Cd3 immunotherapeutics and uses 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 - 29 . (canceled) 
     
     
         30 . A CD37-specific binding molecule comprising heavy chain and light chain variable regions in a VHVL orientation, wherein the binding molecule comprises, from amino terminus to carboxy terminus:
 (i) a heavy chain variable region derived from a G28-1 antibody   (ii) a linker   (iii) a light chain variable region derived from a G28-1 antibody;   (iii) a hinge;   (iv) an IgG constant region   
     
     
         31 . The CD37-specific binding molecule of  claim 30 , wherein the heavy chain variable region is a humanized heavy chain variable region, and wherein the light chain variable region is a humanized light chain variable region. 
     
     
         32 . The CD37-specific binding molecule of  claim 30 , wherein the linker consists of 25 amino acids. 
     
     
         33 . The CD37-specific binding molecule of  claim 30 , wherein the linker comprises an amino acid sequence according to SEQ ID NO: 229. 
     
     
         34 . The CD37-specific binding molecule of  claim 30 , wherein the hinge is modified from a wild type IgG hinge. 
     
     
         35 . The CD37-specific binding molecule of  claim 30 , wherein the hinge comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 94, 102, 104, 255, 256, 106, 108, 257, 96, 110, 112, 98, 100, 120, 126, 259-261, 122, and 124. 
     
     
         36 . The CD37-specific binding molecule of  claim 30 , wherein the binding molecule exhibits a higher level of expression as compared to a CD37-specific binding molecule in a VLVH orientation. 
     
     
         37 . The CD37-specific binding molecule of  claim 30 , wherein the binding molecule exhibits a more homogenous population of molecules as compared to CD37-specific binding molecule in a VLVH orientation. 
     
     
         38 . The CD37-specific binding molecule of  claim 30 , wherein the binding molecule exhibits superior binding to CD37 as compared to a CD37-specific binding molecule in a VLVH orientation. 
     
     
         39 . The CD37-specific binding molecule of  claim 38 , wherein the CD37-specific binding molecule in the VHVL orientation has at least 2-fold higher affinity for CD37 as compared to the CD37-specific binding molecule in the VLVH orientation. 
     
     
         40 . The CD37-specific binding molecule of  claim 38 , wherein the CD37-specific binding molecule in the VHVL binds with higher affinity for CD37 as compared to a CD37-specific binding molecule comprising murine heavy chain and murine light chain variable regions. 
     
     
         41 . 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 the CD37-specific binding molecule according to  claim 30 . 
     
     
         42 . The method of  claim 41 , 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. 
     
     
         43 . The method of  claim 41 , 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. 
     
     
         44 . The method of  claim 41 , wherein the disease associated with aberrant B-cell activity is chronic lymphocytic leukemia (CLL). 
     
     
         45 . A method of inhibiting tumor cell growth, comprising contacting a tumor cell with the CD37-specific binding molecule according to  claim 30 .