# US 2013/0156770 A1 · Binding molecules for bcma and cd3 > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2013/0156770 A1 - Document ID: US20130156770A1 - Status: Published application - Kind: A1 - Application number: 13/678,264 - Filed: 2012-11-15 - Published: 2013-06-20 - Earliest claimed: 2011-11-15 - Assignees: Boehringer Ingelheim International GmbH; Amgen Research (Munich) GmbH - Inventors: Peter Kufer; Tobias Raum; Patrick Hoffmann; Roman Kischel; Ralf Lutterbuese; Doris Rau; Paul Adam; Eric Borges; Barbara Hebeis; Susanne Hipp - Web page: https://patentgrep.com/patent/US20130156770A1 ## CPC - C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies} - A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)} - A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) - A61P 7/00: Drugs for disorders of the blood or the extracellular fluid - A61P 17/00: Drugs for dermatological disorders - A61P 19/00: Drugs for skeletal disorders - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61P 35/04: specific for metastasis - A61P 37/00: Drugs for immunological or allergic disorders - A61P 37/02: Immunomodulators - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)} - C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex} - C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)} - C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95} - A61K 2039/505: {comprising antibodies} - A61K 2039/575: {humoral response} - C07K 2317/31: multispecific - C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity - C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues - C07K 2317/56: variable (Fv) region, i.e. VH and/or VL - C07K 2317/565: Complementarity determining region [CDR] - C07K 2317/622: Single chain antibody (scFv) - C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation - C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value - C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance - C07K 2319/00: Fusion polypeptide - C07K 2319/21: containing a His-tag - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - C07K 2319/31: fusions, other than Fc, for prolonged plasma life, e.g. albumin - C07K 2319/43: containing a FLAG-tag - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to a binding molecule comprising a first and a second binding domain, wherein the first binding domain is capable of binding to epitope clusters of BCMA, and the second binding domain is capable of binding to the T cell CD3 receptor complex. Moreover, the invention provides a nucleic acid sequence encoding the binding molecule, a vector comprising said nucleic acid sequence and a host cell transformed or transfected with said vector. Furthermore, the invention provides a process for the production of the binding molecule of the invention, a medical use of said binding molecule and a kit comprising said binding molecule. ## Claims ### Claim 1 A binding molecule which is at least bispecific comprising a first and a second binding domain, wherein (a) the first binding domain is capable of binding to epitope cluster 3 and to epitope cluster 4 of BCMA; and (b) the second binding domain is capable of binding to the T cell CD3 receptor complex; and wherein epitope cluster 3 of BCMA corresponds to amino acid residues 24 to 41 of the sequence as depicted in SEQ ID NO: 1002, and epitope cluster 4 of BCMA corresponds to amino acid residues 42 to 54 of the sequence as depicted in SEQ ID NO: 1002. ### Claim 2 (depends on 1) The binding molecule of claim 1, wherein the first binding domain is not capable of binding to the chimeric extracellular domain of BCMA as depicted in SEQ ID NO: 1015. ### Claim 3 (depends on 1) The binding molecule according to claim 1, wherein the first binding domain is further capable of binding to macaque BCMA. ### Claim 4 (depends on 1) The binding molecule according to claim 1, wherein the second binding domain is capable of binding to CD3 epsilon. ### Claim 5 (depends on 1) The binding molecule according to