Monoclonal antibodies against bcma

Abstract

The invention relates to new antibodies against BCMA, their manufacture and use.

1 .- 23 . (canceled) 
     
     
         24 . A method of treatment of a plasma cell disorder comprising administering to a subject in need thereof an antibody specifically binding to BCMA, wherein the antibody is characterized in comprising a VH region comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17 and a VL region comprising a CDR3L region having SEQ ID NO:20 and a CDR1L and CDR2L region combination selected from the group of:
 a) CDR1L region having SEQ ID NO:23 and CDR2L region having SEQ ID NO:24,   b) CDR1L region having SEQ ID NO:25 and CDR2L region having SEQ ID NO:26, and   c) CDR1L region having SEQ ID NO:27 and CDR2L region having SEQ ID NO:28.   
     
     
         25 . The method of  claim 24 , wherein the antibody is characterized in comprising a VH region comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17; and a VL region comprising a CDR1L region having SEQ ID NO:27, a CDR2L region having SEQ ID NO:28 and a CDR3L region having SEQ ID NO:20. 
     
     
         26 . The method of  claim 24 , wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis. 
     
     
         27 . The method of  claim 24 , wherein the plasma cell disorder is multiple myeloma. 
     
     
         28 . The method of  claim 24 , wherein the antibody is administered at a dose of 200 to 2000 mg/m 2 /week. 
     
     
         29 . The method of  claim 24 , wherein the antibody is characterized in comprising a VH region having SEQ ID NO:10 and a VL region selected from the group consisting of VL regions SEQ ID NO:12, 13, and 14. 
     
     
         30 . The method of  claim 25 , wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis. 
     
     
         31 . The method of  claim 25 , wherein the plasma cell disorder is multiple myeloma. 
     
     
         32 . A method of treatment of a plasma cell disorder comprising administering to a subject in need thereof a bispecific antibody specifically binding to BCMA and human CDR3ε (CD3), wherein the antibody is characterized in comprising a CDR3H region having SEQ ID NO:17 and a CDR3L region having SEQ ID NO:20 and a CDR1H, CDR2H, CDR1L, and CDR2L region combination selected from the group of:
 a) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:23, and CDR2L region having SEQ ID NO:24, 
 b) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:25, and CDR2L region having SEQ ID NO:26, 
 c) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:27, and CDR2L region having SEQ ID NO:28, 
 d) CDR1H region having SEQ ID NO:29 and CDR2H region having SEQ ID NO:30, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, 
 e) CDR1H region having SEQ ID NO:34 and CDR2H region having SEQ ID NO:35, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, and 
 f) CDR1H region having SEQ ID NO:36 and CDR2H region having SEQ ID NO:37, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32. 
 
     
     
         33 . The method of  claim 32 , characterized in comprising a light chain and a heavy chain of an antibody specifically binding to CD3, wherein the variable domains VL and VH or the constant domains CL and CH1 are replaced by each other. 
     
     
         34 . The method of  claim 32 , characterized in that a variable domain VH of an anti-CD3 antibody portion of the bispecific antibody (CD3 VH) comprises heavy chain CDRs of SEQ ID NO: 1, 2 and 3 as respective heavy chain CDR1, CDR2 and CDR3 and the variable domain VL of the anti-CD3 antibody portion (CD3 VL) comprises light chain CDRs having SEQ ID NO: 4, 5 and 6 as respective light chain CDR1, CDR2 and CDR3. 
     
     
         35 . The method of  claim 32 , wherein the bispecific antibody is characterized in comprising a VH region of an anti-BCMA antibody portion of the bispecific antibody comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17; and a VL region of an anti-BCMA antibody portion of the bispecific antibody comprising a CDR1L region having SEQ ID NO:27, a CDR2L region having SEQ ID NO:28 and a CDR3L region having SEQ ID NO:20; and,
 wherein the bispecific antibody is further characterized in comprising a VH region of an anti-CD3 antibody portion of the bispecific antibody comprising a CDR1H region having SEQ ID NO:1, a CDR2H region having SEQ ID NO:2 and a CDR3H region having SEQ ID NO:3; and a VL region of an anti-CD3 antibody portion of the bispecific antibody comprising a CDR1L region having SEQ ID NO:4, a CDR2L region having SEQ ID NO:5 and a CDR3L region having SEQ ID NO:6.   
     
     
         36 . The method of  claim 32 , wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis. 
     
     
         37 . The method of  claim 32 , wherein the plasma cell disorder is multiple myeloma. 
     
     
         38 . The method of  claim 32 , wherein the bispecific antibody is administered at a dose of 0.1 to 250 mg/m 2 /week. 
     
     
         39 . A method of treatment of a plasma cell disorder comprising administering to a subject in need thereof a bispecific antibody specifically binding to two targets which are the extracellular domain of human BCMA (BCMA) and human CDR3ε (CD3), characterized in comprising a VH region comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17 and a VL region comprising a CDR3L region having SEQ ID NO:20 and a CDR1L and CDR2L region combination selected from the group of:
 a) CDR1L region having SEQ ID NO:23 and CDR2L region having SEQ ID NO:24, 
 b) CDR1L region having SEQ ID NO:25 and CDR2L region having SEQ ID NO:26, and 
 c) CDR1L region having SEQ ID NO:27 and CDR2L region having SEQ ID NO:28. 
 
