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 anti-angiogenic 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.

What is claimed is: 
     
         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 . The composition of  claim 1  wherein the second agent is a polypeptide binding to beta-1 integrin. 
     
     
         5 . The composition of  claim 4  wherein the polypeptide binds to beta-1 integrin associated with any alpha subunit and inhibits tumor cell binding to an extracellular substrate. 
     
     
         6 . The composition of  claim 4  wherein the polypeptide is an antibody specific for beta-1 integrin. 
     
     
         7 . The composition of  claim 6  wherein the antibody specific for beta-1 integrin is a chimeric, single chain or humanized antibody. 
     
     
         8 . The composition of  claim 7  wherein the antibody is AIIB2, BIE11 or a humanized antibody derived from AIIB2 or BIE11. 
     
     
         9 . The composition of  claim 1  wherein the first agent and the second agent are provided by a bivalent antibody having one binding site recognizing VEGF and one binding site recognizing beta 1 integrin. 
     
     
         10 . A method for inhibiting tumor cell growth, comprising the step of administering to a subject having said tumor:
 a combination of a first agent which is anti-angiogenic agent; and   a second agent which blocks tumor cell binding mediated by beta-1 integrin, whereby tumor cell growth is inhibited to an extent greater than inhibition caused by either the first agent or the second agent alone.   
     
     
         11 . The method of  claim 10  wherein the antiangiogenic agent is an antibody binding VEGF. 
     
     
         12 . The method of  claim 10  wherein the antiangiogenic agent is selected from the group consisting of a humanized mouse monoclonal antibody and a fully human antibody. 
     
     
         13 . The method of  claim 10  wherein the second agent is a polypeptide binding to beta-1 integrin. 
     
     
         14 . The method of  claim 13  wherein the polypeptide binds to beta-1 integrin associated with any alpha subunit. 
     
     
         15 . The method of  claim 13  wherein the polypeptide is an isolated antibody specific for beta-1 integrin. 
     
     
         16 . The method of  claim 15  wherein the antibody is a chimeric, single chain or humanized antibody. 
     
     
         17 . The method of  claim 15  wherein the antibody is AIIB2, BIE11 or humanized derivatives thereof. 
     
     
         18 . The method of  claim 10  wherein the tumor is selected from the group consisting of glioblastoma, colorectal, lung, breast, liver, kidney, colon, melanoma, and lymphoma. 
     
     
         19 . A method of treating a tumor of neuro-epithelium tissue comprising the step of contacting the tumor with an inhibitor of beta-1 integrin binding. 
     
     
         20 . The method of  claim 19  wherein the inhibitor is an antibody binding to beta-1 integrin associated with any alpha subunit. 
     
     
         21 . A method for imaging a tumor, comprising:
 administering to a subject having said tumor a combination of a first agent which binds to VEGF; and a second agent which blocks tumor cell binding mediated by beta-1 integrin, wherein one or both first agent and said second agent are labeled.   
     
     
         22 . The method of  claim 21  wherein the second agent is a chimeric, single chain or humanized antibody binding to beta-1 integrin. 
     
     
         23 . The method of  claim 21  wherein the tumor is selected from the group consisting of glioblastoma, colorectal, lung, kidney, liver, ovarian and breast. 
     
     
         24 . A method for inhibiting tumor cell growth comprising the step of delivering to said cell a nucleic acid construct interfering with expression of a gene encoding beta-1 integrin. 
     
     
         25 . The method of  claim 24  wherein said construct is a lentiviral vector encoding an shRNA that binds to beta-1 integrin mRNA to silence beta 1 integrin gene expression. 
     
     
         26 . A method of treating a patient having a tumor, said patient having failed anti-VEGF antibody therapy, comprising the step of administering to said patient an anti-integrin agent. 
     
     
         27 . A kit for treating a patient with recurrent glioblastomamultiforme (GBM) comprising:
 (a) a catheter for placement intratumorally, within a resection cavity, or subdurally; and   (b) an inhibitory anti-beta1 integrin composition formulated for administration through said catheter via convection enhanced delivery (CED) device at a clinically-relevant dose and rate.   
     
     
         28 . A method for inhibiting tumor cell growth, comprising the step of administering to a subject having said tumor:
 a combination of a low-dose first agent which is anti-angiogenic agent; and   a second agent which blocks tumor cell binding mediated by beta-1 integrin, whereby tumor cell growth is inhibited to an equivalent amount as caused by the first agent at a higher clinical dose.