claim 1, wherein the second binding domain is capable of binding to human CD3 and to macaque CD3. ### Claim 6 (depends on 1) The binding molecule according to claim 1, wherein the first and/or the second binding domain are derived from an antibody. ### Claim 7 (depends on 6) The binding molecule according to claim 6, which is selected from the group consisting of (scFv)2, (single domain mAb)2, scFv-single domain mAb, diabodies and oligomers thereof. ### Claim 8 (depends on 1) The binding molecule according to claim 1, wherein the first binding domain comprises a VH region comprising CDR-H1, CDR-H2 and CDR-H3 and a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of: (a) CDR-H1 as depicted in SEQ ID NO: 231, CDR-H2 as depicted in SEQ ID NO: 232, CDR-H3 as depicted in SEQ ID NO: 233, CDR-L1 as depicted in SEQ ID NO: 234, CDR-L2 as depicted in SEQ ID NO: 235 and CDR-L3 as depicted in SEQ ID NO: 236; (b) CDR-H1 as depicted in SEQ ID NO: 241, CDR-H2 as depicted in SEQ ID NO: 242, CDR-H3 as depicted in SEQ ID NO: 243, CDR-L1 as depicted in SEQ ID NO: 244, CDR-L2 as depicted in SEQ ID NO: 245 and CDR-L3 as depicted in SEQ ID NO: 246; (c) CDR-H1 as depicted in SEQ ID NO: 251, CDR-H2 as depicted in SEQ ID NO: 252, CDR-H3 as depicted in SEQ ID NO: 253, CDR-L1 as depicted in SEQ ID NO: 254, CDR-L2 as depicted in SEQ ID NO: 255 and CDR-L3 as depicted in SEQ ID NO: 256; (d) CDR-H1 as depicted in SEQ ID NO: 261, CDR-H2 as depicted in SEQ ID NO: 262, CDR-H3 as depicted in SEQ ID NO: 263, CDR-L1 as depicted in SEQ ID NO: 264, CDR-L2 as depicted in SEQ ID NO: 265 and CDR-L3 as depicted in SEQ ID NO: 266; (e) CDR-H1 as depicted in SEQ ID NO: 271, CDR-H2 as depicted in SEQ ID NO: 272, CDR-H3 as depicted in SEQ ID NO: 273, CDR-L1 as depicted in SEQ ID NO: 274, CDR-L2 as depicted in SEQ ID NO: 275 and CDR-L3 as depicted in SEQ ID NO: 276; (f) CDR-H1 as depicted in SEQ ID NO: 281, CDR-H2 as depicted in SEQ ID NO: 282, CDR-H3 as depicted in SEQ ID NO: 283, CDR-L1 as depicted in SEQ ID NO: 284, CDR-L2 as depicted in SEQ ID NO: 285 and CDR-L3 as depicted in SEQ ID NO: 286; (g) CDR-H1 as depicted in SEQ ID NO: 291, CDR-H2 as depicted in SEQ ID NO: 292, CDR-H3 as depicted in SEQ ID NO: 293, CDR-L1 as depicted in SEQ ID NO: 294, CDR-L2 as depicted in SEQ ID NO: 295 and CDR-L3 as depicted in SEQ ID NO: 296; (h) CDR-H1 as depicted in SEQ ID NO: 301, CDR-H2 as depicted in SEQ ID NO: 302, CDR-H3 as depicted in SEQ ID NO: 303, CDR-L1 as depicted in SEQ ID NO: 304, CDR-L2 as depicted in SEQ ID NO: 305 and CDR-L3 as depicted in SEQ ID NO: 306; (i) CDR-H1 as depicted in SEQ ID NO: 391, CDR-H2 as depicted in SEQ ID NO: 392, CDR-H3 as depicted in SEQ ID NO: 393, CDR-L1 as depicted in SEQ ID NO: 394, CDR-L2 as depicted in SEQ ID NO: 395 and CDR-L3 as depicted in SEQ ID NO: 396; (k) CDR-H1 as depicted in SEQ ID NO: 401, CDR-H2 as depicted in SEQ ID NO: 402, CDR-H3 as depicted in SEQ ID NO: 403, CDR-L1 as depicted in SEQ ID NO: 404, CDR-L2 as depicted in SEQ ID NO: 405 and CDR-L3 as depicted in SEQ ID NO: 406; (l) CDR-H1 as depicted in SEQ ID NO: 411, CDR-H2 as depicted in SEQ ID NO: 412, CDR-H3 as depicted in SEQ ID NO: 413, CDR-L1 as depicted in SEQ ID NO: 414, CDR-L2 as depicted in SEQ ID NO: 415 and CDR-L3 as depicted in SEQ ID NO: 416; (m) CDR-H1 as depicted in SEQ ID NO: 421, CDR-H2 as depicted in SEQ ID NO: 422, CDR-H3 as depicted in SEQ ID NO: 423, CDR-L1 as depicted in SEQ ID NO: 424, CDR-L2 as depicted in SEQ ID NO: 425 and CDR-L3 as depicted in SEQ ID NO: 426; (n) CDR-H1 as depicted in SEQ ID NO: 431, CDR-H2 as depicted in SEQ ID NO: 432, CDR-H3 as depicted in SEQ ID NO: 433, CDR-L1 as depicted in SEQ ID NO: 434, CDR-L2 as depicted in SEQ ID NO: 435 and CDR-L3 as depicted in SEQ ID NO: 436; (o) CDR-H1 as depicted in SEQ ID NO: 441, CDR-H2 as depicted in SEQ ID NO: 442, CDR-H3 as depicted in SEQ ID NO: 443, CDR-L1 as depicted in SEQ ID NO: 444, CDR-L2 as depicted in SEQ ID NO:445 and CDR-L3 as depicted in SEQ ID NO: 446; (p) CDR-H1 as depicted in