Cd37-binding molecules and immunoconjugates thereof

Abstract

Methods of using CD37 agents, including, but not limited to, antibodies and immunoconjugates, that bind to CD37 to deplete B-cells (e.g., non-cancerous B-cells) and methods of treating autoimmune and inflammatory diseases are further provided.

1 - 10 . (canceled) 
     
     
         11 . A method for treating a patient having multiple sclerosis comprising administering to said patient a therapeutically effective amount of an antibody that specifically binds to CD37 or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the CDR1, CDR2, and CDR3 of said heavy chain variable region and the CDR1, CDR2, and CDR3 of said light chain variable region comprise the polypeptide sequences of:
 (a) SEQ ID NOs: 4, 5, and 6 and SEQ ID NOs: 28, 29, and 30, respectively;   (b) SEQ ID NOs: 7, 8, and 9 and SEQ ID NOs: 31, 32, and 33, respectively;   (c) SEQ ID NOs: 10, 11, and 12 and SEQ ID NOs: 34, 35, and 36, respectively;   (d) SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 37, 38, and 39, respectively;   (e) SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 37, 40, and 39, respectively;   (f) SEQ ID NOs: 16, 17, and 18 and SEQ ID NOs: 41, 42, and 43, respectively;   (g) SEQ ID NOs: 19, 20, and 21 and SEQ ID NOs: 44, 45, and 46, respectively;   (h) SEQ ID NOs: 19, 20, and 21 and SEQ ID NOs: 44, 47, and 46, respectively;   (i) SEQ ID NOs: 22, 23, and 24 and SEQ ID NOs: 48, 49, and 50, respectively;   (j) SEQ ID NOs: 22, 23, and 24 and SEQ ID NOs: 48, 51, and 50, respectively; or   (k) SEQ ID NOs: 25, 26, and 27 and SEQ ID NOs: 52, 53, and 54, respectively.   
     
     
         12 . The method of  claim 11 , wherein the heavy chain variable region and the light chain variable region of the antibody or antigen-binding fragment thereof comprise the polypeptide sequences of:
 (a) SEQ ID NO:56 and SEQ ID NO:73, respectively;   (b) SEQ ID NO:57 and SEQ ID NO:74, respectively;   (c) SEQ ID NO:58 and SEQ ID NO:74, respectively;   (d) SEQ ID NO:60 and SEQ ID NO:76, respectively;   (e) SEQ ID NO:62 and SEQ ID NO:78, respectively;   (f) SEQ ID NO:63 and SEQ ID NO:79, respectively;   (g) SEQ ID NO:65 and SEQ ID NO:81, respectively;   (h) SEQ ID NO:67 and SEQ ID NO:83, respectively;   (i) SEQ ID NO:69 and SEQ ID NO:85, respectively;   (j) SEQ ID NO:71 and SEQ ID NO:87, respectively;   
     
     
         13 - 26 . (canceled) 
     
     
         27 . The method of  claim 11 , wherein the antibody or antigen-binding fragment thereof is linked via a linker (L) to a cytotoxic agent (C) to form an immunoconjugate. 
     
     
         28 - 35 . (canceled) 
     
     
         36 . The method of  claim 27 , wherein the immunoconjugate comprises 2-6 (C). 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 27 , wherein said linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker. 
     
     
         39 . The method of  claim 27 , wherein said linker is selected from the group consisting of: N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP); N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) or N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC); N-sulfosuccinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (sulfoSMCC); N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB); and N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol] ester (NHS-PEG4-maleimide). 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 27 , wherein said cytotoxic agent is selected from the group consisting of a maytansinoid, maytansinoid analog, doxorubicin, a modified doxorubicin, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, aristatin, tomaymycin derivative, and leptomycin derivative or a prodrug of the agent. 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 41 , wherein said cytotoxic agent is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2)-deacetyl-N(2)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         44 - 68 . (canceled) 
     
