Anti cd37 antibodies

Abstract

Chimeric and humanized anti-CD37 antibodies and pharmaceutical compositions containing them are useful for the treatment of B cell malignancies and autoimmune and inflammatory diseases that involve B cells in their pathology.

1 ) An antibody molecule that binds to human CD37 and that is derived from
 a) a murine monoclonal antibody that is defined by
 i) a variable heavy chain comprising the amino acid sequence shown in SEQ ID NO: 2; and 
 ii) a variable light chain comprising the amino acid sequence shown in SEQ ID NO:4, or from 
   b) a non-human antibody recognizing the same epitope of human CD37 as the antibody defined in a) or recognizing an epitope that is close to or overlaps with said epitope;   
       wherein said antibody molecule is a chimeric or a humanized antibody. 
     
     
         2 ) An antibody molecule of  claim 1  that is a chimeric antibody defined by
 i) a variable heavy chain comprising the amino acid sequence shown in SEQ ID NO: 2;   ii) a variable light chain comprising the amino acid sequence shown in SEQ ID NO:4,   iii) constant heavy and light chains that are of human origin.   
     
     
         3 ) An antibody of  claim 2 , wherein
 i) the constant heavy chain is a IgG1 chain, and   ii) the constant light chain is a kappa chain.   
     
     
         4 ) An antibody of  claim 3 , wherein said constant heavy chain i) comprises the amino acid sequence shown in SEQ ID NO:24 and wherein said constant light chain ii) comprises the amino acid sequence shown in SEQ ID NO:26. 
     
     
         5 ) An antibody of  claim 1  that is a humanized antibody defined by
 a) CDRs contained within the variable heavy chain as shown in SEQ ID NO:2,   b) CDRs contained within the variable light chain as shown in SEQ ID NO:4,   c) frameworks supporting said CDRs that are derived from a human antibody,   d) constant heavy and light chains that are from a human antibody.   
     
     
         6 ) An antibody of  claim 5  comprising a variable heavy chain with a sequence shown in SEQ ID NO:6. 
     
     
         7 ) An antibody of  claim 6  comprising a variable light chain with a sequence shown in SEQ ID NO:12, 14, 16, 18, 20 or 22. 
     
     
         8 ) An antibody of  claim 5  comprising a variable heavy chain with a sequence shown in SEQ ID NO:8. 
     
     
         9 ) An antibody of  claim 8  comprising a variable light chain with a sequence shown in SEQ ID NO:12, 14, 16, 18, 20 or 22. 
     
     
         10 ) An antibody of  claim 5  comprising a variable heavy chain with a sequence shown in SEQ ID NO:10. 
     
     
         11 ) An antibody of  claim 10  comprising a variable light chain with a sequence shown in SEQ ID NO:12, 14, 16, 18, 20 or 22. 
     
     
         12 ) An antibody of  claim 1 , wherein said antibody has one or more mutations in the Fc domain that modulate one or more effector functions. 
     
     
         13 ) An antibody of  claim 12 , wherein said modulation of effector function is an increase in antibody-dependent cell-mediated cytotoxicity. 
     
     
         14 ) An antibody of  claim 12 , wherein said one or more mutations in the Fc domain is a single substitution at position 332, numbered according to the Kabat EU numbering index. 
     
     
         15 ) An antibody of  claim 12 , wherein said one or more mutations in the Fc domain is a combination of substitutions at positions 239 and 332, numbered according to the Kabat EU numbering index. 
     
     
         16 ) An antibody of  claim 12 , wherein said one or more mutations in the Fc domain is a combination of substitutions at positions 236 and 332, numbered according to the Kabat EU numbering index. 
     
     
         17 ) An antibody of  claim 12 , wherein said one or more mutations in the Fc domain is a combination of substitutions at positions 236, 239 and 332, numbered according to the Kabat EU numbering index. 
     
     
         18 ) An antibody of  claim 14 , wherein said substitutions are 1332E, S239D and G236A. 
     
     
         19 ) An antibody that binds to human CD37 and has a heavy chain comprising the amino acid sequence of SEQ ID NO:28. 
     
     
         20 ) The antibody of  claim 19 , which has a light chain comprising the amino acid sequence of SEQ ID NO:30. 
     
     
         21 ) An antibody that binds to human CD37 and has a heavy chain comprising the amino acid sequence of SEQ ID NO:36. 
     
     
         22 ) The antibody of  claim 21 , which has a light chain comprising the amino acid sequence of SEQ ID NO:38. 
     
