Bcma antibodies and use of same to treat cancer and immunological disorders

Abstract

The invention provides humanized antibodies that specifically bind to BCMA. The antibodies are useful for treatment and diagnoses of various cancers and immune disorders as well as detecting BCMA.

1 . A humanized, chimeric or veneered antibody, which is a humanized, chimeric or veneered form of an antibody deposited as ATCC PTC-6937. 
     
     
         2 . The antibody of  claim 1 , comprising a mature heavy chain variable region having at least 90% sequence identity to hSG16.17 VI-13 (SEQ ID NO: 13) and a mature light chain variable region having at least 90% sequence identity to hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         3 . The antibody of  claim 2 , comprising a mature heavy chain variable region having at least 95% sequence identity to hSG16.17 VH3 (SEQ ID NO: 13) and a mature light chain variable region having at least 95% sequence identity to hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         4 . The antibody of  claim 1 , comprising the three Kabat CDRs (SEQ ID NOs: 60-62) of hSG16.17 VH3 (SEQ ID NO: 13) and three Kabat CDRs (SEQ ID NOs: 90-92) of hSG16.17 VK2 (SEQ ID NO: 19) provided that position H58 can be occupied by N or K, position H60 can be occupied by A or N, position H61 can be occupied by Q or E, position H62 can be occupied by K or N, position H64 can be occupied by Q or K, position H65 can be occupied by G or T, position L24 can be occupied by R or L, and position L53 can be occupied by S or R. 
     
     
         5 . The antibody of  claim 1  comprising the three Kabat CDRs (SEQ ID NOs: 60-62) of hSG16.17 VH3 (SEQ ID NO: 13) and three Kabat CDRs (SEQ ID NOs: 90-92) of hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         6 . The antibody of  claim 1 , wherein positions H20, H48, H69, H71, H73, H76, H80, H88, H91 and H93 are occupied by L, I, M, A, K, N, V, A, F, and T respectively, and positions L46, L48 and L87 are occupied by V, V and F respectively. 
     
     
         7 . The antibody of  claim 1 , wherein the mature heavy chain variable has the sequence of hSG16.17 VH3 (SEQ ID NO: 13) and the mature light chain variable region has the sequence of hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         8 . The antibody of  claim 3 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region. 
     
     
         9 . The antibody of  claim 6 , wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcγ receptor relative to the natural human constant region. 
     
     
         10 . The antibody of  claim 8  or  9 , wherein the heavy chain constant region is of IgG1 isotype. 
     
     
         11 . The antibody of  claims 8 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO: 5 and the light chain constant region has an amino acid sequence comprising SEQ ID NO: 3. 
     
     
         12 . The antibody of  claim 8 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:7 (S239C) and the light chain constant region has an amino acid sequence comprising SEQ ID NO:3. 
     
     
         13 . The antibody of  claim 3 , which is a naked antibody. 
     
     
         14 . The antibody of  claim 3 , wherein the antibody is conjugated to a cytotoxic or cytostatic agent. 
     
     
         15 . The antibody of  claim 14 , wherein the antibody is conjugated to a cytotoxic agent. 
     
     
         16 . The antibody of  claim 15 , wherein the cytotoxic agent is conjugated to the antibody via an enzyme cleavable linker. 
     
     
         17 . The antibody of  claim 15 , wherein the cytotoxic agent is a DNA minor groove binder. 
     
     
         18 . The antibody of  claim 17 , wherein the cytotoxic agent has the formula 
       
         
           
           
               
               
           
         
       
     
     
         19 . The antibody of  claim 15 , wherein the cytotoxic agent is MMAE or MMAF. 
     
     
         20 . A pharmaceutical composition comprising an antibody of any preceding claim and a pharmaceutically acceptable carrier. 
     
     
         21 . A method of treating a patient having or at risk of having a cancer that expresses BCMA comprising administering to the patient an effective regimen of an antibody of  claim 1 . 
     