     
         69 . A method for treating a patient having multiple sclerosis comprising administering to said patient a composition comprising immunoconjugates, wherein the immunoconjugates comprise an antibody that that specifically binds to CD37 or antigen-binding fragment thereof (A) linked via a linker (L) to a cytotoxic agent (C),
 wherein the composition comprises an average of 3 to 4 (C) per antibody or antigen-binding fragment thereof (A), and   wherein said antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the CDR1, CDR2, and CDR3 of said heavy chain variable region and the CDR1, CDR2, and CDR3 of said light chain variable region comprise the polypeptide sequences of:   (a) SEQ ID NOs: 4, 5, and 6 and SEQ ID NOs: 28, 29, and 30, respectively;   (b) SEQ ID NOs: 7, 8, and 9 and SEQ ID NOs: 31, 32, and 33, respectively;   (c) SEQ ID NOs: 10, 11, and 12 and SEQ ID NOs: 34, 35, and 36, respectively;   (d) SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 37, 38, and 39, respectively;   (e) SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 37, 40, and 39, respectively;   (f) SEQ ID NOs: 16, 17, and 18 and SEQ ID NOs: 41, 42, and 43, respectively;   (g) SEQ ID NOs: 19, 20, and 21 and SEQ ID NOs: 44, 45, and 46, respectively;   (h) SEQ ID NOs: 19, 20, and 21 and SEQ ID NOs: 44, 47, and 46, respectively;   (i) SEQ ID NOs: 22, 23, and 24 and SEQ ID NOs: 48, 49, and 50, respectively;   (j) SEQ ID NOs: 22, 23, and 24 and SEQ ID NOs: 48, 51, and 50, respectively; or   (k) SEQ ID NOs: 25, 26, and 27 and SEQ ID NOs: 52, 53, and 54, respectively.   
     
     
         70 . The method of  claim 11 , wherein the CDR1, CDR2, and CDR3 of said heavy chain variable region and the CDR1, CDR2, and CDR3 of said light chain variable region comprise the polypeptide sequences of SEQ ID NOs: 4, 5, and 6 and SEQ ID NOs: 28, 29, and 30, respectively. 
     
     
         71 . The method of  claim 12 , wherein the heavy chain variable region and the light chain variable region of the antibody or antigen-binding fragment thereof comprise the polypeptide sequences of SEQ ID NO:57 and SEQ ID NO:74, respectively. 
     
     
         72 . The method of  claim 11 , wherein the CDR1, CDR2, and CDR3 of said heavy chain variable region and the CDR1, CDR2, and CDR3 of said light chain variable region comprise the polypeptide sequences of SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 37, 40, and 39, respectively. 
     
     
         73 . The method of  claim 12 , wherein the heavy chain variable region and the light chain variable region of the antibody or antigen-binding fragment thereof comprise the polypeptide sequences of SEQ ID NO:65 and SEQ ID NO:81, respectively. 
     
     
         74 . The method of  claim 72 , wherein the antibody or antigen-binding fragment thereof is linked via a linker (L) to a cytotoxic agent (C) to form an immunoconjugate. 
     
     
         75 . The method of  claim 73 , wherein the antibody or antigen-binding fragment thereof is linked via a linker (L) to a cytotoxic agent (C) to form an immunoconjugate. 
     
     
         76 . The method of  claim 74 , wherein said linker is N-succinimidyl 4-(maleimidomethyl) cyclohaxanecarboxylate (SMCC). 
     
     
         77 . The method of  claim 75 , wherein said linker is N-succinimidyl 4-(maleimidomethyl) cyclohaxanecarboxylate (SMCC). 
     
     
         78 . The method of  claim 74 , wherein said cytotoxic agent is a maytansinoid. 
     
     
         79 . The method of  claim 75 , wherein said cytotoxic agent is a maytansinoid. 
     
     
         80 . The method of  claim 78 , wherein said maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         81 . The method of  claim 79 , wherein said maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         82 . An isolated polynucleotide comprising a polynucleotide sequence selected from the group consisting of: SEQ ID NOs:121-170, 182, 183, 193, and 194.