Combination of FcgammaRIIB-Specific Antibodies and CD20-Specific Antibodies and Methods of Use Thereof

Abstract

The present invention relates to methods of treatment, prevention, management or amelioration of one or more symptoms of diseases or disorders associated with CD20 expression that encompass administration of a combination of: (A) one or more antibodies that specifically bind FcγRIIB, particularly human FcγRIIB, with greater affinity than said antibodies bind FcγRIIA, and (B) one or more antibodies that specifically bind to CD20. Such methods include methods of treating, preventing, managing or ameliorating one or more symptoms of a B cell related disease or disorder or an inflammatory disorder. The invention also provides pharmaceutical compositions comprising an anti-FcγRIIB antibody and an anti-CD20 antibody.

1 . A method for treating a B cell malignancy in a subject, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising:
 (A) an effective amount of a first isolated antibody, or an antigen-binding fragment thereof, that specifically binds the extracellular domain of native human FcγRIIB with greater affinity than said antibody or fragment thereof binds native human FcγRIIA; and   (B) an effective amount of a second isolated antibody, or an antigen-binding fragment thereof, that specifically binds human CD20; and   (C) a pharmaceutically acceptable carrier;   wherein said effective amounts of said first and second antibodies or said fragments thereof cause said pharmaceutical composition to mediate a synergistically increased tumor volume reduction relative to the additive tumor volume reductions mediated by:
 (1) a pharmaceutical composition comprising said effective amount of said first antibody or fragment thereof but lacking said effective amount of said second antibody or fragment thereof; and 
 (2) a pharmaceutical composition comprising said effective amount of said second antibody or fragment thereof but lacking said effective amount of said first antibody or fragment thereof. 
   
     
     
         2 . The method of  claim 1 , wherein at least one of the first antibody or the second antibody is a monoclonal antibody, a human antibody, a humanized antibody, a single chain antibody or a chimeric antibody. 
     
     
         3 . The method of  claim 1 , wherein at least one of the first antibody or the second antibody further comprises an Fc domain having at least one amino acid substitution relative to the amino acid sequence of a wild-type Fc region. 
     
     
         4 . The method of  claim 3 , wherein the Fc domain of the heavy chain of the first antibody and/or the second antibody comprises at least one amino acid substitution at position 297 with another amino acid at that position, wherein the numbering is according to the EU index as in Kabat. 
     
     
         5 . The method of  claim 4 , wherein the Fc domain of the heavy chain of the first antibody and/or the second antibody has a glutamine at position 297. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the first antibody fragment and/or the second antibody fragment is a F(ab′)2 fragment or a F(ab) fragment. 
     
     
         9 . The method of  claim 1 , wherein the first antibody and/or the second antibody is operably linked to a heterologous polypeptide or conjugated to a therapeutic agent. 
     
     
         10 . The method of  claim 1 , wherein the first antibody and/or the second antibody is conjugated to:
 (A) an antibody that immunospecifically binds to a cell surface receptor other than FcγRIIB or CD20; or   (B) an antibody that immunospecifically binds to a tumor-associated antigen.   
     
     
         11 . The method of  claim 1 , wherein the first antibody reduces binding of an Ig-Fc to FcγRIIB. 
     
     
         12 . The method of  claim 1 , wherein the second antibody is 2B8 antibody (rituximab), 2H7 antibody, 1F5 antibody, B1 antibody, ibritumomab, tositumomab, or an antigen-binding fragment thereof. 
     
     
         13 . The method of  claim 1 , wherein the first antibody is a bispecific antibody comprising a first heavy chain-light chain pair that specifically binds FcγRIIB with greater affinity than said heavy chain-light chain pair binds FcγRIIA, and a second heavy chain-light chain pair that specifically binds a tumor antigen. 
     
     
         14 . The method of  claim 1 , wherein said B cell malignancy is a B cell lymphocytic leukemia or non-Hodgkin's lymphoma. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A humanized antibody that specifically binds the extracellular domain of native human FcγRIIB with greater affinity than said antibody or fragment thereof binds native human FcγRIIA comprising a heavy chain and a light chain, wherein said heavy chain comprises:
 (i) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 68; and 
 (ii) a human Fc domain having a substitution at position 297 with another amino acid at that position, wherein the numbering is according to the EU index as in Kabat. 
 
     
     
         18 . The humanized antibody of  claim 17 , wherein the Fc domain has a glutamine at position 297. 
     
     
         19 . The humanized antibody of  claim 17 , wherein said light chain comprises a light chain variable region having the amino acid sequence of SEQ ID NO:62. 
     
     
         20 . The humanized antibody of  claim 18 , wherein said light chain comprises a light chain variable region having the amino acid sequence of SEQ ID NO:62. 
     
     
         21 . A pharmaceutical composition comprising the humanized antibody of  claim 17  and a pharmaceutically acceptable carrier. 
     
     
         22 . A pharmaceutical composition comprising the humanized antibody of  claim 20  and a pharmaceutically acceptable carrier. 
     
     
         23 . A polynucleotide encoding the heavy chain of the humanized antibody of  claim 17 . 
     
     
         24 . A polynucleotide encoding the light chain of the humanized antibody of  claim 20 .