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 . An isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for an epitope of CD38 (SEQ ID NO: 22),
 (i) wherein said antibody or functional fragment thereof is able to mediate killing of a CD38+ target cell by ADCC with an at least five-fold better efficacy than chimeric OKT10 (SEQ ID NOS: 23 and 24) under the same or substantially the same conditions when a human PBMC cell is employed as an effector cell, wherein said CD38+ target cell is selected from the group consisting of LP-1 (DSMZ: ACC41) and RPMI-8226 (ATCC: CCL-155), and wherein the ratio of effector cells to target cells is between about 30:1 and about 50:1; or   (ii) wherein said antibody or functional fragment thereof is able to mediate killing of a CD38-transfected CHO cell by CDC with an at least two-fold better efficacy than chimeric OKT10 (SEQ ID NOS: 23 and 24) under the same or substantially the same conditions; or   (iii) wherein the epitope comprises one or more amino acid residues of amino acid residues 1 to 215 of CD38 (SEQ ID NO: 22).   
     
     
         2 . An isolated nucleic acid sequence that encodes an antigen-binding region of a human antibody or functional fragment thereof that is specific for an epitope of CD38. 
     
     
         3 . The isolated nucleic acid sequence of  claim 2 , encoding a variable heavy chain of an isolated antibody or functional fragment thereof, which comprises (i) a sequence selected from the group consisting of SEQ ID NOS: 1, 2, 3 and 4 or (ii) a nucleic acid sequence that hybridizes under high stringency conditions to the complementary strand of SEQ ID NO: 1, 2, 3 or 4. 
     
     
         4 . The isolated nucleic acid sequence of  claim 2  encoding a variable light chain of an isolated antibody or functional fragment thereof, which comprises (i) a sequence selected from the group consisting of SEQ ID NOS: 9, 10, 11 and 12 or (ii) a nucleic acid sequence that hybridizes under high stringency conditions to the complementary strand of SEQ ID NO: 9, 10, 11 or 12. 
     
     
         5 . A vector comprising the isolated nucleic acid sequence of  claim 2 . 
     
     
         6 . An isolated cell comprising the vector of  claim 5 . 
     
     
         7 . A pharmaceutical composition comprising
 (A) an antibody or functional fragment selected from the group consisting of:
 (i) an isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for an epitope of CD38 (SEQ ID NO: 22), wherein said antibody or functional fragment thereof is able to mediate killing of a CD38+ target cell by ADCC with an at least five-fold better efficacy than chimeric OKT10 (SEQ ID NOS: 23 and 24) under the same or substantially the same conditions when a human PBMC cell is employed as an effector cell, wherein said CD38+ target cell is selected from the group consisting of LP-1 (DSMZ: ACC41) and RPMI-8226 (ATCC: CCL-155), and wherein the ratio of effector cells to target cells is between about 30:1 and about 50:1; 
 (ii) an isolated human or humanized antibody or functional fragment thereof, comprising an antigen-binding region that is specific for an epitope of CD38 (SEQ ID NO: 22), wherein said antibody or functional fragment thereof is able to mediate killing of a CD38-transfected CHO cell by CDC with an at least two-fold better efficacy than chimeric OKT10 (SEQ ID NOS: 23 and 24) under the same or substantially the same conditions; and 
 (iii) an isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for an epitope of CD38, wherein the epitope comprises one or more amino acid residues of amino acid residues 1 to 215 of CD38 (SEQ ID NO: 22); and 
   (B) a pharmaceutically acceptable carrier or excipient therefor.   
     
     
         8 . A method for treating a disorder or condition associated with the undesired presence of CD38+ cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising
 (A) an antibody or functional fragment selected from the group consisting of:
 (i) an isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for an epitope of CD38 (SEQ ID NO: 22), wherein said antibody or functional fragment thereof is able to mediate killing of a CD38+ target cell by ADCC with an at least five-fold better efficacy than chimeric OKT10 (SEQ ID NOS: 23 and 24) under the same or substantially the same conditions when a human PBMC cell is employed as an effector cell, wherein said CD38+target cell is selected from the group consisting of LP-1 (DSMZ: ACC41) and RPMI-8226 (ATCC: CCL-155), and wherein the ratio of effector cells to target cells is between about 30:1 and about 50:1; 
 (ii) an isolated human or humanized antibody or functional fragment thereof, comprising an antigen-binding region that is specific for an epitope of CD38 (SEQ ID NO: 22), wherein said antibody or functional fragment thereof is able to mediate killing of a CD38-transfected CHO cell by CDC with an at least two-fold better efficacy than chimeric OKT10 (SEQ ID NOS: 23 and 24) under the same or substantially the same conditions; and 
 (iii) an isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for an epitope of CD38, wherein the epitope comprises one or more amino acid residues of amino acid residues 1 to 215 of CD38 (SEQ ID NO: 22); and 
   (B) a pharmaceutically acceptable carrier or excipient therefor.   
     
     
         9 . The method of  claim 8 , wherein the disorder or condition is a haematological disease. 
     
     
         10 . The method of  claim 9 , wherein the haematological disease is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, and acute lymphocytic leukemia. 
     
     
         11 . The method of  claim 8 , wherein said disorder or condition is an inflammatory disease 
     
     
         12 . The method of  claim 11 , wherein said inflammatory disease is rheumatoid arthritis or systemic lupus erythematosus.