliferation of anti-CD3 cloned from a mouse hybridoma in human/cynomolgus monkey PBMC cells for antibody screening .

Human anti-CD3 antibodies were cloned from immunized mice, expressed as mouse IgG1, and purified using protein A affinity beads. Human/cynomolgus monkey peripheral blood mononuclear cells (hu/cyPBMC) were obtained by Ficoll density gradient centrifugation (density: 1.083 g/mL, GE) from blood filters obtained from local blood banks. Red blood cells were removed by incubation in LCK buffer (155 mM NH ₄ Cl, 10 mM KHCO ₃ , 100 mM EDTA, Gibco) for 3 min at room temperature. Cells were centrifuged for 5 min at 600 g. The supernatant containing lysed red blood cells was discarded and PBMC were washed twice in 50 ml 1× PBS/1% BSA/1 mM EDTA. The pelleted cells were adjusted to ¹⁰⁷ cells/ml in culture medium, X-VIVO-15, serum-free medium (Lonza), and PBMC were seeded at ¹⁰⁶ (100 μl) per well in round-bottomed 96-well culture plates. Selected Abs were 10x serially diluted from 1000 ng to 1 ng per ml for mixing with human PBMC and 5x serially diluted from 5000 ng to 200 ng per ml for mixing with cynomolgus monkey PBMC. For T cell PBMC proliferation assay by ³ H-thymidine incorporation, 2-day cultures were performed in triplicate. During the last 16 hours of culture, ³ H-thymidine (0.5 mCi/well) was added and incorporation was determined. Cells were collected and lysed, and DNA was captured on a glass fiber filter. Radioactivity (cpm), as a measure of proliferation, was determined in a beta scintillation counter.

Figures 10A and 10B show that selected anti-CD3 1A4, 1C10, 2B4, and 7A3 antibodies had thymidine incorporation in human and cynomolgus monkey PBMCs. Table 11 shows their KD measured by Biacore. In vitro characterization showed that anti-CD3 1C10 and 2B4 antibodies were similar to the positive control SP34 anti-CD3 antibody (BD Biosciences).

Table 11. Kinetic results for anti-xCD3e ab/bsc_hCD3ed for data corresponding to 80 nM - 0.64 nM Ligand ka kd t _1/2 (min) KD (nM) UCHT1 (+) 1.80E+05 < 8.55E-04 > 13.5 < 4.74 2B4 3.74E+05 2.74E-03 4.21 7.33 1C10 2.96E+05 2,37E-03 4.88 8.00 SP34 (+) 2.84E+05 3.04E-03 3.80 10.73 7A3* 82.70 1A4* 99.97

Note:

Data are shown for satisfactory kinetic matches only. (+) = positive controls

*Kinetic determinations are rough estimates because the antibody is heterogeneous. Only steady state affinity is measured.

Example 15: In vitro study of the effect of a bispecific antibody on T-cell-mediated killing

This example illustrates the in vitro cytotoxicity of anti-EpCam/CD3 bispecific antibodies in SW480 mixed with isolated pan-T cells from healthy donors.

A: Anti-CD antibodies h2B4-1d, TK, hnpsTK and yaesTK

Human anti-CD3 (h2B4-1d (or h2B4), h2B4-TK (or h2B4-VH-wt VL_TK), h2B4-hnpsTK (or h2B4-VH-hnps VL_TK) and h2B4-yaesTK (or h2B4-VH-yaes VL_TK)) antibodies and human anti-EpCam antibodies were expressed as human IgG2dA engineered with RRRR or EEEE for bispecific exchange as described in Example 8.

SW480 was chosen as the target cell line for the cell death assay, and effector and human T cells were purified from human peripheral blood mononuclear cells (huPBMC). Target and effector cells were seeded in 96-well round-bottom plates in cell culture medium containing 5% fetal bovine serum (FBS). The number of target cells was maintained constant at ^2x104 cells/well. A 10-fold serial dilution of the bispecific antibody, from 3 μg to 3 pg per ml, was added to the cells in triplicate. The total reaction volume was 200 μl. Reaction mixtures were incubated for 48 and 72 h. For cytotoxicity analysis, lactate dehydrogenase (LDH), a stable cytosolic enzyme released upon cell lysis, was quantified using the CytoTox ^96® Non-Radioactive Cytotoxicity Assay Kit (Promega, G1780). The plate was read using a Vmax kinetic microplate reader (Molecular Devices) at 490 nM. Optimum density values were corrected for background media and spontaneous lysis of target and effector cells. Specific cytotoxicity was calculated according to the following formula:

[% spec. lysis = sample reading at 490 nM - E+T mixed control)/(total T cell lysis reading at 490 nM - control medium) x 100%]

Figures 11A and 11B show that all human anti-EpCam_h2B4 bispecific antibodies had cell killing activity in vitro, and antibody-mediated T cell activation was monitored by a T cell activation marker. Table 12A shows their EC50 values. Table 12B shows the Biacore KD in bispecific antibody format.

Table 12A Day 2: EC50 (nM) h2B4-1d_Ep 537.1 h2B4-TK_Ep 405.3 h2B4-hnpsTK_Ep 424.7 h2B4-yaesTK_Ep 1126

Table 12B: Summary table for kinetic parameters of anti-CD3 hIgG2dA bispecific antibodies at 37°C Sample ID - bschIgG2dA ka (1/Mc) kd (1/c) t1/2 (min) KD (nM) h2B4-1d_Ep 5.86E+05 2,37E-02 0.49 40.4 h2B4-TK_Ep 6.87E+05 2,13E-02 0.54 31.0 h2B4-hnpsTK_Ep 7.54E+05 2,35E-02 0.49 31.2 h2B4-yaesTK_Ep 4.74E+05 2,58E-02 0.45 54.4

B: Anti-CD antibodies m25A8, h25A8-B12 and h25A8-B13

Human anti-CD3 h2B4(h2B4_1d) and h25A8 (m25A8, h25A8-B12 and h25A8-B13) and human anti-EpCam antibodies were expressed as human IgG2dA engineered with RRRR or EEEE for bispecific exchange as described in Example 8.

Figures 11C and 11D show that all human anti-EpCam_anti-CD3 bispecific antibodies have in vitro cell killing activity, and antibody-mediated T cell activation was monitored using a T cell activation marker. Table 12C shows the EC50 value for in vitro cell killing. Table 12D shows the Biacore kinetics in bispecific antibody format at 37°C. Table 12E shows the in vitro characterization using SEC-MALS (size-exclusion chromatography with multi-angle light scattering) and DSC (differential scanning calorimetry).

Table 12C: EC50 for cell killing in vitro Day 1: EC50 (nM) h2B4-1d_Ep 52.9 m25A8_Ep 127.6 h25A8-B12_Ep 99.36 h25A8-B13_Ep 57.11

Table 12D: Summary table of the kinetics of anti-CD3 hIgG2dA bispecific antibodies at 37°C Sample ID - bschIgG2dA ka (1/Mc) kd (1/c) t1/2 (min) KD (nM) h25A8-B5_Ep 1.29E+06 5,81E-02 0.20 45.0 h25A8-B8_Ep 1.19E+06 2,22E-02 0.52 18.7 h25A8-B12_Ep 1.15E+06 2,41E-02 0.48 21.0 h25A8-B13_Ep 1.20E+06 2,19E-02 0.53 18.3 h25A8-C8_Ep 1.20E+06 3.01E-02 0.38 25.1 h2B4-1d_Ep 5.86E+05 2,37E-02 0.49 40.4

Table 12E: In vitro characterization SEC-MALS DSC % monomers % of units Tm1 C
(CH2) Tm2 C
(Fab) Tm3 C
(CH3) m28A8 99.9 0,1 66.3 67.8 76.1 hIgG2dA_h25A8-B12 99.2 0.8 70.91 73.06 78.31 hIgG2dA_h25A8-B13 99.5 0.5 70.88 72.86 78.2 hIgG2dA-h2B4TK 98.8 1.4 70.2 74.5 79.4

Example 16: In vitro study of the effect of a bispecific antibody on T-cell-mediated killing of patient-derived primary myeloma samples

This example illustrates the in vitro cytotoxicity of anti-BCMA/CD3 bispecific antibodies in primary myeloma cells .

Human anti-BCMA (P5A2, A02_Rd4_0.6nM_C01, A02_Rd4_6nM_C16, Combo_Rd4_0.6nM_C29, and P6E01 L3PY/H3TAQ) and human anti-CD3 (h2B4) antibodies were expressed as human IgG2dA engineered with EEEE or RRRR for bispecific exchange as described in Example 8.

Total bone marrow mononuclear cells from myeloma patients were seeded in clear U-bottom plates at a total bone marrow mononuclear cell count of 3,000-5,000 myeloma cells/well. Cells were treated with 10-fold serially diluted bispecific antibody. Five days after treatment, total viable cells were determined by flow cytometry using CD138 and CD38 antibodies (Biolegend, CA). Cells were incubated with antibodies at 4°C in PBS + 0.5% FBS for 30 minutes. Cells were washed and Fixable Viability Dye eFluor 780 (eBioscience, Inc., CA) in PBS was added to the cells for 30 minutes at 4°C. Before cell harvesting on a BD flow cytometer, cells were washed and CountBright Absolute Counting Beads (Molecular Probes, OR) were added. The percentage of viable cells was determined as the number of viable cells in treated versus untreated wells using counting beads. EC50 was calculated using Prism software.

Table 13A shows that all human anti-BCMA_h2B4 bispecific antibodies have cell killing activity in patient myeloma samples and patient T cells are functional effector cells. Table 13B shows killing for one anti-BCMA bispecific antibody in patient multiple myeloma samples with different effector to target (E:T) ratios.

Table 13A Anti-BCMA bispecific
(Patient MM00146) EC50 (nM) P6E01 L3PY/H3TAQ 0,015 P5A2 0.946 A02_Rd4_0.6nM_C01 0.064 A02_Rd4_6nM_C16 0.029 NNC_2b41d hIgG2dA 3,302

Table 13B Patient Combo_Rd4_0.6nM_C29 EC50 (nM) E:T MM00146 0.035 1:1 MM00147 0.031 2:1 MM00151 0.02 3:1 MM00152 0.289 1:2

Example 17: ELISPOT of antibody-secreting cells from cynomolgus monkeys injected with anti-BCMA/CD3 bispecific antibodies

This example illustrates the depletion of IgG-secreting cells in cynomolgus monkeys using anti-BCMA/CD3 bispecific antibodies.