     
         22 . The method of  claim 20 , wherein the cancer is a hematological cancer. 
     
     
         23 . The method of  claim 22 , wherein the hematological cancer is a myeloma, leukemia or a lymphoma. 
     
     
         24 . The method of  claim 22 , wherein the hematological cancer is multiple myeloma. 
     
     
         25 . The method of  claim 22 , wherein the hematological cancer is non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma. 
     
     
         26 . The method of  claim 22 , wherein the hematological cancer is myelodysplastic syndromes (MDS), myeloproliferative syndromes (MPS), Waldenström's macroglobulinemia or Burkett's lymphoma. 
     
     
         27 . A method of treating a patient having or at risk of having an immune disorder mediated by immune cells expressing BCMA comprising administering to the patient an effective regimen of a humanized antibody of  claim 1 . 
     
     
         28 . The method of  claim 27 , which is a B cell mediated disorder. 
     
     
         29 . The method of  claim 27 , wherein the immune disorder is rheumatoid arthritis, systemic lupus E (SLE), Type I diabetes, asthma, atopic dermitus, allergic rhinitis, thrombocytopenic purpura, multiple sclerosis, psoriasis, Sjorgren's syndrome, Hashimoto's thyroiditis, Grave's disease, primary biliary cirrhosis, Wegener's granulomatosis, tuberculosis, and graft versus host disease. 
     
     
         30 . A humanized, chimeric or veneered antibody, which is a humanized, chimeric or veneered form of the rat SG16.45 antibody having a mature heavy chain variable region of SEQ ID NO: 23 and a mature light chain variable region of SEQ ID NO: 33. 
     
     
         31 . The antibody of  claim 30 , comprising a mature heavy chain variable region having at least 90% sequence identity to hSG16.45 VH5 (SEQ ID NO: 31) and a mature light chain variable region having at least 90% sequence identity to hSG16.45 VK2 (SEQ ID NO: 36). 
     
     
         32 . The antibody of  claim 31 , comprising a mature heavy chain variable region having at least 95% sequence identity to hSG16.45 VH5 (SEQ ID NO: 31) and a mature light chain variable region having at least 95% sequence identity to hSG16.45 VK2 (SEQ ID NO: 36). 
     
     
         33 . The antibody of  claim 30 , comprising the three Kabat CDRs (SEQ ID NOs: 152-154) of hSG16.45 VH5 (SEQ ID NO: 31) and three Kabat CDRs (SEQ ID NOs: 179-181) of hSG16.45 VK2 (SEQ ID NO: 36) provided that position H50 can be occupied by A or S, position L24 can be occupied by R or L and position L26 can be occupied by S or T. 
     
     
         34 . The antibody of  claim 30  comprising the three Kabat CDRs (SEQ ID NOs: 152-154) of hSG16.45 VH5 (SEQ ID NO: 31) and three Kabat CDRs (SEQ ID NOs: 179-181) of hSG16.45 VK2 (SEQ ID NO: 36). 
     
     
         35 . The antibody of  claim 34 , wherein positions H30, H93 and H94 are occupied by N, T and S respectively. 
     
     
         36 . The antibody of  claim 30 , wherein the mature heavy chain variable region has the sequence of hSG16.45 VH5 (SEQ ID NO: 31) and the mature light chain variable region has the sequence of hSG16.45 VK2 (SEQ ID NO: 36) or the mature heavy chain variable region has the sequence of hSG16.45 VH1 (SEQ ID NO: 27) and the mature light chain variable region has the sequence of hSG16.45 VK1 (SEQ ID NO: 35) or the mature heavy chain variable region has the sequence of hSG16.45 VH1 (SEQ ID NO: 27) and the mature light chain variable region has the sequence of hSG16.45 VK3 (SEQ ID NO: 37). 
     
     
         37 . The antibody of  claim 30 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region. 
     
     
         38 . The antibody of  claim 37 , wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcγ receptor relative to the natural human constant region. 
     
