Cd37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof

Abstract

The present disclosure provides a humanized anti-CD37 small modular immunopharmaceutical (SMIP) molecule, as well as synergistic combination therapies of CD37-specific binding molecules (such as anti-CD37 SMIP proteins or antibodies) with bifunctional chemotherapeutics (such as bendamustine) that can be administered concurrently or sequentially, for use in treating or preventing B-cell related autoimmune, inflammatory, or hyperproliferative diseases.

1 . A composition comprising a CD37-specific binding molecule and bendamustine. 
     
     
         2 . The composition of  claim 1 , wherein the CD37-specific binding molecule is a CD37-specific antibody or SMIP. 
     
     
         3 . The composition of  claim 1 , wherein the CD37-specific molecule is a humanized antibody or humanized SMIP. 
     
     
         4 . The composition of any one of  claims 1  to  3 , wherein the CD37-specific binding molecule competes with G28-1 mAb in CD37-specific binding. 
     
     
         5 . The composition of  claim 1 , wherein the CD37-specific binding protein comprises a light chain CDR1 as set forth in SEQ ID NO:61 or 62, a light chain CDR2 as set forth in SEQ ID NO:64, and a light chain CDR3 as set forth in SEQ ID NO:66; and
 a heavy chain CDR1 as set forth in SEQ ID NO:63, a heavy chain CDR2 as set forth in SEQ ID NO:65, and a heavy chain CDR3 as set forth in SEQ ID NO:67, 68 or 69.   
     
     
         6 . The composition of  claim 1 , wherein the CD37-specific binding protein comprises, from amino terminus to carboxy terminus:
 (i) a humanized heavy chain variable region,   (ii) a linker,   (iii) a humanized light chain variable region,   (iv) an IgG1 hinge, and   (v) a human IgG1 CH2 region, and (vi) a human IgG1 CH3 region.   
     
     
         7 . The composition of  claim 1 , wherein the CD37-specific binding molecule comprises, from amino terminus to carboxy terminus:
 (i) a heavy chain variable region comprising a heavy chain CDR3 as set forth in SEQ ID NO:67 or 68;   (ii) a linker;   (iii) a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO:61;   (iv) an IgG1 hinge; and   (v) a human IgG1 CH2 region, and (vi) a human IgG1 CH3 region.   
     
     
         8 . The composition of  claim 1 , wherein the CD37-specific binding molecule comprises, from amino terminus to carboxy terminus:
 (i) a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO:63, a heavy chain CDR2 as set forth in SEQ ID NO:65, and a heavy chain CDR3 as set forth in SEQ ID NO:67 or 68;   (ii) a linker;   (iii) a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO:61, a light chain CDR2 as set forth in SEQ ID NO:64, and a light chain CDR3 as set forth in SEQ ID NO:66;   (iv) an IgG1 hinge; and   (v) a human IgG1 CH2 region, and (vi) a human IgG1 CH3 region.   
     
     
         9 . The composition of  claim 8 , wherein the CD37-specific binding molecule is a humanized CD37-specific binding molecule that comprises from amino terminus to carboxyl terminus:
 (i) a humanized heavy chain variable region,   (ii) a linker as set forth in SEQ ID NO:229,   (iii) a humanized light chain variable region,   (iv) an IgG1 hinge,   (v) a human IgG1 CH2 region, and   (vi) a human IgG1 CH3 region, wherein   (a) the humanized heavy chain variable region comprising from amino terminus to carboxyl terminus: a human heavy chain FR1, a heavy chain CDR1 as set forth in SEQ ID NO:63, a human heavy chain FR2, a heavy chain CDR2 as set forth in SEQ ID NO:65, a human heavy chain FR3, a heavy chain CDR3 as set forth in SEQ ID NO:67, 68 or 69, and a human heavy chain FR4, and   (b) the humanized light chain variable region comprises from amino terminus to carboxyl terminus: a human light chain FR1, a light chain CDR1 as set forth in SEQ ID NO:61 or 62, a human light chain FR2, a light chain CDR2 as set forth in SEQ ID NO:64, a human light chain FR3, and a light chain CDR3 as set forth in SEQ ID NO:66, and a human light chain FR4.   
     
     
         10 . A method for reducing B-cells or treating a disease associated with aberrant B-cell activity, comprising administering to a subject in need thereof an effective amount of a CD37-specific binding molecule and bendamustine. 
     
     
         11 . The method of  claim 10 , wherein the disease associated with aberrant B-cell activity is a B-cell lymphoma, a B-cell leukemia, a B-cell myeloma, a disease characterized by autoantibody production, or a disease characterized by inappropriate T-cell stimulation associated with a B-cell pathway. 
     
     
         12 . The method of  claim 11 , wherein the disease characterized by autoantibody production is idiopathic inflammatory myopathy, rheumatoid arthritis, myasthenia gravis, Grave's disease, type I diabetes mellitus, multiple sclerosis, an autoimmune disease, dermatomyositis, polymyositis, or Waldenstrom's macroglobinemia. 
     
     
         13 . The method of  claim 10 , wherein the disease associated with aberrant B-cell activity is selected from the group consisting of chronic lymphocytic leukemia (CLL), non-Hodgkins lymphoma (NHL), and hairy cell leukemia. 
     
     
         14 . The method of  claim 10 , wherein the CD37-specific binding molecule and bendamustine are administered concurrently. 
     
     
         15 . The method of  claim 10 , wherein the CD37-specific binding molecule and bendamustine are administered sequentially. 
     
     
         16 . The method of  claim 10 , wherein the CD37-specific binding molecule and bendamustine are formulated together. 
     
     
         17 . The method of  claim 10 , wherein the CD37-specific binding molecule is a CD37-specific antibody or SMIP. 
     
     
         18 . The method of  claim 10 , wherein the CD37-specific molecule is a humanized antibody or a humanized SMIP. 
     
     
         19 . The method of  claim 10 , wherein the CD37-specific binding molecule competes with G28-1 mAb in CD37-specific binding. 
     
     
         20 . The method of  claim 10 , wherein the CD37-specific binding molecule is a humanized CD37-specific binding molecule that comprises from amino terminus to carboxyl terminus:
 (i) a humanized heavy chain variable region,   (ii) a linker as set forth in SEQ ID NO:229,   (iii) a humanized light chain variable region,   (iv) an IgG1 hinge,   (v) a human IgG1 CH2 region, and   (vi) a human IgG1 CH3 region, wherein
 (a) the humanized heavy chain variable region comprising from amino terminus to carboxyl terminus: a human heavy chain FR1, a heavy chain CDR1 as set forth in SEQ ID NO:63, a human heavy chain FR2, a heavy chain CDR2 as set forth in SEQ ID NO:65, a human heavy chain FR3, a heavy chain CDR3 as set forth in SEQ ID NO:67, 68 or 69, and a human heavy chain FR4, and 
 (b) the humanized light chain variable region comprises from amino terminus to carboxyl terminus: a human light chain FR1, a light chain CDR1 as set forth in SEQ ID NO:61 or 62, a human light chain FR2, a light chain CDR2 as set forth in SEQ ID NO:64, a human light chain FR3, and a light chain CDR3 as set forth in SEQ ID NO:66, and a human light chain FR4.