Cynomolgus macaques (n=2) were administered bispecific anti-BCMA_CD3 antibodies (h2B4-VH-hnps VL_TK), A02_Rd4_0.6nM_C01/H2B4 and Combo_Rd4_0.6nM_C29/H2B, via intravenous bolus injection at two doses, on days 1 and 8, at 100 μg/kg and 300 μg/kg. Animals were examined twice daily and at each time of blood collection. Peripheral blood mononuclear cells (PBMC) were collected on days -6, 4 and 10. Bone marrow samples were collected on day 10, when the animals were autopsied.

Blood was collected into Becton Dickinson® CPT™ Cell Preparation Tubes containing sodium heparin and a density gradient, and PBMC were then collected at the edge of the gradient after centrifugation.

The bone marrow sample (from the femur) was collected by washing with approximately 5 ml of 100% fetal bovine serum (FBS) and then single-cell suspensions were prepared by suspending the washed bone marrow in 50 ml of buffer.

Cells were counted using a Cellometer Vision and adjusted with RPMI 1640 complete culture medium to a concentration of ^5x106 cells/ml for PBMC and ^2x106 cells/ml for bone marrow cells. Total IgG-secreting cells were counted using the Mabtech ELISpot ^BASIC kit (#3850-2HW-Plus). Briefly, PBMC or bone marrow cells were added to wells in triplicate at a defined concentration (PBMC at ^5x105 /well and bone marrow cells at ^2x105 /well), and then the cells were serially diluted in the plate. After overnight incubation, the plates were washed and biotinylated antibodies were added for detection. The plates were incubated for 2 hours and streptavidin-HRP was added for 1 hour. IgG spots were visualized using TMB (tetramethylbenzidine) substrate solution and counted using the ImmunoSpot Imaging Analyzer (CTL) and ImmunoSpot 5.1 software. Data are expressed as the mean (+/- SD) number of IgG-secreting cells from three replicates.

The resulting numbers of IgG-secreting cells in PBMCs and bone marrow are shown in Tables 14A and 14B, respectively. Depletion of IgG-secreting cells was observed for the anti-BCMA/CD3 bispecific antibodies in both PBMCs compared to pre-treatment and in bone marrow compared to vehicle and negative controls. A dose-dependent effect was observed in bone marrow.

Table 14A PBMC Day -6 4 10 Carrier 204, 320 323, 538 127, 137 0.1 mg/kg Combo_Rd4_0.6nM_C29 107, 128 5, 0 0,0 0.3 mg/kg Combo_Rd4_0.6nM_C29 304, 362 0.5 0,0 0.1 mg/kg A02_Rd4_0.6nM_C01 447, 672 16, 27 21.10 0.3 mg/kg A02_Rd4_0.6nM_C01 512, 224 25, 8 0, 0 0.3 mg/kg NNC_2b41d 139, 361 1345, 1154 992, 928

Table 14B Bone marrow 10th day Carrier 2614, 8093 0.1 mg/kg Combo_Rd4_0.6nM_C29 35, 18 0.3 mg/kg Combo_Rd4_0.6nM_C29 35, 22 0.1 mg/kg A02_Rd4_0.6nM_C01 996, 960 0.3 mg/kg A02_Rd4_0.6nM_C01 2170, 93 0.3 mg/kg NNC_2b41d 5980, 2893

Example 18: Anti-BCMA/CD3 bispecific antibodies induce tumor regression and inhibition in the MM1.S tumor model

This example illustrates tumor regression and inhibition in the MM1.S orthotopic myeloma model.

In vivo efficacy testing of BCMA bispecific antibodies was performed with MM1.S expressing luciferase and GFP in an orthotopic model. One day before tumor cell injection, mice were irradiated with 100 cGy using an RS 2000 Biological Research Irradiator (RAD Source Technologies, GA). Five million MM1.S LucGFP cells were injected intravenously via the tail vein into 6- to 8-week-old Nod/Scid/IL2Rg ^-/- (NSG) females. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μL per animal at a concentration of 15 mg/mL) followed by isoflurane anesthesia and whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted by the interaction of tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). When the total flux reached an average of 15E6 across all animals, animals were treated by tail vein bolus injection with 20 million expanded PBMC-derived T cells. Briefly, pan-T cells purchased from AllCells (Alameda, CA) were activated with the Human T Cell Activation/Expansion Kit (Miltenyi, San Diego, CA). After 3 days, 15 U/mL IL2 (ebioscience, San Diego, CA) was added every other day until day 11. Cells were then harvested, activation/expanding beads were removed with a magnet, and cells were washed and resuspended in PBS. One day after T cell injection, mice were imaged as described above and animals were randomized into groups of seven mice; A02_Rd4_0.6nM_C01 at 0.03 mg/kg and 0.3 mg/kg and Combo_Rd4_0.6nM_C29 at 0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg. A single dose of human anti-BCMA/CD3 (h2B4-VH-wt VL_TK) bispecific antibody and negative control (NNC) bispecific antibody were administered as a bolus injection into the tail vein. Animals were sacrificed when hindlimb paralysis was detected, the endpoint for the MM1.S orthotopic model. In Fig. 12 showed that a single dose of human anti-BCMA/CD3 bispecific antibody resulted in dose-dependent tumor regression.

Example 19: Two doses of anti-BCMA/CD3 bispecific antibody induce tumor regression in the aggressive Molp8 tumor model

This example illustrates tumor regression induced by two doses of anti-BCMA/CD3 bispecific antibodies in an orthotopic Molp8 myeloma model.

An in vivo study of the efficacy of BCMA bispecific antibodies was performed with Molp8 expressing luciferase and GFP in an orthotopic model. Two million Molp8 LucGFP cells were injected intravenously into the tail vein of 6-8-week-old NSG females. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μl per animal at a concentration of 15 mg/ml) followed by isoflurane anesthesia and subsequent whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted from the interaction of tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). When the total flux reached an average of 25E6 for all animals, they were randomized into three groups of seven mice; 1) Combo_Rd4_0.6nM_C29, 0.3 mg/kg, 2) Combo_Rd4_0.6nM_C29, 0.3 mg/kg, two doses, and 3) NNC_2B4, 0.3 mg/kg, two doses. Animals were injected with 20 million expanded T cells via a bolus injection into the tail vein as described in Example 18. Two days after T cell injection, mice were injected with the bispecific antibodies. Animals were sacrificed when they exhibited greater than 15% weight loss, the endpoint for the orthotopic Molp8 model. Figure 13 shows that two doses of human anti-BCMA/CD3 (h2B4-VH-wt VL_TK) bispecific antibody resulted in enhanced tumor regression.

Example 20: Anti-BCMA/CD3 bispecific antibodies in combination with standard treatment for multiple myeloma in an orthotopic Molp8 tumor model

This example demonstrates no adverse effects on anti-BCMA/CD3 bispecific antibodies when combined with bortezomib or lenalidomide and superior efficacy with anti-BCMA/CD3 bispecific antibodies compared to the combination of bortezomib and lenalidomide.

In vivo efficacy studies of BCMA bispecific antibodies were performed with Molp8 expressing luciferase and GFP in an orthotopic model. Two million Molp8 LucGFP cells were injected intravenously into the tail vein of 6-8-week-old female NSGs. Intraperitoneal injection of D-luciferin (Regis Technologies, Morton Grove, IL) (200 μl per animal at a concentration of 15 mg/ml) followed by isoflurane anesthesia and subsequent whole-body bioluminescence imaging (BLI) allowed monitoring of tumor burden. Bioluminescent signals emitted from the interaction of tumor cell-expressed luciferase and luciferin were captured by imaging using IVIS Spectrum CT (Perkin Elmer, MA) and quantified as total flux (photons/sec) using Living Image 4.4 (Caliper Life Sciences, Alameda, CA). Animals were administered 20 million expanded T cells via a bolus injection into the tail vein on day 7 as described in Example 18. Two days after T cell injection, mice were imaged and randomized into five groups of seven mice with a mean 17E6 total flux/group: 1) Combo_Rd4_0.6nM_C29, 0.3 mg/kg, 2) Combo_Rd4_0.6nM_C29, 0.3 mg/kg and 1 mg/kg bortezomib, 3) Combo_Rd4_0.6nM_C29, 0.3 mg/kg and 50 mg/kg lenalidomide, 4) 1 mg/kg bortezomib and 50 mg/kg lenalidomide, and 5) vehicle. Anti-BCMA/CD3 (in PBS) was administered by tail vein bolus injection, bortezomib (in PBS) was administered by intraperitoneal injection, and lenalidomide (30% PEG400/5% propylene glycol/0.5% Tween80) was administered by gavage. Vehicle consisted of 30% PEG400/5% propylene glycol/0.5% Tween80 and was administered by gavage. Animals were sacrificed when they had more than 15% weight loss, the endpoint for the Molp8 orthotopic model. Figure 14 shows that the combination of anti-BCMA/CD3 (h2B4-VH-hnps VL-TK) bispecific antibody with bortezomib or lenalidomide did not adversely affect the efficacy of the anti-BCMA/CD3 bispecific antibody. In this model, anti-BCMA/CD3 bispecific antibody alone or in combination with lenalidomide or bortezomib is more effective than the combination of lenalidomide and bortezomib.

Example 21: In vitro study of anti-BCMA/CD3 bispecific antibody in combination with lenalidomide, carfilzomib or doxorubicin in the OPM2 cell line

This example demonstrates the absence of adverse effects on T cell function when combined with carfilzomib, doxorubicin and lenalidomide on the activity of the anti-BCMA/CD3 bispecific antibody compared to the bispecific antibody alone.