SEQ ID NO: 451, CDR-H2 as depicted in SEQ ID NO: 452, CDR-H3 as depicted in SEQ ID NO: 453, CDR-L1 as depicted in SEQ ID NO: 454, CDR-L2 as depicted in SEQ ID NO: 455 and CDR-L3 as depicted in SEQ ID NO: 456; (q) CDR-H1 as depicted in SEQ ID NO: 461, CDR-H2 as depicted in SEQ ID NO: 462, CDR-H3 as depicted in SEQ ID NO: 463, CDR-L1 as depicted in SEQ ID NO: 464, CDR-L2 as depicted in SEQ ID NO: 465 and CDR-L3 as depicted in SEQ ID NO: 466; (r) CDR-H1 as depicted in SEQ ID NO: 471, CDR-H2 as depicted in SEQ ID NO: 472, CDR-H3 as depicted in SEQ ID NO: 473, CDR-L1 as depicted in SEQ ID NO: 474, CDR-L2 as depicted in SEQ ID NO: 475 and CDR-L3 as depicted in SEQ ID NO: 476; (s) CDR-H1 as depicted in SEQ ID NO: 481, CDR-H2 as depicted in SEQ ID NO: 482, CDR-H3 as depicted in SEQ ID NO: 483, CDR-L1 as depicted in SEQ ID NO: 484, CDR-L2 as depicted in SEQ ID NO: 485 and CDR-L3 as depicted in SEQ ID NO: 486; (t) CDR-H1 as depicted in SEQ ID NO: 491, CDR-H2 as depicted in SEQ ID NO: 492, CDR-H3 as depicted in SEQ ID NO: 493, CDR-L1 as depicted in SEQ ID NO: 494, CDR-L2 as depicted in SEQ ID NO: 495 and CDR-L3 as depicted in SEQ ID NO: 496; and (u) CDR-H1 as depicted in SEQ ID NO: 501, CDR-H2 as depicted in SEQ ID NO: 502, CDR-H3 as depicted in SEQ ID NO: 503, CDR-L1 as depicted in SEQ ID NO: 504, CDR-L2 as depicted in SEQ ID NO: 505 and CDR-L3 as depicted in SEQ ID NO: 506. ### Claim 9 (depends on 1) The binding molecule according to claim 1, wherein the first binding domain comprises a VH region selected from the group consisting of VH regions as depicted in SEQ ID NO: 237, SEQ ID NO: 247, SEQ ID NO: 257, SEQ ID NO: 267, SEQ ID NO: 277, SEQ ID NO: 287, SEQ ID NO: 297, SEQ ID NO: 307, SEQ ID NO: 397, SEQ ID NO: 407, SEQ ID NO: 417, SEQ ID NO: 427, SEQ ID NO: 437, SEQ ID NO: 447, SEQ ID NO: 457, SEQ ID NO: 467, SEQ ID NO: 477, SEQ ID NO: 487, SEQ ID NO: 497, and SEQ ID NO: 507. ### Claim 10 (depends on 1) The binding molecule according to claim 1, wherein the first binding domain comprises a VL region selected from the group consisting of VL regions as depicted in SEQ ID NO: 238, SEQ ID NO: 248, SEQ ID NO: 258, SEQ ID NO: 268, SEQ ID NO: 278, SEQ ID NO: 288, SEQ ID NO: 298, SEQ ID NO: 308, SEQ ID NO: 398, SEQ ID NO: 408, SEQ ID NO: 418, SEQ ID NO: 428, SEQ ID NO: 438, SEQ ID NO: 448, SEQ ID NO: 458, SEQ ID NO: 468, SEQ ID NO: 478, SEQ ID NO: 488, SEQ ID NO: 498, and SEQ ID NO: 508. ### Claim 11 (depends on 1) The binding molecule according to claim 1, wherein the first binding domain comprises a VH region and a VL region selected from the group consisting of: (a) a VH region as depicted in SEQ ID NO: 237, and a VL region as depicted in SEQ ID NO: 238; (b) a VH region as depicted in SEQ ID NO: 247, and a VL region as depicted in SEQ ID NO: 248; (c) a VH region as depicted in SEQ ID NO: 257, and a VL region as depicted in SEQ ID NO: 258; (d) a VH region as depicted in SEQ ID NO: 267, and a VL region as depicted in SEQ ID NO: 268; (e) a VH region as depicted in SEQ ID NO: 277, and a VL region as depicted in SEQ ID NO: 278; (f) a VH region as depicted in SEQ ID NO: 287, and a VL region as depicted in SEQ ID NO: 288; (g) a VH region as depicted in SEQ ID NO: 297, and a VL region as depicted in SEQ ID NO: 298; (h) a VH region as depicted in SEQ ID NO: 307, and a VL region as depicted in SEQ ID NO: 308; (i) a VH region as depicted in SEQ ID NO: 397, and a VL region as depicted in SEQ ID NO: 398; (k) a VH region as depicted in SEQ ID NO: 407, and a VL region as depicted in SEQ ID NO: 408; (l) a VH region as depicted in SEQ ID NO: 417, and a VL region as depicted in SEQ ID NO: 418; (m) a VH region as depicted in SEQ ID NO: 427, and a VL region as depicted in SEQ ID NO: 428; (n) a VH region as depicted in SEQ ID NO: 437, and a VL region as depicted in SEQ ID NO: 438; (o) a VH region as depicted in SEQ ID NO: 447, and a VL region as depicted in SEQ ID NO: 448; (p) a VH region as depicted in SEQ ID NO: 457, and a VL region as depicted in SEQ ID