     
     
         40 . The method of  claim 39 , characterized in comprising a BCMA VH region having SEQ ID NO:10 and a VL region having SEQ ID NO:12, or a BCMA VH region having SEQ ID NO:10 and a VL region having SEQ ID NO:13, or a BCMA VH region having SEQ ID NO:10 and a VL region having SEQ ID NO:14. 
     
     
         41 . A method of treatment of a plasma cell disorder comprising administering to a subject in need thereof a bispecific antibody specifically binding to BCMA and CD3, wherein the bispecific antibody is characterized in comprising
 a) a first light chain and a first heavy chain of a first anti-BCMA antibody characterized in comprising a CDR3H region having SEQ ID NO:17 and a CDR3L region having SEQ ID NO:20 and a CDR1H, CDR2H, CDR1L, and CDR2L region combination selected from the group of:
 i) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:23, and CDR2L region having SEQ ID NO:24, 
 ii) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:25, and CDR2L region having SEQ ID NO:26, 
 iii) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:27, and CDR2L region having SEQ ID NO:28, 
 iv) CDR1H region having SEQ ID NO:29 and CDR2H region having SEQ ID NO:30, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, 
 v) CDR1H region having SEQ ID NO:34 and CDR2H region having SEQ ID NO:35, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, and 
 vi) CDR1H region having SEQ ID NO:36 and CDR2H region having SEQ ID NO:37, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32; and 
   b) a second light chain and a second heavy chain of a second antibody which specifically binds to CD3, and wherein the variable domains VL and VH in the second light chain and second heavy chain of the second antibody are replaced by each other; and   c) wherein in a constant domain CL of the first light chain a) an amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and wherein in a constant domain CH1 of the first heavy chain a) an amino acid at position 147 and an amino acid at position 213 are substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to EU index of Kabat).   
     
     
         42 . The method of  claim 41 , wherein the bispecific antibody is characterized in comprising in addition a Fab fragment of said first antibody (BCMA-Fab) and wherein in the constant domain CL of said BCMA-Fab the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and wherein in the constant domain CH1 of said BCMA-Fab the amino acid at positions 147 and the amino acid at position 213 are substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to EU index of Kabat) (see e.g.  FIGS. 2A, 2C ). 
     
     
         43 . The method of  claim 41 , wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis. 
     
     
         44 . The method of  claim 41 , wherein the plasma cell disorder is multiple myeloma. 
     
     
         45 . A method of treatment of a plasma cell disorder comprising administering to a subject in need thereof a bispecific antibody specifically binding to BCMA and CD3, characterized in comprising
 a) a first light chain and a first heavy chain of a first antibody specifically binding to human B cell maturation antigen (BCMA), characterized in comprising a CDR3H region having SEQ ID NO:17 and a CDR3L region having SEQ ID NO:20 and a CDR1H, CDR2H, CDR1L, and CDR2L region combination selected from the group of:
 i) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:23, and CDR2L region having SEQ ID NO:24, 
 ii) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:25, and CDR2L region having SEQ ID NO:26, 
 iii) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:27, and CDR2L region having SEQ ID NO:28, 
 iv) CDR1H region having SEQ ID NO:29 and CDR2H region having SEQ ID NO:30, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, 
 v) CDR1H region having SEQ ID NO:34 and CDR2H region having SEQ ID NO:35, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, and 
 vi) CDR1H region having SEQ ID NO:36 and CDR2H region having SEQ ID NO:37, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32; and 
   b) a second light chain and a second heavy chain of a second antibody which specifically binds to CD3, and wherein the variable domains VL and VH in the second light chain and second heavy chain of the second antibody are replaced by each other; and wherein   c) in a constant domain CL of the second light chain under b) an amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and wherein in a constant domain CH1 of the second heavy chain under b) an amino acid at positions 147 and an amino acid at position 213 are substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to EU index of Kabat).   
     
     
         46 . The method of  claim 45 , wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis. 
     
     
         47 . The method of  claim 45 , wherein the plasma cell disorder is multiple myeloma. 
     
     
         48 . A method of treatment of a plasma cell disorder comprising administering to a subject in need thereof a bispecific antibody specifically binding to BCMA and to CD3, characterized in comprising a heavy and light chain set selected from the group consisting of polypeptides:
 i) SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51 (2×),   ii) SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54 (2×), or   iii) SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:56, and SEQ ID NO:57 (2×).   
     
     
         49 . The method of  claim 48 , wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis. 
     
     
         50 . The method of  claim 48 , wherein the plasma cell disorder is multiple myeloma. 
     
     
         51 . The method of  claim 48 , wherein the bispecific antibody is administered at a dose of 0.1 to 250 mg/m 2 /week.