Therapeutic antibodies and their uses

Abstract

The present invention relates to antibodies, e.g., 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 the BCMA antibodies, compositions comprising the BCMA antibodies, and methods of using the BCMA antibodies and their conjugates for treating conditions associated with cells expressing BCMA (e.g., cancer or autoimmune disease). The invention further relates to heteromultimeric antibodies that specifically bind to CD3 and a tumor cell antigen, (e.g., bispecific antibodies that specifically bind to CD3 and BCMA). Compositions comprising such heteromultimeric antibodies, methods for producing and purifying such heterodimeric antibodies, and their use in diagnostics and therapeutics are also provided.

It is claimed: 
     
         1 . An isolated antibody, or an antigen binding fragment thereof, which specifically binds to B-Cell Maturation Antigen (BCMA), wherein the antibody comprises
 (a) a heavy chain variable (VH) region comprising (i) 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 SYX2MX 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); (ii) 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 X 10  is G or T (SEQ ID NO: 305), or 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 (SEQ ID NO: 306); and iii) a VH CDR3 comprising the sequence VSPIX 1 X 2 X 3 X 4 , wherein 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), or YWPMX 1 X 2 , wherein X 1  is D, S, T, or A; and X 2  is I, S, L, P, or D (SEQ ID NO: 308); and/or   (b) a light chain variable (VL) region comprising (i) 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); (ii) 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 (iii) 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).   
     
     
         2 . An isolated antibody, or an antigen binding fragment thereof, which specifically binds to BCMA, wherein the antibody comprises:
 a VH region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown 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, 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.   
     
     
         3 . The antibody or the antigen binding fragment of  claim 2 , wherein the VH region comprises (i) a VH CDR1 comprising SEQ ID NO:150, 151, 152, 156, or 157; (ii) 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 (iii) a VH CDR3 comprising SEQ ID NO: 155, 161, 197, 205, or 164; and/or wherein the VL region comprises (i) 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; (ii) a VL CDR2 comprising SEQ ID NO: 221; and (iii) 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. 
     
     
         4 . The antibody or the antigen binding fragment of  claim 3 , wherein the VH region comprises (i) a VH CDR1 comprising SEQ ID NO: 151, 156, or 157; (ii) a VH CDR2 comprising SEQ ID NO: 158 or 159; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and/or wherein the VL region comprises (i) a VL CDR1 comprising SEQ ID NO: 209; (ii) a VL CDR2 comprising SEQ ID NO: 221; and (iii) a VL CDR3 comprising SEQ ID NO: 225. 
     
     
         5 . The antibody or the antigen binding fragment of  claim 4 , wherein the VH region comprises the sequence shown in SEQ ID NO: 112 or a variant with one or several conservative amino acid substitutions in residues that are not within a CDR and/or the VL region comprises the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof with one or several amino acid substitutions in amino acids that are not within a CDR. 
     
     
         6 . The antibody or the antigen binding fragment of  claim 5 , wherein the antibody comprises a light chain comprising the sequence shown in SEQ ID NO: 357 and a heavy chain comprising the sequence shown in SEQ ID NO: 358. 
     
     
         7 . The antibody or the antigen binding fragment of  claim 3 , wherein the antibody comprises a VH region produced by the expression vector with ATCC Accession No. PTA-122094. 
     
     
         8 . The antibody or the antigen binding fragment of  claim 4 , wherein the antibody comprises a VL region produced by the expression vector with ATCC Accession No. PTA-122093. 
     
     
         9 . An isolated antibody which specifically binds to BCMA and competes with the antibody of  claim 4 . 
     
     
         10 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen binding fragment of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . An isolated polynucleotide comprising a nucleotide sequence encoding the antibody of  claim 1 . 
     
     
         12 . A vector comprising the polynucleotide of  claim 11 . 
     
     
         13 . An isolated host cell that recombinantly produces the antibody or the antigen binding fragment of  claim 1 . 
     
