US2009060911A1PendingUtilityA1

Enhancement of antibody-mediated immune responses

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Assignee: UNIV ROCKEFELLERPriority: Apr 13, 2000Filed: Aug 1, 2008Published: Mar 5, 2009
Est. expiryApr 13, 2020(expired)· nominal 20-yr term from priority
Inventors:Jeffrey V. Ravetch
C07K 2317/732C07K 16/32A61K 2039/505C07K 2317/52A61P 33/00A61P 35/04A61K 38/00C07K 2317/72A61P 37/04A61P 35/02C07K 16/30A61P 31/12C07K 2317/73A61P 31/04A61P 43/00A61P 35/00A61P 31/00Y02A50/30
63
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Claims

Abstract

The present invention is related to enhancing the function of anti-tumor antibodies by regulating FcγRIIB-mediated activity. In particular disrupting SHIP activation by FcγRIIB enhances cytotoxicity elicited by a therapeutic antibody in vivo in a human. The invention further provides an antibody, e.g., an anti-tumor antibody, with a variant Fc region that results in binding of the antibody to FcγRIIB with reduced affinity. A variety of transgenic mouse models demonstrate that the inhibiting FcγRIIB molecule is a potent regulator of cytotoxicity in vivo.

Claims

exact text as granted — not AI-modified
1 . A method for enhancing cytotoxicity elicited by a therapeutic antibody in vivo in a subject, which method comprises disrupting activation of SHIP by Fc-gamma-receptor IIB (FcγRIIB). 
   
   
       2 . The method according to  claim 1 , wherein the SHIP activation by FcγRIIB results from antibody binding to FcγRIIB. 
   
   
       3 . The method according to  claim 2 , wherein antibody binding is inhibited by a competitive inhibitor. 
   
   
       4 . The method according to  claim 2 , wherein antibody binding is inhibited by modifying the Fc portion of the antibody to reduce its affinity for FcγRIIB. 
   
   
       5 . The method according to  claim 1 , wherein SHIP activation by FcγRIIB is disrupted by inhibiting the expression of FcγIIB. 
   
   
       6 . The method according to  claim 5 , wherein FcγRIIB expression is disrupted with an antisense nucleic acid specific for the γIIB chain mRNA. 
   
   
       7 . The method according to  claim 5 , wherein FcγRIIB expression is disrupted with an intracellular antibody specific for the γIIB chain. 
   
   
       8 . The method according to  claim 1 , wherein SHIP activation is inhibited by an inositol phosphatase inhibitor. 
   
   
       9 . The method according to  claim 1 , wherein SHIP activation is inhibited by inhibiting SHIP expression. 
   
   
       10 . The method according to  claim 1 , wherein the antibody is an anti-tumor antibody. 
   
   
       11 . The method according to  claim 10  wherein the antibody is specific for a tumor cell growth receptor. 
   
   
       12 . The method according to  claim 11 , wherein the antibody is specific for a HER12/neu growth factor receptor. 
   
   
       13 . The method according to  claim 11 , wherein the antibody is specific for a CD20 B cell antigen. 
   
   
       14 . The method according to  claim 1 , wherein the antibody binds to human activating Fc receptors. 
   
   
       15 . The method according to  claim 14 , wherein the subject expresses human Fc receptors. 
   
   
       16 . An antibody with a variant Fc region, which antibody binds FcγRIIB with reduced affinity. 
   
   
       17 . The antibody of  claim 16 , which binds activating Fc-receptors with at least the same affinity as wildtype antibody. 
   
   
       18 . The antibody of  claim 16 , which is an anti-tumor antibody. 
   
   
       19 . The antibody of  claim 18 , which is specific for a tumor cell growth receptor. 
   
   
       20 . The antibody of  claim 19 , which is specific for a HER2/neu growth factor receptor. 
   
   
       21 . The antibody of  claim 19 , which is specific for a CD20 B cell antigen.

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