NO: 458; (q) a VH region as depicted in SEQ ID NO: 467, and a VL region as depicted in SEQ ID NO: 468; (r) a VH region as depicted in SEQ ID NO: 477, and a VL region as depicted in SEQ ID NO: 478; (s) a VH region as depicted in SEQ ID NO: 487, and a VL region as depicted in SEQ ID NO: 488; (t) a VH region as depicted in SEQ ID NO: 497, and a VL region as depicted in SEQ ID NO: 498; and (u) a VH region as depicted in SEQ ID NO: 507, and a VL region as depicted in SEQ ID NO: 508. ### Claim 12 (depends on 10) The binding molecule according to claim 10, wherein the first binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 239, SEQ ID NO: 249, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 399, SEQ ID NO: 409, SEQ ID NO: 419, SEQ ID NO: 429, SEQ ID NO: 439, SEQ ID NO: 449, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 489, SEQ ID NO: 499, and SEQ ID NO: 509. ### Claim 13 (depends on 1) The binding molecule according to claim 1 having the amino acid sequence shown in SEQ ID NO:300 or SEQ ID NO: 500. ### Claim 14 (depends on 1) A nucleic acid sequence encoding a binding molecule of claim 1 or a vector comprising a nucleic acid sequence encoding a binding molecule of claim 1. ### Claim 15 (depends on 14) A host cell transformed or transfected with the nucleic acid sequence or with the vector as defined in claim 14. ### Claim 16 (depends on 1, 15) A process for the production of a binding molecule according to claim 1, said process comprising (a) culturing the host cell as defined in claim 15 under conditions allowing the expression of the binding molecule and recovering the produced binding molecule from the culture; or (b) using epitope cluster 3 and epitope cluster 4 of BCMA for the generation of a binding molecule, preferably an antibody, which is capable of binding to BCMA, wherein epitope cluster 3 of BCMA corresponds to amino acid residues 24 to 41 of the sequence as depicted in SEQ ID NO: 1002, and epitope cluster 4 of BCMA corresponds to amino acid residues 42 to 54 of the sequence as depicted in SEQ ID NO: 1002; or (c) generating the binding molecule which is an antibody, which is capable of binding to BCMA, comprising (c1) immunizing an animal with a polypeptide comprising epitope cluster 3 and epitope cluster 4 of BCMA, wherein epitope cluster 3 of BCMA corresponds to amino acid residues 24 to 41 of the sequence as depicted in SEQ ID NO: 1002, and epitope cluster 4 of BCMA corresponds to amino acid residues 42 to 54 of the sequence as depicted in SEQ ID NO: 1002, (c2) obtaining said antibody, and optionally (c3) converting said antibody into a binding molecule which is capable of binding to human BCMA and preferably to the T cell CD3 receptor complex. ### Claim 17 (depends on 1, 16) A pharmaceutical composition comprising a binding molecule according to claim 1, or a binding molecule produced according to the process of claim 16. ### Claim 18 (depends on 1, 16) A method for the treatment or amelioration of a disease selected from the group consisting of plasma cell disorders and B cell disorders that correlate with BCMA expression and autoimmune diseases, comprising the step of administering to a subject in need thereof the binding molecule according to claim 1, or produced according to the process of claim 16. ### Claim 19 (depends on 18) The method according to claim 18, wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, plasmacytoma, plasma cell leukemia, macro-globulinemia, amyloidosis, Waldenstrom's macroglobulinemia, solitary bone plasmacytoma, extramedullary plasmacytoma, osteosclerotic myeloma, heavy chain diseases, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma. ### Claim 20 (depends on 18) The method according to claim 18, wherein the autoimmune disease is systemic lupus erythematodes. ### Claim 21 (depends on 1, 14, 15) A kit comprising a binding molecule as defined in claim 1, a nucleic acid molecule or vector as defined in claim 14, and/or a host cell as defined in claim 15.