     
         14 . A method of producing an antibody, comprising culturing the host cell of  claim 13  under conditions that result in production of the antibody, and isolating the antibody from the host cell or culture. 
     
     
         15 . A method of treating a condition associated with cells expressing BCMA in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of  claim 10 . 
     
     
         16 . The method of  claim 15 , wherein the condition is a cancer. 
     
     
         17 . The method of  claim 16 , wherein the cancer is a B-cell related cancer selecting from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte predominant Hodgkin's lymphoma, Kahler's 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 macroglobulienemia, diffuse large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosa-associated lymphatic tissue lymphoma, small cell lymphocytic lymphoma, mantle cell lymphoma, Burkitt lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmactyic lymphoma, Waldenström macroglobulinemia, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell/histiocyte-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-associated multicentric Castleman disease, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell related lymphoma. 
     
     
         18 . An isolated antibody, or an antigen binding fragment thereof, which specifically binds to CD3, wherein the antibody comprises a VH CDR1, VH CDR2, and VH CDR3 of 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 (VL) region comprising 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. 
     
     
         19 . The antibody or the antigen binding fragment of  claim 18 , wherein the antibody comprises a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 324 or 388; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 323 or 387. 
     
     
         20 . The antibody or the antigen binding fragment of  claim 18 , wherein the VH region comprises (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 402, 403, 407, 408, 415, 416, 418, 419, 420, 424, 425, 426, 446, 447, or 448 (ii) 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 iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429, or 451; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435, or 440, 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452, or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453. 
     
     
         21 . The antibody or the antigen binding fragment of  claim 20 , wherein the VH region comprises (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 407, or 408 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 336, 404, 405, or 417; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335 or 406; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343 or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341 or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342 or 439. 
     
     
         22 . An isolated antibody which specifically binds to CD3 and competes with the antibody of  claim 21 . 
     
     
         23 . An isolated polynucleotide comprising a nucleotide sequence encoding the antibody of  claim 18 . 
     
     
         24 . A vector comprising the polynucleotide of  claim 23 . 
     
     
         25 . An isolated host cell that recombinantly produces the antibody or the antigen binding fragment of  claim 18 . 
     
     
         26 . A method of producing an antibody, comprising culturing the host cell of  claim 25  under conditions that result in production of the antibody, and isolating the antibody from the host cell or culture. 
     
     
         27 . A bispecific antibody wherein the bispecific antibody 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 the 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 variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of 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 (VL) region comprising 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. 
     
     
         28 . The bispecific antibody of  claim 27 , wherein the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown 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 (ii) 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 iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335, 406, 423, 429, or 451; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 340, 343, 430, 431, 435, 440, or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341, 433, 452, or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342, 432, 434, 437, 438, 439, 446, or 453. 
     
     
         29 . The bispecific antibody of  claim 28 , wherein the first antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 324 or 388; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 323 or 387; and the second antibody variable domain comprises a heavy chain variable (VH) region comprising a VH CDR1, VH CDR2, and VH CDR3 of the VH sequence shown in SEQ ID NO: 112; and/or a light chain variable (VL) region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence shown in SEQ ID NO: 38. 
     
     
         30 . The bispecific antibody of  claim 27 , wherein the second antibody variable domain comprises
 a. a heavy chain variable (VH) region comprising (i) 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); (ii) 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 X 10  is G or T (SEQ ID NO: 305), or 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 (SEQ ID NO: 306); and iii) a VH CDR3 comprising the sequence VSPIX 1 X 2 X 3 X 4  wherein 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), or YWPMX 1 X 2 , wherein X 1  is D, S, T, or A; and X 2  is I, S, L, P, or D (SEQ ID NO: 308); and/or   b. a light chain variable (VL) region comprising (i) 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, 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; and X 12  is A, S, or G (SEQ ID NO: 309); (ii) 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 (iii) 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).   
     