CD3+ T cells from PBMCs were selected by negative selection using a human pan T cell isolation kit (Miltenyi, San Diego CA). OPM2 cells and CD3+ T cells were seeded in clear U-bottomed plates at 20,000 and 100,000 cells/well, respectively. OPM2 and CD3+ T cells were first incubated with standard drugs for 2 hours at 37°C. 1.56 nM carfilzomib and 6.25 nM doxorubicin were dissolved in PBS containing 0.02% DMSO. Lenalidomide was dissolved in PBS containing 0.1% DMSO at 195 nM. Cells were treated with 10-fold serially diluted bispecific antibody. Three days after treatment, total viable cells were determined by flow cytometry using antibodies to CD138, CD4, and CD8 (Biolegend). Cells were incubated with antibodies at 4°C in PBS + 0.5% FBS for 30 min. Cells were washed and Fixable Viability Dye eFluor 780 (eBioscience, Inc., CA) in PBS was added to the cells for 30 min at 4°C. Before cell isolation on a BD flow cytometer, cells were washed and CountBright Absolute Counting Beads (Molecular Probes, OR) were added. The percentage of viable cells was determined as the number of viable cells in treated versus untreated wells using counting beads. In Fig. 15A, 15B and 15C, respectively, show that carfilzomib, lenalidomide and doxorubicin do not adversely affect the function of Combo_Rd4_0.6nM_C29-CD3 (h2B4-VH-hnps VL-TK) bispecific antibody in OPM2 cells.

Example 22: In vitro study of anti-BCMA/CD3 bispecific antibody in combination with lenalidomide and carfilzomib in the KMS12BM cell line

This example illustrates the synergistic effect on function of an anti-BCMA/CD3 bispecific antibody when combined with carfilzomib and lenalidomide compared to each molecule alone.

CD3+ T cells from PBMCs were selected by negative selection using a human pan T cell isolation kit (Miltenyi, San Diego CA). KMS12BM cells and CD3+ T cells were seeded in clear U-bottomed plates at 20,000 and 100,000 cells/well, respectively. Cells were treated with 0.017 nM anti-BCMA/CD3 bispecific antibodies in combination with carfilzomib and a range of lenalidomide concentrations. 1.25 nM carfilzomib was diluted in PBS containing 0.02% DMSO. Lenalidomide was dissolved in PBS containing 0.1% DMSO starting at 4 μM, diluted 4-fold. Three days after treatment, total viable cells were determined by flow cytometry using antibodies to CD138, CD4, and CD8 (Biolegend, CA). Cells were incubated with antibodies at 4°C in PBS + 0.5% FBS for 30 min. Cells were washed and Fixable Viability Dye eFluor 780 (eBioscience, Inc., CA) in PBS was added to the cells for 30 min at 4°C. Before cell isolation on a BD flow cytometer, cells were washed and CountBright Absolute Counting Beads (Molecular Probes, OR) were added. The percentage of viable cells was determined as the number of viable cells in treated versus untreated wells using counting beads. In Fig. 16 showed that at the concentrations tested, carfilzomib, lenalidomide, and the anti-BCMA/CD3 (h2B4-VH-hnps VL-TK) bispecific antibody had little cytotoxic function when used alone. When all three agents were combined, a synergistic effect was observed in KMS12BM cells that was dose-dependent on the lenalidomide concentration.

Although the disclosed principles have been described with reference to various applications, methods, kits and compositions, it will be appreciated that various changes and modifications may be made without departing from the principles set forth herein and the invention claimed below. The above examples are provided to better illustrate the disclosed principles and are not intended to limit the scope of the disclosure herein. Although the present teaching has been described in terms of such typical embodiments, one skilled in the art will readily appreciate that numerous variations and modifications of these typical embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the present disclosure.

All references cited herein, including patents, patent applications, documents, textbooks, and the like, and references cited therein, to the extent not already incorporated, are hereby incorporated by reference in their entirety. In the event that one or more of the incorporated literature and the like differs from or conflicts with this application, including, but not limited to, defined terms, use of a term, methods described, and the like, this application shall control.

In the foregoing description and examples, certain specific embodiments of the invention have been described in detail and the best mode contemplated by the inventors has been described. It should be understood, however, that no matter how detailed the foregoing is set forth in the 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.

--->

LIST OF SEQUENCES

<110> PFIZER INC.

Kuo, Tracy C

Chaparro Riggers, Javier

Chen, Wei

Chen, Amy S

Pascua, Edward D

Van Blarcom, Thomas J

Boustany, Leila M

Ho, Wei-Hsien

Yeung, Yik A

Strop, Pavel

Rajpal, Arvind

<120> THERAPEUTIC ANTIBODIES AND THEIR USES

<130> PC72209-02

<150> US 62/146,504

<151> 2015-04-13

<150> US 62/146,843

<151> 2015-04-13

<150> US 62/301,582

<151> 2016-02-29

<160> 502

<170> PatentIn version 3.5

<210> 1

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 1

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 2

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 2

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 3

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 3

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ala Gln Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 4

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 4

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys His Tyr Gly Trp Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 5

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 5

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 6

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 6

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 7

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 7

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Arg Val Ser Pro Ile Ala Ala Leu Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 8

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 8

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ala Pro Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 9

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 9

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 10

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 10

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 11

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 11

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys His Tyr Gly Trp Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 12

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 12

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 13

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 13

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 14

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 14

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asp Phe

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 15

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 15

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys His Tyr Gly Trp Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 16

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 16

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 17

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 17

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 18

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 18

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Pro Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 19

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 19

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala His

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 20

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 20

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Phe

20 25 30

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 21

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 21

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro His

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 22

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 22

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys Tyr Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 23

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 23

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Lys Phe Tyr Pro Tyr Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 24

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 24

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Arg

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 25

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 25

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Tyr Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 26

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 26

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Gln Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 27

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 27

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Leu Thr Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 28

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 28

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser His Ala Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 29

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 29

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Leu

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ser Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 30

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 30

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Tyr Ala Gly Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 31

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 31

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Ala Ala Glu Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 32

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 32

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Val Ser Pro Ile Ala Ala Gln Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 33

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 33

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 34

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 34

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 35

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 35

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Ala Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 36

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 36

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 37

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 37

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Met Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 38

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 38

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 39

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 39

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Phe Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 40

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 40

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asp Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Thr Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 41

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 41

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Gly Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 42

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 42

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Thr Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 43

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 43

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Tyr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 44

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 44

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 45

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 45

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Val Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 46

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 46

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 47

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 47

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Leu Asp Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 48

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 48

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Val Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 49

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 49

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Val Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 50

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 50

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Asp Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 51

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 51

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Leu Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 52

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 52

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Lys Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 53

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 53

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Thr Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 54

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 54

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 55

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 55

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Tyr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 56

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 56

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Gly Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 57

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 57

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Glu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 58

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 58

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Val Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 59

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 59

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Glu Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Gly Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 60

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 60

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Cys Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 61

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 61

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Glu Met Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala His Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 62

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 62

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Phe Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Thr Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 63

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 63

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 64

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 64

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Trp Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 65

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 65

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Gln

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 66

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 66

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Met Ser Ser Gly Gly Pro Leu Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ala Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 67

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 67

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Val Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 68

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 68

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Met Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 69

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 69

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Gly Pro Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 70

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 70

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Tyr Arg Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 71

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 71

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Trp Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 72

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 72

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 73

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 73

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 74

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 74

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 75

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 75

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Phe Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 76

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 76

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 77

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 77

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Thr Ser Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 78

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 78

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 79

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 79

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Glu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Val Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 80

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 80

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Tyr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Pro Pro

85 90 95

Leu Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 81

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 81

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 82

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 82

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Phe Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 83

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 83

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Trp Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 84

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 84

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Trp Leu Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Glu Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 85

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 85

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 86

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 86

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Leu

20 25 30

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 87

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 87

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Thr Val Gly Ser Gly Gly Ser Ile Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 88

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 88

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Ala Cys Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 89

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 89

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Cys Asp Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Arg Ser Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 90

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 90

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ala Val Pro Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Phe Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 91

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 91

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Cys Ser Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Phe Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 92

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 92

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 93

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 93

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Val Arg Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Lys Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 94

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 94

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Ala

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Cys Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 95

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 95

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Ile His Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 96

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 96

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Trp Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Cys Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 97

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 97

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala His Ile Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 98

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 98

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 99

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 99

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Pro Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 100

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 100

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Pro

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 101

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 101

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 102

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 102

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Pro Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 103

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 103

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Glu Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 104

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 104

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Phe Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 105

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 105

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Gln

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 106

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 106

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Thr Trp Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 107

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 107

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Lys Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 108

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 108

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Val

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Arg Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 109

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 109

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ile Ala Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Val Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 110

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 110

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Leu Phe Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 111

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 111

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Pro Arg Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Asp Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 112

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 112

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 113

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 113

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Glu Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 114

<211> 114

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 114

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ala Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser

<210> 115

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 115

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 116

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 116

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Met

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 117

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 117

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Gly Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 118

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 118

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ala Asp Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 119

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 119

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Pro Ile Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Gly Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 120

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 120

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Asp Ser Gly Gly Phe Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 121

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 121

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Glu Phe Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 122

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 122

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 123

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 123

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Met Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 124

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 124

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Ser Ser Thr

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Tyr Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 125

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 125

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Cys Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 126

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 126

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Gly Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 127

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 127

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ala Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Ser Leu Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 128

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 128

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Val Arg

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Trp Pro

85 90 95

Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 129

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 129

Ser Tyr Ala Met Thr

1 5

<210> 130

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 130

Gly Phe Thr Phe Gly Ser Tyr

1 5

<210> 131

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 131

Gly Phe Thr Phe Gly Ser Tyr Ala Met Thr

1 5 10

<210> 132

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 132

Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 133

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 133

Ser Gly Ser Gly Gly Asn

1 5

<210> 134

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 134

Val Ser Pro Ile Ala Ser Gly Met Asp Tyr

1 5 10

<210> 135

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 135

Val Ser Pro Ile Ala Ala Gln Met Asp Tyr

1 5 10

<210> 136

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 136

Val Ser Pro Ile Ala Ala Leu Met Asp Tyr

1 5 10

<210> 137

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 137

Val Ser Pro Ile Ala Ala Pro Met Asp Tyr

1 5 10

<210> 138

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 138

Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Arg Lys

1 5 10 15

Gly

<210> 139

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 139

Ala Ile Asp Tyr Ser Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 140

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 140

Asp Tyr Ser Ser Gly Asn

1 5

<210> 141

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 141

Ala Ile Ser Tyr Gln Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 142

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 142

Ser Tyr Gln Gly Gly Asn

1 5

<210> 143

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 143

Ala Ile Ser Leu Thr Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 144

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 144

Ser Leu Thr Gly Gly Asn

1 5

<210> 145

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 145

Ala Ile Ser His Ala Gly Gly Asn Thr Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 146

