METHODS OF USING ANTI-CD79b IMMUNOCONJUGATES

Abstract

Provided herein are methods of treating B-cell proliferative disorders in particular Follicular Lymphoma and/or Diffuse Large B-Cell Lymphoma using immunoconjugates comprising anti-CD79b antibodies in combination with additional therapeutic agents.

1 . A method for treating a B-cell proliferative disorder in an individual comprising administering to the individual an effective amount of (a) an immunoconjugate comprising an anti-CD79b antibody linked to a cytotoxic agent, (b) an anti-CD20 antibody, and (c) an alkylating agent. 
     
     
         2 . The method of  claim 1 , wherein the anti-CD20 antibody is rituximab. 
     
     
         3 . The method of  claim 1 , wherein the anti-CD20 antibody is a humanized B-Lyl antibody. 
     
     
         4 . The method of  claim 3 , wherein the humanized B-Lyl antibody is obinituzumab. 
     
     
         5 . The method of  claim 1 , wherein the anti-CD20 antibody is ofatumumab, ublituximab, and/or ibritumomab tiuxetan. 
     
     
         6 . The method of  claim 1 , wherein the alkylating agent is 4-[5-[Bis(2-chloroethy)amino]-1-methylbenzimidazol-2-yl]butanoic acid and salts thereof. 
     
     
         7 . The method of  claim 6 , wherein the alkylating agent is bendamustine. 
     
     
         8 . The method of  claim 7 , wherein the cytotoxic agent is an antimitotic agent. 
     
     
         9 . The method of  claim 8 , wherein the antimitotic agent is an inhibitor of the polymerization of tubulin. 
     
     
         10 . The method of  claim 7 , wherein the immunoconjugate has the formula Ab-(L-D)p, wherein:
 (a) Ab is the antibody which binds CD79b;   (b) L is a linker;   (c) D is the cytotoxic agent and the cytotoxic agent is selected from a maytansinoid or an auristatin; and   (d) p ranges from 1-8.   
     
     
         11 . The method of  claim 10 , wherein D is an auristatin. 
     
     
         12 . The method of  claim 10 , wherein D has formula D E   
       
         
           
           
               
               
           
         
         and wherein R 2  and R 6  are each methyl, R 3  and R 4  are each isopropyl, R 5  is H, R 7  is sec-butyl, each R 8  is independently selected from CH 3 , O—CH 3 , OH, and H; R 9  is H; and R 18  is —C(R 8 ) 2 —C(R 8 ) 2 -aryl. 
       
     
     
         13 . The method of  claim 10 , wherein D is MMAE. 
     
     
         14 . The method of  claim 13 , wherein the linker is cleavable by a protease. 
     
     
         15 . The method of  claim 14 , wherein the linker comprises a val-cit dipeptide or a Phe-homoLys dipeptide. 
     
     
         16 . The method of  claim 13 , wherein the linker is acid-labile. 
     
     
         17 . The method of  claim 16 , wherein the linker comprises hydrazone. 
     
     
         18 . The method of  claim 10  having the formula: 
       
         
           
           
               
               
           
         
         wherein S is a sulfur atom. 
       
     
     
         19 . The method of  claim 18 , wherein p ranges from 2-5. 
     
     
         20 . The method of  claim 19 , wherein the antibody is a monoclonal antibody. 
     
     
         21 . The method of  claim 20 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
         22 . The method of  claim 21 , wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26. 
     
     
         23 . The method of  claim 22 , wherein the antibody comprises (a) a VH comprising the amino acid sequence of SEQ ID NO:19 and (b) a VL sequence comprises the amino acid sequence of SEQ ID NO:20. 
     
     
         24 . The method of  claim 23 , wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:36 and (b) a light chain comprising the amino acid sequence of SEQ ID NO:35. 
     
     
         25 . The method of  claim 23 , wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:37 and (b) a light chain comprising the amino acid sequence of SEQ ID NO:35. 
     
     
         26 . The method of  claim 23 , wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:36 and (b) a light chain comprising the amino acid sequence of SEQ ID NO:38. 
     
     
         27 . The method of  claim 23 , wherein the B-cell proliferative disorder is cancer. 
     
     
         28 . The method of  claim 27 , wherein the B-cell proliferative disorder is lymphoma, non-Hodgkins lymphoma (NHL), aggressive NHL, relapsed aggressive NHL, relapsed indolent NHL, refractory NHL, refractory indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), or mantle cell lymphoma. 
     
     
         29 . The method of  claim 27 , wherein the B-cell proliferative disorder is NHL, such as indolent NHL and/or aggressive NHL. 
     
     
         30 . The method of  claim 27 , wherein the B-cell proliferative disorder is indolent follicular lymphoma or diffuse large B-cell lymphoma.