     
         39 . The antibody of  claim 37 , wherein the heavy chain constant region is of IgG1 isotype. 
     
     
         40 . The antibody of  claims 37 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO: 5 and the light chain constant region has an amino acid sequence comprising SEQ ID NO: 3. 
     
     
         41 . The antibody of  claim 37 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:7 (S239C) and the light chain constant region has an amino acid sequence comprising SEQ ID NO:3. 
     
     
         42 . The antibody of  claim 30 , which is a naked antibody. 
     
     
         43 . The antibody of  claim 30 , wherein the antibody is conjugated to a cytotoxic or cytostatic agent. 
     
     
         44 . The antibody of  claim 43 , wherein the antibody is conjugated to a cytotoxic agent. 
     
     
         45 . The antibody of  claim 44 , wherein the cytotoxic agent is conjugated to the antibody via an enzyme cleavable linker. 
     
     
         46 . The antibody of  claim 43 , wherein the cytotoxic agent is a DNA minor groove binder. 
     
     
         47 . The antibody of  claim 46 , wherein the cytotoxic agent has the formula 
       
         
           
           
               
               
           
         
       
     
     
         48 . The antibody of  claim 44 , wherein the cytotoxic agent is MMAE or MMAF. 
     
     
         49 . The antibody of  claim 1  or  claim 30 , wherein less than 5% of N-glycoside linked sugar chains at an asn residue at EU position 297 of heavy chain constant region include fucose or an analog thereof in which cells expressing the antibody were cultured to reduce fucosylation of the antibody. 
     
     
         50 . A pharmaceutical composition comprising an antibody of  claim 30  and a pharmaceutically acceptable carrier. 
     
     
         51 . A method of treating a patient having or at risk of having a cancer that expresses BCMA comprising administering to the patient an effective regimen of a humanized antibody of  claim 30 . 
     
     
         52 . The method of  claim 51 , wherein the cancer is a hematological cancer. 
     
     
         53 . The method of  claim 52 , wherein the hematological cancer is a myeloma, leukemia or a lymphoma. 
     
     
         54 . The method of  claim 52 , wherein the hematological cancer is multiple myeloma. 
     
     
         55 . The method of  claim 52 , wherein the hematological cancer is non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma. 
     
     
         56 . The method of  claim 52 , wherein the hematological cancer is myelodysplastic syndromes (MDS), myeloproliferative syndromes (MPS), Waldenström's macroglobulinemia or Burkett's lymphoma. 
     
     
         57 . A method of treating a patient having or at risk of having an immune disorder mediated by immune cells expressing BCMA comprising administering to the patient an effective regimen of an antibody of  claim 30 . 
     
     
         58 . The method of  claim 56 , which is a B cell mediated disorder. 
     
     
         59 . The method of  claim 56 , wherein the immune disorder is rheumatoid arthritis, systemic lupus E (SLE), Type I diabetes, asthma, atopic dermitus, allergic rhinitis, thrombocytopenic purpura, multiple sclerosis, psoriasis, Sjorgren's syndrome, Hashimoto's thyroiditis, Grave's disease, primary biliary cirrhosis, Wegener's granulomatosis, tuberculosis, and graft versus host disease. 
     
     
         60 . A humanized antibody the specifically binds to the human BCMA protein, the antibody comprising a mature heavy chain variable region having at least 90% sequence identity to hSG16.17 VH3 (SEQ ID NO: 13) and a mature light chain variable region having at least 90% sequence identity to hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         61 . The antibody of  claim 60 , comprising a mature heavy chain variable region having at least 95% sequence identity to hSG16.17 VH3 (SEQ ID NO: 13) and a mature light chain variable region having at least 95% sequence identity to hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         62 . The antibody of  claim 60 , comprising the three Kabat CDRs (SEQ ID NOs: 60-62) of hSG16.17 VH3 (SEQ ID NO: 13) and three Kabat CDRs (SEQ ID NOs: 90-92) of hSG16.17 VK2 (SEQ ID NO: 19) provided that position H58 can be occupied by N or K, position H60 can be occupied by A or N, position H61 can be occupied by Q or E, position H62 can be occupied by K or N, position H64 can be occupied by Q or K, position H65 can be occupied by G or T, position L24 can be occupied by R or L, and position L53 can be occupied by S or R. 
     