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 146

Ser His Ala Gly Gly Asn

1 5

<210> 147

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 147

Ala Ile Ser Gly Ser Gly Gly Asn Thr Phe Tyr Ala Asp Gln Leu Lys

1 5 10 15

Gly

<210> 148

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 148

Val Ser Pro Ile Tyr Ala Gly Met Asp Tyr

1 5 10

<210> 149

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 149

Val Ser Pro Ile Ala Ala Glu Met Asp Tyr

1 5 10

<210> 150

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 150

Ser Tyr Ala Met Asn

1 5

<210> 151

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 151

Gly Phe Thr Phe Ser Ser Tyr

1 5

<210> 152

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 152

Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn

1 5 10

<210> 153

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 153

Ala Ile Ser Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 154

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 154

Ser Asp Ser Gly Gly Ser

1 5

<210> 155

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 155

Tyr Trp Pro Met Asp Ile

1 5

<210> 156

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 156

Ser Tyr Pro Met Ser

1 5

<210> 157

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 157

Gly Phe Thr Phe Ser Ser Tyr Pro Met Ser

1 5 10

<210> 158

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 158

Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 159

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 159

Gly Gly Ser Gly Gly Ser

1 5

<210> 160

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 160

Ala Ile Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 161

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 161

Tyr Trp Pro Met Asp Ser

1 5

<210> 162

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 162

Ala Ile Gly Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 163

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 163

Ala Ile Ser Asp Ser Gly Gly Ser Ala Trp Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 164

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 164

Tyr Trp Pro Met Ser Leu

1 5

<210> 165

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 165

Ala Ile Ser Asp Phe Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 166

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 166

Ser Asp Phe Gly Gly Ser

1 5

<210> 167

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 167

Ala Ile Thr Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 168

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 168

Thr Ala Ser Gly Gly Ser

1 5

<210> 169

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 169

Ala Ile Ser Asp Ser Gly Gly Ser Arg Trp Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 170

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 170

Tyr Trp Pro Met Thr Pro

1 5

<210> 171

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 171

Ala Val Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 172

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 172

Leu Asp Ser Gly Gly Ser

1 5

<210> 173

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 173

Tyr Trp Pro Met Ser Asp

1 5

<210> 174

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 174

Ala Ile Ser Asp Ser Gly Gly Ser Lys Trp Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 175

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 175

Ala Ile Ser Asp Ser Gly Gly Ser Gly Trp Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 176

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 176

Ala Ile Ser Asp Ser Gly Gly Ser Cys Trp Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 177

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 177

Ala Ile Phe Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 178

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 178

Phe Ala Ser Gly Gly Ser

1 5

<210> 179

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 179

Ser Gly Trp Gly Gly Ser

1 5

<210> 180

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 180

Ala Ile Met Ser Ser Gly Gly Pro Leu Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 181

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 181

Met Ser Ser Gly Gly Pro

1 5

<210> 182

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 182

Tyr Trp Pro Met Ala Leu

1 5

<210> 183

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 183

Ala Ile Leu Met Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 184

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 184

Leu Met Ser Gly Gly Ser

1 5

<210> 185

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 185

Ala Ile Ser Asp Ser Gly Gly Tyr Arg Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 186

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 186

Ser Asp Ser Gly Gly Tyr

1 5

<210> 187

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 187

Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 188

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 188

Leu Ser Ser Gly Gly Ser

1 5

<210> 189

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 189

Tyr Trp Pro Met Ser Pro

1 5

<210> 190

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 190

Ala Ile Gly Gly Ser Gly Gly Trp Ser Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 191

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 191

Gly Gly Ser Gly Gly Trp

1 5

<210> 192

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 192

Ala Thr Val Gly Ser Gly Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 193

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 193

Val Gly Ser Gly Gly Ser

1 5

<210> 194

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 194

Ala Ile Gly Gly Ser Gly Gly Ser Ile His Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 195

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 195

Ala His Ile Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 196

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 196

Ile Gly Ser Gly Gly Ser

1 5

<210> 197

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 197

Tyr Trp Pro Met Asp Pro

1 5

<210> 198

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 198

Ala Ile Gly Gly Ser Gly Gly Ser Leu Gly Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 199

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 199

Ala Ile Gly Gly Ser Gly Thr Trp Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 200

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 200

Gly Gly Ser Gly Thr Trp

1 5

<210> 201

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 201

Ala Leu Phe Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 202

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 202

Phe Gly Ser Gly Gly Ser

1 5

<210> 203

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 203

Ala Ala Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 204

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 204

Leu Gly Ser Gly Gly Ser

1 5

<210> 205

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 205

Tyr Trp Pro Met Ala Asp

1 5

<210> 206

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 206

Ala Ile Ser Asp Ser Gly Gly Phe Val Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 207

