Anti-cd38 human antibodies and uses thereof

Abstract

The present invention provides recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for CD38, which plays an integral role in various disorders or conditions. These antibodies, accordingly, can be used to treat, for example, hematological malignancies such as multiple myeloma. Antibodies of the invention also can be used in the diagnostics field, as well as for investigating the role of CD38 in the progression of disorders associated with malignancies. The invention also provides nucleic acid sequences encoding the foregoing antibodies, vectors containing the same, pharmaceutical compositions and kits with instructions for use. The invention also provides isolated novel epitopes of CD38 and methods of use therefore.

1 - 114 . (canceled) 
     
     
         115 . A method for treating a hematological malignancy associated with CD38 upregulation comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising:
 (a) an isolated monoclonal non-chimeric, non-CDR grafted antibody based on a human sequence that binds human CD38 (SEQ ID NO: 22),
 (i) wherein said antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 1nM or less when a human PBMC cell is employed as the effector cell, wherein said CD38+ target cell is selected from LP-1 (DSMZ: ACC41) or RPMI-8226 (ATCC: CCL-155), and wherein the ratio of effector cells to target cells is from 30:1 to 50:1, 
 (ii) wherein said antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 of 3.2 nM or less, 
 (iii) wherein said antibody comprises a VH3 variable heavy chain, and 
 (iv) wherein the antibody comprises an IgG1 constant region, 
   (b) a pharmaceutically acceptable carrier or excipient thereof.   
     
     
         116 . The method according to  claim 115 , where said antibody comprises a kappa variable light chain. 
     
     
         117 . The method according to  claim 115 , wherein said hematological malignancy is multiple myeloma. 
     
     
         118 . The method according to  claim 115 , wherein said hematological malignancy is chronic lymphocytic leukemia. 
     
     
         119 . The method according to  claim 115 , wherein said hematological malignancy is chronic myelogenous leukemia. 
     
     
         120 . The method according to  claim 115 , wherein said hematological malignancy is acute lymphocytic leukemia. 
     
     
         121 . The method according to  claim 115 , wherein said antibody comprises a variable heavy chain comprising a framework 1 region comprising SGGGLVQPGGSLRLSC (SEQ ID NO: 44), a framework 2 region comprising VRQAPGKGLEW (SEQ ID NO: 45), a framework 3 region comprising FTISRDNSKNTLYLQMNSLRAEDTAV (SEQ ID NO: 46) and a framework 4 region comprising GQGTLVTV (SEQ ID NO: 47). 
     
     
         122 . The method according to  claim 121 , wherein said antibody comprises a variable light chain comprising a framework 1 region comprising TQSP (SEQ ID NO: 48), a framework 2 region comprising QKPG (SEQ ID NO: 49), a framework 3 region comprising RFSGSGSGTDFTL (SEQ ID NO: 50) and a framework 4 region comprising TFGQGTKVEIK (SEQ ID NO: 51). 
     
     
         123 . The method according to  claim 115 , wherein said antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 0.60 nM or less. 
     
     
         124 . The method according to  claim 123 , wherein said antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 0.28 nM or less. 
     
     
         125 . The method according to  claim 124 , wherein said antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 0.17 nM or less. 
     
     
         126 . The method according to  claim 115 , wherein said antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 of 0.94 nM or less. 
     
     
         127 . The method according to  claim 126 , wherein said antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 of 0.41 nM or less. 
     
     
         128 . The method according to  claim 115 , wherein said antibody binds within amino acids 44-206 of CD38 (SEQ ID NO: 22). 
     
     
         129 . The method according to  claim 115 , wherein said antibody binds within amino acids 44-66 of CD38 (SEQ ID NO: 22). 
     
     
         130 . The method according to  claim 115 , wherein said antibody binds within amino acids 110-122 of CD38 (SEQ ID NO: 22). 
     
     
         131 . The method according to  claim 115 , wherein said antibody binds within amino acids 148-164 of CD38 (SEQ ID NO: 22). 
     
     
         132 . The antibody according to  claim 115 , wherein said antibody binds within amino acids 186-200 of CD38 (SEQ ID NO: 22). 
     
     
         133 . The method according to  claim 115 , wherein said antibody binds within amino acids 202-224 of CD38 (SEQ ID NO: 22). 
     
     
         134 . The method according to  claim 115 , wherein said antibody competes in binding to CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 5 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO:13. 
     
     
         134 . The method according to  claim 115 , wherein said antibody binds within amino acids 192-206 of CD38 (SEQ ID NO: 22). 
     
     
         136 . The method according to  claim 115 , wherein said antibody competes in binding to CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 6 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 14. 
     
     
         137 . The method according to  claim 115 , wherein said antibody binds within amino acids 82-94 of CD38 (SEQ ID NO: 22). 
     
     
         138 . The method according to  claim 115 , wherein said antibody binds within amino acids 158-170 of CD38 (SEQ ID NO: 22). 
     
     
         139 . The method according to  claim 115 , wherein said antibody competes in binding to CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 7 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 15. 
     
     
         140 . The method according to  claim 115 , wherein said antibody binds within amino acids 82-94 of CD38 (SEQ ID NO: 22). 
     
     
         141 . The method according to  claim 115 , wherein said antibody within amino acids 142-154 of CD38 (SEQ ID NO: 22). 
     
     
         142 . The method according to  claim 115 , wherein said antibody binds within amino acids 158-170 of CD38 (SEQ ID NO: 22). 
     
     
         143 . The method according to  claim 115 , wherein said antibody binds within amino acids 188-200 of CD38 (SEQ ID NO: 22). 
     
     
         144 . The method according to  claim 115 , wherein said antibody binds within amino acids 280-296 of CD38 (SEQ ID NO: 22).