     
         63 . The antibody of  claim 60  comprising the three Kabat CDRs (SEQ ID NOs: 60-62) of hSG16.17 VH3 (SEQ ID NO: 13) and three Kabat CDRs (SEQ ID NOs: 90-92) of hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         64 . The antibody of  claim 60 , wherein positions H20, H48, H69, H71, H73, H76, H80, H88, H91 and H93 are occupied by L, I, M, A, K, N, V, A, F, and T respectively, and positions L46, L48 and L87 are occupied by V, V and F respectively. 
     
     
         65 . The antibody of  claim 60 , wherein the mature heavy chain variable has the sequence of hSG16.17 VH3 (SEQ ID NO: 13) and the mature light chain variable region has the sequence of hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         66 . The antibody of  claim 60 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region. 
     
     
         67 . The antibody of  claim 65 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region. 
     
     
         68 . A pharmaceutical composition comprising an antibody of  claim 67  and a pharmaceutically acceptable carrier. 
     
     
         69 . The pharmaceutical composition of  claim 68 , wherein less than about 10% of the antibodies have core fucosylation by fucose or a fucose analogue. 
     
     
         70 . The pharmaceutical composition of  claim 68 , wherein less than about 5% of the antibodies have core fucosylation by fucose or a fucose analogue. 
     
     
         71 . The pharmaceutical composition of  claim 69 , wherein about 2% of the antibodies have core fucosylation by fucose or a fucose analogue. 
     
     
         72 . A nucleic acid encoding a mature heavy chain variable region and/or a mature light chain variable region of a humanized antibody that specifically binds to the human BCMA protein, the antibody comprising a mature heavy chain variable region having at least 90% sequence identity to hSG16.17 VH3 (SEQ ID NO: 13) and a mature light chain variable region having at least 90% sequence identity to hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         73 . The nucleic acid of  claim 72 , wherein the antibody comprises a mature heavy chain variable region having at least 95% sequence identity to hSG16.17 VH3 (SEQ ID NO: 13) and a mature light chain variable region having at least 95% sequence identity to hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         74 . The nucleic acid of  claim 72 , wherein the antibody comprises the three Kabat CDRs (SEQ ID NOs: 60-62) of hSG16.17 VH3 (SEQ ID NO: 13) and three Kabat CDRs (SEQ ID NOs: 90-92) of hSG16.17 VK2 (SEQ ID NO: 19) provided that position H58 can be occupied by N or K, position H60 can be occupied by A or N, position H61 can be occupied by Q or E, position H62 can be occupied by K or N, position H64 can be occupied by Q or K, position H65 can be occupied by G or T, position L24 can be occupied by R or L, and position L53 can be occupied by S or R. 
     
     
         75 . The nucleic acid of  claim 72 , wherein the antibody comprises the three Kabat CDRs (SEQ ID NOs: 60-62) of hSG16.17 VH3 (SEQ ID NO: 13) and three Kabat CDRs (SEQ ID NOs: 90-92) of hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         76 . The nucleic acid of  claim 72 , wherein positions H20, H48, H69, H71, H73, H76, H80, H88, H91 and H93 of the antibody are occupied by L, I, M, A, K, N, V, A, F, and T respectively, and positions L46, L48 and L87 are occupied by V, V and F respectively. 
     
     
         77 . The nucleic acid of  claim 72 , wherein the mature heavy chain variable region of the antibody has the sequence of hSG16.17 VH3 (SEQ ID NO: 13) and the mature light chain variable region of the antibody has the sequence of hSG16.17 VK2 (SEQ ID NO: 19). 
     