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 207

Ser Asp Ser Gly Gly Phe

1 5

<210> 208

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 208

Ala Cys Leu Asp Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 209

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 209

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 210

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 210

Gly Ala Ser Ser Arg Ala Thr

1 5

<210> 211

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 211

Gln His Tyr Gly Ser Pro Pro Ser Phe Thr

1 5 10

<210> 212

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 212

Arg Ala Ser Gln Ser Leu Gly Ser Phe Tyr Leu Ala

1 5 10

<210> 213

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 213

Lys His Tyr Gly Trp Pro Pro Ser Phe Thr

1 5 10

<210> 214

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 214

Gln His Tyr Asn Tyr Pro Pro Ser Phe Thr

1 5 10

<210> 215

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 215

Arg Ala Ser Gln Ser Val Gly Asp Phe Tyr Leu Ala

1 5 10

<210> 216

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 216

Gln His Tyr Pro Tyr Pro Pro Ser Phe Thr

1 5 10

<210> 217

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 217

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Pro Ser

1 5 10

<210> 218

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 218

Arg Ala Ser Gln Ser Val Ser Ala His Tyr Leu Ala

1 5 10

<210> 219

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 219

Arg Ala Ser Gln Ser Val Ser Ser Phe Phe Leu Ala

1 5 10

<210> 220

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 220

Lys Tyr Tyr Pro Tyr Pro Pro Ser Phe Thr

1 5 10

<210> 221

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 221

Asp Ala Ser Ile Arg Ala Thr

1 5

<210> 222

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 222

Gln Gln Tyr Gly Ser Trp Pro Leu Thr

1 5

<210> 223

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 223

Arg Ala Ser Gln Ser Val Ser Val Leu Tyr Leu Ala

1 5 10

<210> 224

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 224

Gln Gln Tyr Gln Arg Trp Pro Leu Thr

1 5

<210> 225

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 225

Gln Gln Tyr Gln Ser Trp Pro Leu Thr

1 5

<210> 226

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 226

Arg Ala Ser Gln Ser Val Ser Asp Leu Tyr Leu Ala

1 5 10

<210> 227

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 227

Gln Gln Tyr Gln Thr Trp Pro Leu Thr

1 5

<210> 228

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 228

Arg Ala Ser Gln Ser Val Ser Asn Leu Tyr Leu Ala

1 5 10

<210> 229

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 229

Gln Gln Tyr Gln Gly Trp Pro Leu Thr

1 5

<210> 230

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 230

Arg Ala Ser Gln Ser Val Ser Ala Tyr Tyr Leu Ala

1 5 10

<210> 231

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 231

Gln Gln Tyr Glu Arg Trp Pro Leu Thr

1 5

<210> 232

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 232

Arg Ala Ser Gln Ser Val Ser Ser Leu Tyr Leu Ala

1 5 10

<210> 233

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 233

Gln Gln Tyr Gln Val Trp Pro Leu Thr

1 5

<210> 234

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 234

Gln Gln Tyr Leu Asp Trp Pro Leu Thr

1 5

<210> 235

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 235

Arg Ala Ser Gln Ser Val Ser Ala Leu Tyr Leu Ala

1 5 10

<210> 236

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 236

Gln Gln Tyr Leu Ala Trp Pro Leu Thr

1 5

<210> 237

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 237

Gln Gln Tyr Phe Thr Trp Pro Leu Thr

1 5

<210> 238

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 238

Arg Ala Ser Gln Ser Val Ser Pro Tyr Tyr Leu Ala

1 5 10

<210> 239

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 239

Arg Ala Ser Gln Ser Val Ser Val Glu Tyr Leu Ala

1 5 10

<210> 240

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 240

Gln Gln Tyr Ala Arg Trp Pro Leu Thr

1 5

<210> 241

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 241

Arg Ala Ser Gln Ser Val Ser Glu Leu Tyr Leu Ala

1 5 10

<210> 242

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 242

Gln Gln Tyr Phe Gly Trp Pro Leu Thr

1 5

<210> 243

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 243

Arg Ala Ser Gln Ser Val Glu Met Ser Tyr Leu Ala

1 5 10

<210> 244

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 244

Gln Gln Tyr Ala His Trp Pro Leu Thr

1 5

<210> 245

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 245

Arg Ala Ser Gln Ser Val Ser Ala Gln Tyr Leu Ala

1 5 10

<210> 246

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 246

Gly Pro Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 247

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 247

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Trp Ala

1 5 10

<210> 248

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 248

Gln Gln Tyr Glu Ser Trp Pro Leu Thr

1 5

<210> 249

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 249

Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 250

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 250

Arg Ala Ser Gln Ser Val Ser Phe Leu Tyr Leu Ala

1 5 10

<210> 251

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 251

Arg Ala Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 252

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 252

Asp Ala Ser Ser Arg Ala Pro

1 5

<210> 253

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 253

Gln Gln Tyr Ser Thr Ser Pro Leu Thr

1 5

<210> 254

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 254

Arg Ala Ser Gln Ser Val Ser Pro Glu Tyr Leu Ala

1 5 10

<210> 255

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 255

Gln Gln Tyr Ser Val Trp Pro Leu Thr

1 5

<210> 256

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 256

Gln Gln Tyr Ser Ala Trp Pro Leu Thr

1 5

<210> 257

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 257

Arg Ala Ser Gln Ser Val Ser Ser Val Tyr Leu Ala

1 5 10

<210> 258

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 258

Gln Gln Tyr Ser Thr Trp Pro Leu Thr

1 5

<210> 259

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 259

Gln Gln Tyr Ser Arg Trp Pro Leu Thr

1 5

<210> 260

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 260

Arg Ala Ser Gln Ser Val Ser Pro Leu Tyr Leu Ala

1 5 10

<210> 261

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 261

Gln Gln Tyr Ser Ala Phe Pro Leu Thr

1 5

<210> 262

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 262

Trp Leu Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 263

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 263

Gln Gln Tyr Ser Glu Trp Pro Leu Thr

1 5

<210> 264

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 264

Gln Gln Tyr Ser Ser Trp Pro Leu Thr

1 5

<210> 265

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 265

Arg Ala Ser Gln Ser Val Ser Ser Leu Phe Leu Ala

1 5 10

<210> 266

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 266

Ala Cys Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 267

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 267

Arg Ala Ser Cys Asp Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 268

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 268

Gln Gln Tyr Met Arg Ser Pro Leu Thr

1 5

<210> 269

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 269

Arg Ala Ser Glu Ala Val Pro Ser Thr Tyr Leu Ala

1 5 10

<210> 270

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 270

Cys Ser Ser Gln Ser Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 271

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 271

Arg Ala Ser Val Arg Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 272

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 272

Gln Gln Tyr Met Lys Trp Pro Leu Thr

1 5

<210> 273

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 273

Arg Ala Ser Gln Ser Val Ser Ala Ala Tyr Leu Ala

1 5 10

<210> 274

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 274

Gln Gln Tyr Met Cys Trp Pro Leu Thr

1 5

<210> 275

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 275

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Trp Gly

1 5 10

<210> 276

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 276

Gln Gln Tyr Gln Cys Trp Pro Leu Thr

1 5

<210> 277

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 277

Arg Ala Ser Gln Ser Val Ser Ser Pro Tyr Leu Ala

1 5 10

<210> 278

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 278

Gln Gln Tyr Lys Ala Trp Pro Leu Thr

1 5

<210> 279

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 279

Arg Ala Ser Gln Ser Val Ser Tyr Leu Tyr Leu Ala

1 5 10

<210> 280

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 280

Gln Gln Tyr Met Glu Trp Pro Leu Thr

1 5

<210> 281

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 281

Gln Gln Tyr Gln Ala Trp Pro Leu Thr

1 5

<210> 282

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 282

Gln Gln Tyr Gln Lys Trp Pro Leu Thr

1 5

<210> 283

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 283

Arg Ala Ser Gln Ser Val Ser Ala Val Tyr Leu Ala

1 5 10

<210> 284

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 284

Gln Gln Tyr Arg Ala Trp Pro Leu Thr

1 5

<210> 285

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 285

Arg Ala Ser Ile Ala Val Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 286

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 286

Gln Gln Tyr Met Val Trp Pro Leu Thr

1 5

<210> 287

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 287

Arg Pro Arg Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 288

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 288

Gln Gln Tyr Gln Asp Trp Pro Leu Thr

1 5

<210> 289

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 289

Gln Gln Tyr Gln Glu Trp Pro Leu Thr

1 5

<210> 290

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 290

Arg Ala Ser Gln Ser Val Ser Ala Ser Tyr Leu Ala

1 5 10

<210> 291

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 291

Gln Gln Tyr Met Ser Trp Pro Leu Thr

1 5

<210> 292

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 292

Arg Ala Ser Gln Ser Val Ser Tyr Met Tyr Leu Ala

1 5 10

<210> 293

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 293

Gln Gln Tyr Lys Ser Trp Pro Leu Thr

1 5

<210> 294

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 294

Gln Gln Tyr Tyr Gly Trp Pro Leu Thr

1 5

<210> 295

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 295

Arg Ala Ser Gln Pro Ile Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 296

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 296

Gln Gln Tyr Glu Phe Trp Pro Leu Thr

1 5

<210> 297

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 297

Arg Ala Ser Gln Gly Ile Ser Ser Thr Tyr Leu Ala

1 5 10

<210> 298

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 298

Gln Gln Tyr Ala Tyr Trp Pro Leu Thr

1 5

<210> 299

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 299

Arg Ala Ser Gln Ser Val Ser Val Arg Tyr Leu Ala

1 5 10

<210> 300

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 300

Gln Gln Tyr Gly Ser Trp Pro Ile Thr

1 5

<210> 301

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (3)..(3)

<223> Xaa is A or P

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is T, N or S

<400> 301

Ser Tyr Xaa Met Xaa

1 5

<210> 302

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is G or S

<400> 302

Gly Phe Thr Phe Xaa Ser Tyr

1 5

<210> 303

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is G or S

<220>

<221>MISC_FEATURE

<222> (8)..(8)

<223> Xaa is A or P

<220>

<221>MISC_FEATURE

<222> (10)..(10)

<223> Xaa is T, N or S

<400> 303

Gly Phe Thr Phe Xaa Ser Tyr Xaa Met Xaa

1 5 10

<210> 304

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 304

Ala Ile Ser Gly Trp Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 305

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (2)..(2)

<223> Xaa is I, V, T, H, L, A, or C

<220>

<221>MISC_FEATURE

<222> (3)..(3)

<223> Xaa is S, D, G, T, I, L, F, M, or V

<220>

<221>MISC_FEATURE

<222> (4)..(4)

<223> Xaa is G, Y, L, H, D, A, S, or M

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is S, Q, T, A, F, or W

<220>

<221>MISC_FEATURE

<222> (7)..(7)

<223> Xaa is G or T

<220>

<221>MISC_FEATURE

<222> (8)..(8)

<223> Xaa is N, S, P, Y, W, or F

<220>

<221>MISC_FEATURE

<222> (9)..(9)

<223> Xaa is S, T, I, L, T, A, R, V, K, G, or C

<220>

<221>MISC_FEATURE

<222> (10)..(10)

<223> Xaa is F, Y, P, W, H, or G

<220>

<221>MISC_FEATURE

<222> (14)..(14)

<223> Xaa is V, R or L

<220>

<221>MISC_FEATURE

<222> (15)..(15)

<223> Xaa is G or T

<400> 305

Ala Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Xaa Xaa Lys

1 5 10 15

Gly

<210> 306

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (1)..(1)

<223> Xaa is S, V, I, D, G, T, L, F, or M

<220>

<221>MISC_FEATURE

<222> (2)..(2)

<223> Xaa is G, Y, L, H, D, A, S, or M

<220>

<221>MISC_FEATURE

<222> (3)..(3)

<223> Xaa is S, G, F or W

<220>

<221>MISC_FEATURE

<222> (4)..(4)

<223> Xaa is G or S

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is G or T

<220>

<221>MISC_FEATURE

<222> (6)..(6)

<223> Xaa is N, S, P, Y, or W

<400> 306

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 307

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is either A or Y

<220>

<221>MISC_FEATURE

<222> (6)..(6)

<223> Xaa is A or S

<220>

<221>MISC_FEATURE

<222> (7)..(7)

<223> Xaa is G, Q, L, P or E

<400> 307

Val Ser Pro Ile Xaa Xaa Xaa Met Asp Tyr

1 5 10

<210> 308

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is D, S, T or A

<220>

<221>MISC_FEATURE

<222> (6)..(6)

<223> Xaa is I, S, L, P, or D

<400> 308

Tyr Trp Pro Met Xaa Xaa

1 5

<210> 309

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (1)..(1)

<223> Xaa is R, G, W, A, or C

<220>

<221>MISC_FEATURE

<222> (2)..(2)

<223> Xaa is A, P, G, L, C, or S

<220>

<221>MISC_FEATURE

<222> (3)..(3)

<223> Xaa is S, G or R

<220>

<221>MISC_FEATURE

<222> (4)..(4)

<223> Xaa is Q, C, E, V or I

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is S, P, G, A, R, or D

<220>

<221>MISC_FEATURE

<222> (6)..(6)

<223> Xaa is V, G, I, or L

<220>

<221>MISC_FEATURE

<222> (7)..(7)

<223> Xaa is S, E, D, P or G

<220>

<221>MISC_FEATURE

<222> (8)..(8)

<223> Xaa is S, P, F, A, M, E, V, N, D, or Y

<220>

<221>MISC_FEATURE

<222> (9)..(9)

<223> Xaa is I, T, V, E, F, S, A, M, Q, Y, H, or R

<220>

<221>MISC_FEATURE

<222> (10)..(10)

<223> Xaa is Y or F

<220>

<221>MISC_FEATURE

<222> (11)..(11)

<223> Xaa is L, W or P

<220>

<221>MISC_FEATURE

<222> (12)..(12)

<223> Xaa is A, S or G

<400> 309

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 310

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (1)..(1)

<223> Xaa is G or D

<220>

<221>MISC_FEATURE

<222> (4)..(4)

<223> Xaa is either S or I

<220>

<221>MISC_FEATURE

<222> (7)..(7)

<223> Xaa is T or P

<400> 310

Xaa Ala Ser Xaa Arg Ala Xaa

1 5

<210> 311

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (1)..(1)

<223> Xaa represents Q or K

<220>

<221>MISC_FEATURE

<222> (2)..(2)

<223> Xaa is H or Y

<220>

<221>MISC_FEATURE

<222> (4)..(4)

<223> Xaa is G, N or P

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is S, W or Y

<400> 311

Xaa Xaa Tyr Xaa Xaa Pro Pro Ser Phe Thr

1 5 10

<210> 312

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (4)..(4)

<223> Xaa is G, Q, E, L, F, A, S, M, K, R, or Y

<220>

<221>MISC_FEATURE

<222> (5)..(5)

<223> Xaa is S, R, T, G, V, F, Y, D, A, H, V, E, K, or C

<220>

<221>MISC_FEATURE

<222> (6)..(6)

<223> Xaa is W, F or S

<220>

<221>MISC_FEATURE

<222> (8)..(8)

<223> Xaa is L or I

<400> 312

Gln Gln Tyr Xaa Xaa Xaa Pro Xaa Thr

1 5

<210> 313

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (30)..(30)

<223> Xaa is G or S

<220>

<221>MISC_FEATURE

<222> (33)..(33)

<223> Xaa is A or P

<220>

<221>MISC_FEATURE

<222> (35)..(35)

<223> Xaa is T, N or S

<220>

<221>MISC_FEATURE

<222> (51)..(51)

<223> Xaa is I, V, T, H, L, A, or C

<220>

<221>MISC_FEATURE

<222> (52)..(52)

<223> Xaa is S, D, G, T, I, L, F, M, or V

<220>

<221>MISC_FEATURE

<222> (53)..(53)

<223> Xaa is G, Y, L, H, D, A, S, or M

<220>

<221>MISC_FEATURE

<222> (54)..(54)