     
         23 ) An antibody that binds to human CD37 and has a heavy chain comprising the amino acid sequence of SEQ ID NO:32. 
     
     
         24 ) The antibody of  claim 23 , which has a light chain comprising the amino acid sequence of SEQ ID NO:34. 
     
     
         25 ) An antibody that binds to human CD37 and has a heavy chain comprising the amino acid sequence of SEQ ID NO:40. 
     
     
         26 ) The antibody of  claim 25 , which has a light chain comprising the amino acid sequence of SEQ ID NO:42. 
     
     
         27 ) A DNA molecule comprising a region encoding the variable heavy chain of an antibody of  claim 1 . 
     
     
         28 ) The DNA molecule of  claim 27 , wherein said variable heavy chain encoding region is fused to a region encoding a constant heavy chain of human origin. 
     
     
         29 ) The DNA molecule of  claim 28 , wherein said human constant heavy chain is IgG1. 
     
     
         30 ) The DNA molecule of  claim 29 , wherein said IgG1 is encoded by a sequence shown in SEQ ID NO:23. 
     
     
         31 ) The DNA molecule of  claim 28 , wherein said human constant heavy chain has one or more substitutions in the Fc region at position 332, 229 or 236, numbered according to the Kabat EU numbering index. 
     
     
         32 ) A DNA molecule comprising a region encoding the variable light chain of an antibody of  claim 1 . 
     
     
         33 ) The DNA molecule of  claim 32 , wherein said variable light chain encoding region is fused to a region encoding a constant light chain of human origin. 
     
     
         34 ) The DNA molecule of  claim 33 , wherein said constant light chain is a kappa chain. 
     
     
         35 ) The DNA molecule of  claim 34 , wherein said kappa light chain is encoded by a sequence shown in SEQ ID NO:25. 
     
     
         36 ) An expression vector comprising a DNA molecule comprising a region encoding the variable heavy chain of  claim 1  and/or a DNA molecule comprising a region encoding the variable light chain of an antibody of  claim 1 . 
     
     
         37 ) A host cell carrying one or more vectors of  claim 36 . 
     
     
         38 ) A host cell carrying an expression vector comprising a DNA molecule comprising a region encoding the variable heavy chain of an antibody of  claim 1 , and a second expression vector comprising a DNA molecule comprising a region encoding the variable light chain of an antibody of  claim 1 . 
     
     
         39 ) The host cell of  claim 37 , which is a mammalian cell. 
     
     
         40 ) A method for producing an antibody comprising transfecting a mammalian host cell with one or more vectors of  claim 36 , culturing the host cell and recovering and purifying the antibody molecule. 
     
     
         41 ) A pharmaceutical composition comprising, as the active ingredient, one or more anti-CD37 antibody molecules of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         42 ) The pharmaceutical composition of  claim 41 , further comprising one or more additional therapeutic agents. 
     
     
         43 ) The pharmaceutical composition of  claim 42 , wherein said one or more additional therapeutic agents are selected from agents that target a B cell antigen other than CD37. 
     
     
         44 ) The pharmaceutical composition of  claim 43 , wherein said B cell antigen is CD20. 
     
     
         45 ) The pharmaceutical composition of  claim 42 , wherein said one or more additional therapeutic agents are selected from agents that induce apoptosis. 
     
     
         46 ) The pharmaceutical composition of  claim 45 , wherein said agent is a modulator of a TRAIL receptor. 
     
     
         47 ) The pharmaceutical composition of  claim 41  for depleting B cells that express CD37 on their surface. 
     
     
         48 ) The pharmaceutical composition of  claim 47  for the treatment of B cell malignancies. 
     
     
         49 ) The pharmaceutical composition of  claim 48 , wherein said B cell malignancy is selected from B cell non-Hodgkins lymphoma, B cell chronic lymphocytic leukemia and multiple myeloma. 
     
     
         50 ) The pharmaceutical composition of  claim 47  for the treatment of autoimmune or inflammatory diseases that involve B cells in their pathology. 
     
     
         51 ) The method of depleting CD37 expressing B cells from a population of cells, comprising administering to said population of cells an antibody molecule of  claim 1  or a pharmaceutical composition containing such antibody molecule. 
     
     
         52 ) The method of  claim 51 , which is carried out in vitro. 
     
     
         53 ) A method for treating a patient suffering from a B cell malignancy selected from B cell non-Hodgkins lymphoma, B cell chronic lymphocytic leukemia and multiple myeloma, comprising administering to said patient an effective amount of a pharmaceutical composition of  claim 41 .