Methods and Compositions for Improving Antiangiogenic Therapy with Anti-Integrins

Abstract

Described here are methods and compositions for treating tumors and metastases that improve anti-angiogenesis therapy. By inhibiting these mechanisms in a biological system with an anti-beta one integrin composition in combination with an antiangiogenic composition, tumors and metastases may be deprived of an adequate blood supply, thereby resulting in tumor cell growth arrest and possibly regression, including tumor cell death. The present compositions comprise an anti-beta one integrin agent in combination with an anti-VEGF agent, in a pharmaceutical composition or compositions. Methods of treatment and of imaging are also described.

1 . A pharmaceutical composition for inhibiting tumor cell growth, comprising a combination of
 a first agent which is an inhibitor of vascular endothelial growth factor (“VEGF”); and   a second agent which blocks beta-1 integrin binding, whereby said combination inhibits tumor cell growth to a greater extent than either the first agent or the second agent separately.   
     
     
         2 . The composition of  claim 1  wherein the inhibitor of VEGF is an antibody binding VEGF. 
     
     
         3 . The composition of  claim 2  wherein the antibody is a humanized mouse antibody. 
     
     
         4 .- 28 . (canceled) 
     
     
         29 . A method for attenuating the development of anti-vascular endothelial growth factor (VEGF) antibody resistance in a subject having cancer and receiving an anti-VEGF antibody therapy to treat the cancer, comprising:
 administering a therapeutically effective amount of an anti-integrin beta-1 antibody which binds to a beta-1 subunit of an integrin having any alpha subunit to a subject having cancer and receiving an anti-VEGF antibody therapy to treat the cancer,   to attenuate the development of anti-VEGF resistance in the subject.   wherein the anti-integrin beta-1 antibody is the AIIB2 antibody or a humanized version thereof.   
     
     
         30 . The method according to  claim 29 , wherein the anti-integrin beta-1 antibody is administered to the subject in a pharmaceutical composition that does not comprise an anti-VEGF antibody. 
     
     
         31 . The method according to  claim 29 , further comprising administering the anti-VEGF antibody therapy to the subject. 
     
     
         32 . The method according to  claim 31 , wherein the anti-VEGF antibody of the anti-VEGF antibody therapy is administered to the subject in a pharmaceutical composition that does not comprise the anti-integrin beta-1 antibody. 
     
     
         33 . The method according to  claim 31 , wherein the anti-VEGF antibody of the anti-VEGF antibody therapy is administered to the subject in a pharmaceutical composition that comprises the anti-integrin beta-1 antibody. 
     
     
         34 . The method according to  claim 29 , wherein the anti-VEGF antibody of the anti-VEGF antibody therapy is bevacizumab. 
     
     
         35 . The method according to  claim 29 , wherein the anti-integrin beta-1 antibody is administered parenterally. 
     
     
         36 . The method according to  claim 29 , wherein the anti-integrin beta-1 antibody is administered intratumorally. 
     
     
         37 . The method according to  claim 29 , wherein the cancer is selected from the group consisting of: glioblastoma, colorectal, lung, kidney, liver, ovarian and breast. 
     
     
         38 . The method according to  claim 29 , wherein the cancer is glioblastoma multiforme (GBM). 
     
     
         39 . The method according to  claim 38 , wherein the anti-integrin beta-1 antibody is administered through a catheter via a convection enhanced delivery (CED) device. 
     
     
         40 . The method according to  claim 29 , wherein the anti-integrin beta-1 antibody is a humanized antibody. 
     
     
         41 . The method according to  claim 29 , wherein the anti-integrin beta-1 antibody is a single chain antibody.