<223> Xaa is S, Q, T, A, F, or W

<220>

<221>MISC_FEATURE

<222> (56)..(56)

<223> Xaa is G or T

<220>

<221>MISC_FEATURE

<222> (57)..(57)

<223> Xaa is N, S, P, Y, W, or F

<220>

<221>MISC_FEATURE

<222> (58)..(58)

<223> Xaa is S, T, I, L, T, A, R, V, K, G, or C

<220>

<221>MISC_FEATURE

<222> (59)..(59)

<223> Xaa is F, Y, P, W, H, or G

<220>

<221>MISC_FEATURE

<222> (63)..(63)

<223> Xaa is V, R or L

<220>

<221>MISC_FEATURE

<222> (64)..(64)

<223> Xaa is G or T

<220>

<221>MISC_FEATURE

<222> (103)..(103)

<223> Xaa is either A or Y

<220>

<221>MISC_FEATURE

<222> (104)..(104)

<223> Xaa is A or S

<220>

<221>MISC_FEATURE

<222> (105)..(105)

<223> Xaa is G, Q, L, P or E

<400> 313

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Ser Tyr

20 25 30

Xaa Met Xaa Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Xaa Xaa

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Val Ser Pro Ile Xaa Xaa Xaa Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 314

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (30)..(30)

<223> Xaa is G or S

<220>

<221>MISC_FEATURE

<222> (33)..(33)

<223> Xaa is A or P

<220>

<221>MISC_FEATURE

<222> (35)..(35)

<223> Xaa is T, N or S

<220>

<221>MISC_FEATURE

<222> (51)..(51)

<223> Xaa is I, V, T, H, L, A, or C

<220>

<221>MISC_FEATURE

<222> (52)..(52)

<223> Xaa is S, D, G, T, I, L, F, M, or V

<220>

<221>MISC_FEATURE

<222> (53)..(53)

<223> Xaa is G, Y, L, H, D, A, S, or M

<220>

<221>MISC_FEATURE

<222> (54)..(54)

<223> Xaa is S, Q, T, A, F, or W

<220>

<221>MISC_FEATURE

<222> (56)..(56)

<223> Xaa is G or T

<220>

<221>MISC_FEATURE

<222> (57)..(57)

<223> Xaa is N, S, P, Y, W, or F

<220>

<221>MISC_FEATURE

<222> (58)..(58)

<223> Xaa is S, T, I, L, T, A, R, V, K, G, or C

<220>

<221>MISC_FEATURE

<222> (59)..(59)

<223> Xaa is F, Y, P, W, H, or G

<220>

<221>MISC_FEATURE

<222> (63)..(63)

<223> Xaa is V, R or L

<220>

<221>MISC_FEATURE

<222> (64)..(64)

<223> Xaa is G or T

<220>

<221>MISC_FEATURE

<222> (103)..(103)

<223> Xaa is D, S, T or A

<220>

<221>MISC_FEATURE

<222> (104)..(104)

<223> Xaa is I, S, L, P, or D

<400> 314

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Xaa Ser Tyr

20 25 30

Xaa Met Xaa Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Xaa Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Tyr Ala Asp Xaa Xaa

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Xaa Xaa Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 315

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (24)..(24)

<223> Xaa is R, G, W, A, or C

<220>

<221>MISC_FEATURE

<222> (25)..(25)

<223> Xaa is A, P, G, L, C, or S

<220>

<221>MISC_FEATURE

<222> (26)..(26)

<223> Xaa is S, G or R

<220>

<221>MISC_FEATURE

<222> (27)..(27)

<223> Xaa is Q, C, E, V or I

<220>

<221>MISC_FEATURE

<222> (28)..(28)

<223> Xaa is S, P, G, A, R, or D

<220>

<221>MISC_FEATURE

<222> (29)..(29)

<223> Xaa is V, G, I, or L

<220>

<221>MISC_FEATURE

<222> (30)..(30)

<223> Xaa is S, E, D, P or G

<220>

<221>MISC_FEATURE

<222> (31)..(31)

<223> Xaa is S, P, F, A, M, E, V, N, D, or Y

<220>

<221>MISC_FEATURE

<222> (32)..(32)

<223> Xaa is I, T, V, E, S, A, M, Q, Y, H, R, or F

<220>

<221>MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Y or F

<220>

<221>MISC_FEATURE

<222> (34)..(34)

<223> Xaa is L, W or P

<220>

<221>MISC_FEATURE

<222> (35)..(35)

<223> Xaa is A, S or G

<220>

<221>MISC_FEATURE

<222> (51)..(51)

<223> Xaa is G or D

<220>

<221>MISC_FEATURE

<222> (54)..(54)

<223> Xaa is either S or I

<220>

<221>MISC_FEATURE

<222> (57)..(57)

<223> Xaa is T or P

<220>

<221>MISC_FEATURE

<222> (90)..(90)

<223> Xaa represents Q or K

<220>

<221>MISC_FEATURE

<222> (91)..(91)

<223> Xaa is H or Y

<220>

<221>MISC_FEATURE

<222> (93)..(93)

<223> Xaa is G, N or P

<220>

<221>MISC_FEATURE

<222> (94)..(94)

<223> Xaa is S, W or Y

<400> 315

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Xaa Ala Ser Xaa Arg Ala Xaa Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Xaa Xaa Tyr Xaa Xaa Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 316

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<220>

<221>MISC_FEATURE

<222> (24)..(24)

<223> Xaa is R, G, W, A, or C

<220>

<221>MISC_FEATURE

<222> (25)..(25)

<223> Xaa is A, P, G, L, C, or S

<220>

<221>MISC_FEATURE

<222> (26)..(26)

<223> Xaa is S, G or R

<220>

<221>MISC_FEATURE

<222> (27)..(27)

<223> Xaa is Q, C, E, V or I

<220>

<221>MISC_FEATURE

<222> (28)..(28)

<223> Xaa is S, L, P, G, A, R, or D

<220>

<221>MISC_FEATURE

<222> (29)..(29)

<223> Xaa is V, G or I

<220>

<221>MISC_FEATURE

<222> (30)..(30)

<223> Xaa is S, E, D or P

<220>

<221>MISC_FEATURE

<222> (31)..(31)

<223> Xaa is S, P, F, A, M, E, V, N, D, or Y

<220>

<221>MISC_FEATURE

<222> (32)..(32)

<223> Xaa is I, T, V, E, S, A, M, Q, Y, H, or R

<220>

<221>MISC_FEATURE

<222> (33)..(33)

<223> Xaa is Y or F

<220>

<221>MISC_FEATURE

<222> (34)..(34)

<223> Xaa is L, W or P

<220>

<221>MISC_FEATURE

<222> (35)..(35)

<223> Xaa is A, S or G

<220>

<221>MISC_FEATURE

<222> (51)..(51)

<223> Xaa is G or D

<220>

<221>MISC_FEATURE

<222> (54)..(54)

<223> Xaa is either S or I

<220>

<221>MISC_FEATURE

<222> (57)..(57)

<223> Xaa is T or P

<220>

<221>MISC_FEATURE

<222> (93)..(93)

<223> Xaa is G, Q, E, L, F, A, S, M, R, K, or Y

<220>

<221>MISC_FEATURE

<222> (94)..(94)

<223> Xaa is S, R, T, G, R, V, D, A, H, E, K, C, F, or Y

<220>

<221>MISC_FEATURE

<222> (95)..(95)

<223> Xaa is W, S or F

<220>

<221>MISC_FEATURE

<222> (97)..(97)

<223> Xaa is L or I

<400> 316

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

20 25 30

Xaa Xaa Xaa Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Xaa Ala Ser Xaa Arg Ala Xaa Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Xaa Xaa Xaa Pro

85 90 95

Xaa Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 317

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 317

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ala Leu

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ala Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 318

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 318

Leu Leu Gln Gly Gly

1 5

<210> 319

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 319

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Thr Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 320

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 320

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 321

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 321

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 322

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 322

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 323

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 323

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 324

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 324

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 325

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 325

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 326

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 326

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 327

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 327

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 328

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 328

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Asp

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 329

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 329

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Thr Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 330

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 330

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Pro

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 331

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 331

Asp Tyr Tyr Met Thr

1 5

<210> 332

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 332

Gly Phe Thr Phe Ser Asp Tyr

1 5

<210> 333

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 333

Gly Phe Thr Phe Ser Asp Tyr Tyr Met Thr

1 5 10

<210> 334

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 334

Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala Ser

1 5 10 15

Val Lys Gly

<210> 335

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 335

Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr

1 5 10

<210> 336

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 336

Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro Ser

1 5 10 15

Val Lys Gly

<210> 337

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 337

Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 338

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 338

Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Asp Ser

1 5 10 15

Val Lys Gly

<210> 339

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 339

Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp Tyr Ala Pro Ser

1 5 10 15

Val Lys Gly

<210> 340

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 340

Thr Ser Ser Gln Ser Leu Phe Asn Val Arg Ser Arg Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 341

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 341

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 342

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 342

Lys Gln Ser Tyr Asp Leu Phe Thr

1 5

<210> 343

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 343

Lys Ser Ser Gln Ser Leu Phe Asn Val Arg Ser Arg Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 344

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 344

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 345

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 345

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 346

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 346

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 347

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 347

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 348

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 348

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Val

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 349

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 349

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Pro

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 350

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 350

Asp Ile Val Met Ser Gln Ser Pro Pro Ser Leu Ala Val Ser Val Gly

1 5 10 15

Asp Lys Val Thr Met Ser Cys Thr Ser Ser Gln Ser Leu Phe Asn Ser

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ser Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asp Leu Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 351

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 351

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Thr Phe Gly Phe Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Asn Ile

65 70 75 80

Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 352

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 352

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Asp Ser Val Gln Pro Glu Asp Leu Ala Val Tyr Tyr Cys Thr Gln

85 90 95

Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 353

<211> 184

<212> PRT

<213> Homo sapien

<400> 353

Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser

1 5 10 15

Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr

20 25 30

Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser

35 40 45

Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu

50 55 60

Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile

65 70 75 80

Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu

85 90 95

Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu

100 105 110

Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys

115 120 125

Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe

130 135 140

Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys

145 150 155 160

Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu

165 170 175

Ile Glu Lys Ser Ile Ser Ala Arg

180

<210> 354

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 354

Gln Val Gln Leu Gln Gln Pro Gly Ser Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Ile Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Tyr Ser Gly Gly Asp Thr Ile Asn Tyr Asp Glu Lys Phe