     
         78 . The nucleic acid of  claim 72 , wherein the mature heavy chain variable region of the antibody is fused to a heavy chain constant region and the mature light chain variable region of the antibody is fused to a light chain constant region. 
     
     
         79 . The nucleic acid of  claim 77 , wherein the mature heavy chain variable region of the antibody is fused to a heavy chain constant region and the mature light chain variable region of the antibody is fused to a light chain constant region. 
     
     
         80 . A vector comprising a nucleic acid of  claim 72 . 
     
     
         81 . A vector comprising a nucleic acid of  claim 77 . 
     
     
         82 . A first and a second vector comprising nucleic acids that encode the sequence of hSG16.17 VH3 (SEQ ID NO: 13) and the sequence of hSG16.17 VK2 (SEQ ID NO: 19), respectively. 
     
     
         83 . A host cell containing a vector or vectors according to  claims 80 - 82 . 
     
     
         84 . A nucleic acid encoding a mature heavy chain variable region and/or a mature light chain variable region of a humanized antibody that specifically binds to the human BCMA protein, the antibody a mature heavy chain variable region having at least 90% sequence identity to hSG16.45 VH5 (SEQ ID NO: 31) and a mature light chain variable region having at least 90% sequence identity to hSG16.45 VK2 (SEQ ID NO: 36). 
     
     
         85 . The nucleic acid of  claim 84 , wherein the antibody comprises a mature heavy chain variable region having at least 95% sequence identity to hSG16.45 VH5 (SEQ ID NO: 31) and a mature light chain variable region having at least 95% sequence identity to hSG16.45 VK2 (SEQ ID NO: 36). 
     
     
         86 . The nucleic acid of  claim 84 , wherein the antibody comprises the three Kabat CDRs (SEQ ID NOs: 152-154) of hSG16.45 VH5 (SEQ ID NO: 31) and three Kabat CDRs (SEQ ID NOs: 179-181) of hSG16.45 VK2 (SEQ ID NO: 36) provided that position H50 can be occupied by A or S, position L24 can be occupied by R or L and position L26 can be occupied by S or T. 
     
     
         87 . The nucleic acid of  claim 84 , wherein the antibody comprises the three Kabat CDRs (SEQ ID NOs: 152-154) of hSG16.45 VH5 (SEQ ID NO: 31) and three Kabat CDRs (SEQ ID NOs: 179-181) of hSG16.45 VK2 (SEQ ID NO: 36). 
     
     
         88 . The nucleic acid of  claim 84 , wherein positions H30, H93 and H94 of the antibody are occupied by N, T and S respectively. 
     
     
         89 . The nucleic acid of  claim 84 , wherein the mature heavy chain variable region of the antibody has the sequence of hSG16.45 VH5 (SEQ ID NO: 31) and the mature light chain variable region of the antibody has the sequence of hSG16.45 VK2 (SEQ ID NO: 36) or the mature heavy chain variable region of the antibody has the sequence of hSG16.45 VH1 (SEQ ID NO: 27) and the mature light chain variable region of the antibody has the sequence of hSG16.45 VK1 (SEQ ID NO: 35) or the mature heavy chain variable region of the antibody has the sequence of hSG16.45 VH1 (SEQ ID NO: 27) and the mature light chain variable region of the antibody has the sequence of hSG16.45 VK3 (SEQ ID NO: 37). 
     
     
         90 . The nucleic acid of  claim 84 , wherein the mature heavy chain variable region of the antibody is fused to a heavy chain constant region and the mature light chain variable region of the antibody is fused to a light chain constant region. 
     
     
         91 . The nucleic acid of  claim 89 , wherein the mature heavy chain variable region of the antibody is fused to a heavy chain constant region and the mature light chain variable region of the antibody is fused to a light chain constant region. 
     
     
         92 . A vector comprising a nucleic acid of  claim 90 . 
     
     
         93 . A vector comprising a nucleic acid of  claim 91 . 
     
     
         94 . A host cell containing a vector or vectors according to  claims 92 - 93 .