     
         31 . The bispecific antibody of  claim 27 , wherein the second antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO:150, 151, 152, 156, 157, 348, 349, 353, 354, or 355; (ii) a VH CDR2 comprising the sequence shown 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 (iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 155, 161, 197, 205,164, or 352, or 358; and/or wherein the light chain variable (VL) region comprises (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209, 271, 273, 275, 251, 277, 260, 279, 245, 283, 285, 287, 290, 292, 235, 297, 299, or 361; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221, 359 or 362; and (iii) a VL CDR3 comprising the sequence shown 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. 
     
     
         32 . The bispecific antibody of  claim 31 , wherein the
 a. first antibody variable domain comprises a heavy chain variable (VH) region comprising (i) a VH complementarity determining region one (CDR1) comprising the sequence shown in SEQ ID NO: 331, 332, 333, 401, 407, or 408 (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 336, 417, 404, or 405; and iii) a VH CDR3 comprising the sequence shown in SEQ ID NO: 335 or 406; and/or a light chain variable (VL) region comprising (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 343 or 441; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 341 or 436; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 342 or 439; and the   b. the second antibody variable domain comprises a heavy chain VH region comprising a heavy chain variable (VH) region comprising (i) a VH CDR1 comprising the sequence shown in SEQ ID NO: 151, 156, or 157; (ii) a VH CDR2 comprising the sequence shown in SEQ ID NO: 158 OR 159; and (iii) a VH CDR3 comprising SEQ ID NO: 155; and/or wherein the light chain variable (VL) region comprises (i) a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; (ii) a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and (iii) a VL CDR3 comprising the sequence shown in SEQ ID NO: 225.   
     
     
         33 . The bispecific antibody of  claim 27 , wherein both the first and the second antibody variable domains of the heterodimeric protein comprise amino acid modifications at positions 223, 225, and 228 in the hinge region and at position 409 or 368 (EU numbering scheme) in the CH3 region of a human IgG2 (SEQ ID NO: 493). 
     
     
         34 . The bispecific antibody of  claim 33 , further comprising an amino acid modification at position 265 of the human IgG2. 
     
     
         35 . A nucleic acid encoding the antibody of  claim 27 . 
     
     
         36 . A vector comprising the nucleic acid of  claim 35 . 
     
     
         37 . A host cell comprising the nucleic acid of  claim 35  or the vector of  claim 36 . 
     
     
         38 . A pharmaceutical composition comprising the bispecific antibody of  claim 27 . 
     
     
         39 . A method of treating a condition associated with malignant cells expressing a tumor antigen in a subject comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of  claim 38 . 
     
     
         40 . The method of  claim 39 , wherein the condition is a cancer. 
     
     
         41 . The method of  claim 40 , wherein the cancer is a B-cell related cancer selecting from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte predominant Hodgkin's lymphoma, Kahler's 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 macroglobulienemia, diffuse large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosa-associated lymphatic tissue lymphoma, small cell lymphocytic lymphoma, mantle cell lymphoma, Burkitt lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmactyic lymphoma, Waldenström macroglobulinemia, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell/histiocyte-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-associated multicentric Castleman disease, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other B-cell related lymphoma. 
     
     
         42 . A method of inhibiting tumor growth or progression in a subject who has malignant cells expressing BCMA, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition comprising the bispecific antibody of  claim 30  to the subject. 
     
     
         43 . A method of inhibiting metastasis of malignant cells expressing BCMA in a subject, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition comprising the bispecific antibody of  claim 30  to the subject. 
     
     
         44 . A method of inducing tumor regression in a subject who has malignant cells expressing BCMA, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition comprising the bispecific antibody of  claim 30  to the subject. 
     
     
         45 . A method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition comprising the bispecific antibody of  claim 30  to the subject and one or more other therapeutic agent selecting from the group consisting of bortezomib, lenalidomide, carfilzomib, and doxorubicin.