50 55 60

Lys Asn Lys Ala Ile Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Asp Ala Thr Ser Arg Tyr Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 355

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 355

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Ala Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Lys Gln

85 90 95

Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 356

<211> 117

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 356

Gln Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Glu Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr

20 25 30

Tyr Leu His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Phe Pro Gly Ser Asp Asn Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Asn Arg Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 357

<211> 215

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 357

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 358

<211> 255

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 358

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Leu Pro Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

115 120 125

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

130 135 140

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

145 150 155 160

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

165 170 175

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

180 185 190

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

195 200 205

Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

210 215 220

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

<210> 359

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 359

Ser Gly Ser Gly Gly Ser

1 5

<210> 360

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 360

Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 361

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 361

Val Gly Thr Ser Gly Ala Phe Gly Ile

1 5

<210> 362

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 362

Gly Ala Ser Ser Arg Ala Tyr

1 5

<210> 363

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 363

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ser Trp Ser Gly Ala Phe Asp Asn Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 364

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 364

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Pro Pro

85 90 95

Ser Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 365

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 365

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Val Gly Thr Ser Gly Ala Phe Gly Ile Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 366

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 366

Ser Tyr Ala Met Ser

1 5

<210> 367

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 367

Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser

1 5 10

<210> 368

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 368

Ser Ala Ser Gly Gly Ser

1 5

<210> 369

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 369

Ala Ile Ser Ala Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 370

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 370

Leu Ser Trp Ser Gly Ala Phe Asp Asn

1 5

<210> 371

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 371

Gly Phe Thr Phe Arg Ser Tyr

1 5

<210> 372

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 372

Gly Phe Thr Phe Arg Ser Tyr Ala Met Ser

1 5 10

<210> 373

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 373

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Asp Ser Val Gln Pro Glu Asp Leu Ala Val Tyr Tyr Cys Thr Gln

85 90 95

Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 374

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 374

Gln Val Gln Leu Gln Gln Pro Gly Ser Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Ile Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Tyr Ser Gly Gly Asp Thr Ile Asn Tyr Asp Glu Lys Phe

50 55 60

Lys Asn Lys Ala Ile Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Asp Ala Thr Ser Arg Tyr Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 375

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 375

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Ala Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Lys Gln

85 90 95

Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 376

<211> 117

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 376

Gln Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Glu Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr

20 25 30

Tyr Leu His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Phe Pro Gly Ser Asp Asn Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Asn Arg Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 377

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 377

Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu

1 5 10 15

Ala Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala

65 70 75 80

Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Asn Asn

85 90 95

Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 378

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 378

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Glu Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Leu Ser Met

65 70 75 80

Val Tyr Leu Gln Met Asn Ser Leu Lys Asn Glu Asp Thr Ala Met Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 379

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 379

Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly

35 40 45

Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala

65 70 75 80

Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 380

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 380

Glu Val Gln Leu Val Asp Ser Gly Gly Gly Leu Val Gln Pro Lys Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Arg

65 70 75 80

Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Asn Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 381

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 381

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 382

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 382

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 383

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 383

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 384

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 384

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 385

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 385

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ala Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 386

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 386

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 387

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 387

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 388

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 388

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 389

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 389

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

Tyr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 390

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 390

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 391

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 391

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 392

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 392

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 393

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 393

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 394

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 394

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser His Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 395

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 395

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 396

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 396

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 397

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 397

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 398

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 398

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Glu Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 399

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 399

Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Thr Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly

35 40 45

Leu Ile Gly Gly Thr Asn Thr Arg Ala Pro Gly Thr Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Asn Asn

85 90 95

His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 400

<211> 124

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 400

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Lys Thr Tyr Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Arg His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala

100 105 110

Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 401

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 401

Thr Tyr Ala Met Asn

1 5

<210> 402

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 402

Gly Phe Thr Phe Asn Thr Tyr

1 5

<210> 403

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 403

Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn

1 5 10

<210> 404

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 404

Arg Ser Lys Ile Asn Asn Tyr Ala

1 5

<210> 405

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 405

Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 406

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 406

His Glu Thr Leu Arg Ser Gly Ile Ser Trp Phe Ala Ser

1 5 10

<210> 407

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 407

Gly Phe Thr Phe Ser Thr Tyr

1 5

<210> 408

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 408

Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn

1 5 10

<210> 409

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 409

Arg Ser His Ile Asn Asn Tyr Ala

1 5

<210> 410

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 410

Arg Ile Arg Ser His Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 411

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 411

Arg Ser Lys Tyr Asn Asn Tyr Ala

1 5

<210> 412

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 412

Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 413

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 413

Arg Glu Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 414

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 414

Arg Ile Arg Ser Lys Ile Asn Asn Tyr Lys Thr Tyr Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 415

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 415

Gly Phe Thr Phe Thr Asp Tyr

1 5

<210> 416

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 416

Gly Phe Thr Phe Thr Asp Tyr Tyr Met Thr

1 5 10

<210> 417

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 417

Arg Asn Arg Ala Arg Gly Tyr Thr

1 5

<210> 418

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 418

Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala Ser

1 5 10 15

Val Lys Gly

<210> 419

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 419

Gly Tyr Thr Phe Thr Ser Tyr

1 5

<210> 420

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 420

Gly Tyr Thr Phe Thr Ser Tyr Trp Met His

1 5 10

<210> 421

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 421

Tyr Ser Gly Gly Asp Thr

1 5

<210> 422

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 422

Asn Ile Tyr Ser Gly Gly Asp Thr Ile Asn Tyr Asp Glu Lys Phe Lys

1 5 10 15

Asn

<210> 423

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 423

Asp Ala Thr Ser Arg Tyr Phe Phe Asp Tyr

1 5 10

<210> 424

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 424

Thr Tyr Tyr Leu His

1 5

<210> 425

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 425

Gly Tyr Ser Phe Thr Thr Tyr Tyr

1 5

<210> 426

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 426

Gly Tyr Ser Phe Thr Thr Tyr Tyr Leu His

1 5 10

<210> 427

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 427

Phe Pro Gly Ser Asp Asn

1 5

<210> 428

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 428

Trp Ile Phe Pro Gly Ser Asp Asn Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 429

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 429

Asn Arg Asp Tyr Tyr Phe Asp Tyr

1 5

<210> 430

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 430

Thr Ser Ser Gln Ser Leu Phe Asn Ser Arg Ser Arg Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 431

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 431

Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr

1 5 10 15

<210> 432

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 432

Thr Gln Ser Phe Ile Leu Arg Thr

1 5

<210> 433

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 433

Trp Ala Ser Thr Arg Ala Ser

1 5

<210> 434

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 434

Lys Gln Ser Phe Ile Leu Arg Thr

1 5

<210> 435

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 435

Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn

1 5 10

<210> 436

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 436

Gly Thr Asn Thr Arg Ala Pro

1 5

<210> 437

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 437

Val Leu Trp Tyr Asn Asn Tyr Trp Val

1 5

<210> 438

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 438

Ala Leu Trp Tyr Ser Asn His Trp Val

1 5

<210> 439

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 439

Val Leu Trp Tyr Asn Asn His Trp Val

1 5

<210> 440

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 440

Arg Ala Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn

1 5 10

<210> 441

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 441

Arg Thr Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn

1 5 10

<210> 442

<211> 117

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 442

Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Leu Val Lys Leu Ser Cys Lys Gly Ser Gly Phe Asn Ile Lys Asp Tyr

20 25 30

Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asp Pro Glu Asn Gly Asn Asn Lys Tyr Asp Pro Lys Phe

50 55 60

Gln Gly Lys Ala Ser Ile Thr Ala Asp Thr Ser Ser Asn Ile Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Asp Asn Tyr Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 443

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 443

Asp Ile Val Val Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Ile Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Leu Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Ser Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Thr Glu Asp Leu Ala Val Tyr Tyr Cys Met Gln

85 90 95

Ser Phe Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 444

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 444

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Phe Ile Arg Asn Arg Ala Arg Gly Tyr Thr Ser Asp His Asn Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Asp Arg Pro Ser Tyr Tyr Val Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 445

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 445

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Thr Ser Ser Gln Ser Leu Phe Asn Ser

20 25 30

Arg Ser Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Ser Tyr Asp Thr Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 446

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 446

Asp Tyr Tyr Ile His

1 5

<210> 447

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 447

Gly Phe Asn Ile Lys Asp Tyr

1 5

<210> 448

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 448

Gly Phe Asn Ile Lys Asp Tyr Tyr Ile His

1 5 10

<210> 449

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 449

Asp Pro Glu Asn Gly Asn

1 5

<210> 450

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 450

Trp Ile Asp Pro Glu Asn Gly Asn Asn Lys Tyr Asp Pro Lys Phe Gln

1 5 10 15

Gly

<210> 451

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 451

Asn Asp Asn Tyr Ala Phe Asp Tyr

1 5

<210> 452

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 452

Ser Ala Ser Thr Arg Glu Ser

1 5

<210> 453

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 453

Met Gln Ser Phe Thr Leu Arg Thr

1 5

<210> 454

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 454

Leu Leu Gln Gly

1

<210> 455

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 455

Leu Ser Leu Ser Gln Gly

1 5

<210> 456

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 456

Gly Gly Gly Leu Leu Gln Gly Gly

1 5

<210> 457

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 457

Gly Leu Leu Gln Gly

1 5

<210> 458

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 458

Gly Ser Pro Leu Ala Gln Ser His Gly Gly

1 5 10

<210> 459

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 459

Gly Leu Leu Gln Gly Gly Gly

1 5

<210> 460

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 460

Gly Leu Leu Gln Gly Gly

1 5

<210> 461

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 461

Gly Leu Leu Gln

1

<210> 462

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 462

Leu Leu Gln Leu Leu Gln Gly Ala

1 5

<210> 463

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 463

Leu Leu Gln Gly Ala

1 5

<210> 464

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 464

Leu Leu Gln Tyr Gln Gly Ala

1 5

<210> 465

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 465

Leu Leu Gln Gly Ser Gly

1 5

<210> 466

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 466

Leu Leu Gln Tyr Gln Gly

1 5

<210> 467

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 467

Leu Leu Gln Leu Leu Gln Gly

1 5

<210> 468

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 468

Ser Leu Leu Gln Gly

1 5

<210> 469

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 469

Leu Leu Gln Leu Gln

1 5

<210> 470

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 470

Leu Leu Gln Leu Leu Gln

1 5

<210> 471

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 471

Leu Leu Gln Gly Arg

1 5

<210> 472

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 472

Leu Leu Gln Gly Pro Pro

1 5

<210> 473

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 473

Leu Leu Gln Gly Pro Ala

1 5

<210> 474

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 474

Gly Gly Leu Leu Gln Gly Pro Pro

1 5

<210> 475

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 475

Gly Gly Leu Leu Gln Gly Ala

1 5

<210> 476

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 476

Leu Leu Gln Gly Pro Gly Lys

1 5

<210> 477

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 477

Leu Leu Gln Gly Pro Gly

1 5

<210> 478

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 478

Leu Leu Gln Gly Pro

1 5

<210> 479

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 479

Leu Leu Gln Pro

1

<210> 480

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 480

Leu Leu Gln Pro Gly Lys

1 5

<210> 481

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 481

Leu Leu Gln Ala Pro Gly Lys

1 5

<210> 482

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 482

Leu Leu Gln Gly Ala Pro Gly

1 5

<210> 483

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 483

Leu Leu Gln Gly Ala Pro

1 5

<210> 484

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 484

Leu Leu Gln Leu Gln Gly

1 5

<210> 485

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 485

gagatcgtgc tgactcagtc ccctggaacc ctgtccctgt cacctggcga aagagctacc 60

ttgtcctgtc gcgcatcaca atccgtgtcg tcgagctatc tcgcgtggta ccagcagaag 120

cccggacagg ccccaaggct gcttatgtac gacgcctcca tccgggccac tggtatcccc 180

gaccgcttct cgggctccgg aagcggcacc gacttcaccc tgactatttc ccggctcgaa 240

ccggaggatt tcgcc 255

<210> 486

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 486

gaagtccaac tcctcgaatc cggtggcggc cttgtccagc ctggaggttc cttgcgcctg 60

tcatgtgccg ccagcggatt caccttctcg tcctacccga tgtcgtgggt ccgccaggct 120

ccgggaaagg gcctggaatg ggtgtcagcc atcggaggat cggggggctc cctgccctac 180

gccgatatcg tgaagggaag gttcaccatt agccgggaca actccaagaa cactctgtac 240

ctccaaatga acagc 255

<210> 487

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 487

gagatcgtgc tgacacagag ccctggcacc ctgagcctgt ctccaggcga aagagccacc 60

ctgtcctgca gagccagcca gagcgtgtcc agcagctacc tggcctggta tcagcagaag 120

cccggccagg ctccccggct gctgatctat ggcgcctctt ctagagccac cggcatcccc 180

gatagattca gcggctctgg cagcggcacc gacttcaccc tgaccatcag cagactggaa 240

cccgaggact tcgcc 255

<210> 488

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 488

gaagtgcagc tgctggaatc tggcggagga ctggtgcagc ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt caccttcggc agctacgcta tgacctgggt gcgccaggcc 120

cctggcaaag gactggaatg ggtgtccgcc atctctggca gcggcggcaa taccttctac 180

gccgagagcg tgaagggccg gttcaccatc agccgggaca acagcaagaa caccctgtac 240

ctgcagatga acagc 255

<210> 489

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 489

gagatcgtgc tgacacagag ccctggcacc ctgagcctgt ctcctggtga aagagctact 60

ttgtcttgta gagcttctca atccgtttcc gcgtattatt tggcttggta tcaacaaaaa 120

ccaggtcaag ctccaagatt attgatgtac gatgcttcta ttagagccac cggtattcca 180

gatagatttt ctggttctgg ttccggtact gatttcactt tgactatctc tagattggaa 240

ccagaagatt tcgct 255

<210> 490

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 490

gaagttcaat tattggaatc tggtggagga ctggtgcagc ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt caccttcagc agctacgcca tgaactgggt gcgccaggcc 120

cctggtaaag gtttggaatg ggtttctgct attactgcgt ctggtggttc tacttactat 180

gccgatgtgg ttaagggtag attcaccatt tctagagaca actctaagaa caccttgtac 240

ttgcaaatga actcc 255

<210> 491

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 491

gagatcgtgc tgacacagag ccctggcacc ctgagcctgt ctcctggtga aagagctact 60

ttgtcttgta gagcttctca atccgtttcc gatctgtatt tggcttggta tcaacaaaaa 120

ccaggtcaag ctccaagatt attgatgtac gatgcttcta ttagagccac cggtattcca 180

gatagatttt ctggttctgg ttccggtact gatttcactt tgactatctc tagattggaa 240

ccagaagatt tcgct 255

<210> 492

<211> 255

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 492

gaagttcaat tattggaatc tggtggagga ctggtgcagc ctggcggctc tctgagactg 60

tcttgtgccg ccagcggctt caccttcagc agctacgcca tgaactgggt gcgccaggcc 120

cctggtaaag gtttggaatg ggtttctgct atttctgatt ttggtggttc tacttactat 180

gccgatatcg ttaagggtag attcaccatt tctagagaca actctaagaa caccttgtac 240

ttgcaaatga actcc 255

<210> 493

<211> 255

<212> PRT

<213> Homo sapien

<400> 493

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

130 135 140

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

245 250 255

<210> 494

<211> 255

<212> PRT

<213> Homo sapien

<400> 494

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

<210> 495

<211> 255

<212> PRT

<213> Homo sapien

<400> 495

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

245 250 255

<210> 496

<211> 255

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 496

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Arg Val Arg Cys Pro Arg Cys Pro Ala Pro

100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala

130 135 140

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

245 250 255

<210> 497

<211> 255

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 497

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Glu Val Glu Cys Pro Glu Cys Pro Ala Pro

100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala

130 135 140

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Glu Val Lys Gly Phe Tyr Pro Ser Asp

245 250 255

<210> 498

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 498

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 499

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 499

Gln His Tyr Gly Ser Pro Pro Leu Phe Thr

1 5 10

<210> 500

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 500

Arg Ala Ser Gln Asn Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 501

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construction

<400> 501

Gly Ala Ser Tyr Arg Ala Thr

1 5

<210> 502

<211> 198

<212> PRT

<213> Homo sapiens

<400> 502

Met Gln Ser Gly Thr Arg Trp Arg Val Leu Gly Leu Cys Leu Leu Ser

1 5 10 15

Ile Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Ser Ile Thr

20 25 30

Gln Thr Pro Tyr Gln Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr

35 40 45

Cys Ser Gln His Leu Gly Ser Glu Ala Gln Trp Gln His Asn Gly Lys

50 55 60

Asn Lys Glu Asp Ser Gly Asp Arg Leu Phe Leu Pro Glu Phe Ser Glu

65 70 75 80

Met Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Asn Pro

85 90 95

Glu Asp Ala Ser His His Leu Tyr Leu Lys Ala Arg Val Cys Glu Asn

100 105 110

Cys Met Glu Met Asp Val Met Ala Val Ala Thr Ile Val Ile Val Asp

115 120 125

Ile Cys Ile Thr Leu Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser Lys

130 135 140

Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala Gly

145 150 155 160

Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro Asn

165 170 175

Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Gln Asp Leu Tyr Ser Gly

180 185 190

Leu Asn Gln Arg Arg Ile

195

<---

Claims (19)

1. An isolated antibody that specifically binds to B cell maturation antigen (BCMA), wherein the antibody comprises: a heavy chain variable region (VH) comprising (1) a VH CDR1 comprising SEQ ID NO: 151, 156, or 157; (2) a VH CDR2 comprising SEQ ID NO: 158 or 159; and (3) a VH CDR3 comprising SEQ ID NO: 155; and a light chain variable region (VL) comprising (1) a VL CDR1 comprising SEQ ID NO: 209; (2) a VL CDR2 comprising SEQ ID NO: 221; and (3) a VL CDR3 comprising SEQ ID NO: 225. 2. The antibody of claim 1, wherein the VH region comprises the sequence presented in SEQ ID NO: 112, and the VL region comprises the amino acid sequence presented in SEQ ID NO: 38. 3. The antibody of claim 1, wherein the VH region comprises an amino acid sequence encoded by the nucleotide sequence presented in SEQ ID NO: 486, and the VL region comprises an amino acid sequence encoded by the nucleotide sequence presented in SEQ ID NO: 485. 4. The antibody of claim 1, wherein the antibody comprises a VH region produced by an expression vector with ATCC accession number PTA-122094. 5. The antibody of claim 1, wherein the antibody comprises a VL region produced by an expression vector with ATCC accession number PTA-122093. 6. A pharmaceutical composition comprising a therapeutically effective amount of an antibody according to any one of claims 1-5 and a pharmaceutically acceptable carrier. 7. An isolated polynucleotide encoding an antibody according to any one of claims 1-5. 8. An expression vector containing the polynucleotide according to claim 7. 9. An isolated host cell that recombinantly produces an antibody according to any one of claims 1-5, containing a polynucleotide according to claim 7 or a vector according to claim 8. 10. A method for producing an antibody, comprising culturing a host cell according to claim 9 under conditions that lead to the production of the antibody, and isolating the antibody from the host cell or culture. 11. A method for treating a condition associated with BCMA expressing cells in a subject, comprising administering to a subject in need thereof an effective amount of an antibody according to any one of claims 1-5 or a pharmaceutical composition according to claim 6. 12. The method of claim 11, wherein the condition is cancer. 13. The method of claim 12, wherein the cancer is a B-cell related cancer selected from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular Hodgkin's lymphoma with lymphocyte predominance, Kahler disease and myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-cell lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, mucosal lymphoid tissue lymphoma, small lymphocytic lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell/histocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (foot type), EBV (Epstein-Barr virus)-positive diffuse large B-cell lymphoma of the elderly, inflammation-associated diffuse large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising from HHV8-associated multicentric Castleman disease, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell lymphoma. 14. The method of claim 12, wherein the treatment comprises inhibiting the growth or progression of a tumor in the subject. 15. The method of claim 12, wherein the treatment comprises inhibiting the metastasis of BCMA-expressing malignant cells in the subject. 16. The method of claim 12, wherein the treatment comprises inducing tumor regression in a subject having malignant cells expressing BCMA. 17. The method of claim 11, wherein the condition is an autoimmune disorder. 18. The method of claim 17, wherein the autoimmune disorder is systemic lupus erythematosus or rheumatoid arthritis.