Combination tumor treatment with an integrin-binding-fc fusion protein and immune stimulator

Abstract

The present invention provides a method of treating cancer with an integrin-binding-Fc fusion protein alone or in combination with IL-2 and/or an immune stimulant (i.e., an immune checkpoint stimulator), and/or an immune checkpoint inhibitor. The invention also provides composition for use in such methods.

1 . A method for treating cancer in a subject comprising administering to the subject an effective amount of an integrin-binding polypeptide-Fc fusion wherein said integrin-binding polypeptide-Fc fusion is administered in a therapeutically effective amount, wherein said integrin-binding polypeptide comprises a sequence selected from the group consisting of SEQ ID NO:130 (GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCG) and SEQ ID NO:131 (GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCG) and wherein said integrin-binding polypeptide is conjugated to an Fc domain. 
     
     
         2 . The method of  claim 1 , wherein said Fc domain is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         3 . The method of  claim 2 , where said Fc domain is a human Fc domain. 
     
     
         4 . The method of  claim 1 , wherein said integrin-binding polypeptide is conjugated directly to said Fc domain. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein said method further comprises administering an immune checkpoint inhibitor or an immune checkpoint. 
     
     
         8 . The method of  claim 7 , where said immune checkpoint inhibitor is a PD-1 inhibitor. 
     
     
         9 . The method of  claim 8 , where PD-1 inhibitor is an anti-PD-1 antibody. 
     
     
         10 . The method of  claim 1 , wherein said integrin-binding polypeptide-Fc fusion comprises an integrin-binding polypeptide sequence in the presence or absence of a linker, wherein said sequence is selected from the group consisting of GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCG (SEQ ID NO:130), GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCG (SEQ ID NO:131), GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCGGGGGS (SEQ ID NO:132), GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCGGGGGS (SEQ ID NO:133), GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCGGGGGSGGGGSGGGGS (SEQ ID NO:134), and GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCGGGGGSGGGGSGGGGS (SEQ ID NO:135), wherein said integrin-binding polypeptide sequence is directly linked to an Fc domain, wherein said Fc domain is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         11 . The method of  claim 1 , wherein said method further comprises administering an interleukin-2 (IL-2). 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 11 , wherein said IL-2 is administered at a 12 MIU/m2 or lower daily dose. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein said method further comprises administering either (i) IL-2 or (ii) an immune checkpoint inhibitor or an immune checkpoint stimulator. 
     
     
         18 . The method of  claim 1 , wherein said method further comprises administering both (i) IL-2 and (ii) an immune checkpoint inhibitor or an immune checkpoint stimulator. 
     
     
         19 . The method of  claim 17  or  claim 18 , wherein said immune checkpoint inhibitor is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. 
     
     
         20 . The method of  claim 17  or  claim 18 , wherein said immune checkpoint stimulator is selected from the group consisting an anti-4-1BB/CD137 antibody, an anti-IFNα antibody, an anti-GITR antibody, an OX40 antibody, an anti-CD40 antibody, an anti-ICOS antibody, and an anti-CD28 antibody. 
     
     
         21 . The method of  claim 1 , wherein said integrin-binding polypeptide-Fc fusion binds to at least two integrins. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . A polypeptide comprising an integrin-binding polypeptide sequence in the presence or absence of a linker, wherein said sequence is selected from the group consisting of GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCG (SEQ ID NO:130), GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCG (SEQ ID NO:131), GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCGGGGGS (SEQ ID NO:132), GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCGGGGGS (SEQ ID NO:133), GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCGGGGGSGGGGSGGGGS (SEQ ID NO:134), and GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCGGGGGSGGGGSGGGGS (SEQ ID NO:135), wherein said integrin-binding polypeptide sequence is directly linked to an Fc domain, wherein said Fc domain is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         29 . A composition comprising an integrin-binding polypeptide sequence in the presence or absence of a linker, wherein said sequence is selected from the group consisting of GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCG (SEQ ID NO:130), GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCG (SEQ ID NO:131), GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCGGGGGS (SEQ ID NO:132), GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCGGGGGS (SEQ ID NO:133), GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCGGGGGSGGGGSGGGGS (SEQ ID NO:134), and GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCGGGGGSGGGGSGGGGS (SEQ ID NO:135), wherein said integrin-binding polypeptide sequence is directly linked to an Fc domain, wherein said Fc domain is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         30 . (canceled) 
     
     
         31 . A nucleic acid encoding an integrin-binding polypeptide-Fc fusion as described herein. 
     
     
         32 . An expression vector comprising a nucleic acid encoding an integrin-binding polypeptide-Fc fusion as described herein. 
     
     
         33 . A host cell comprising the expression vector of  claim 31 . 
     
     
         34 . A method of making an integrin-binding polypeptide-Fc fusion as described herein comprising
 a) culturing the host cell of  claim 33  under conditions wherein said integrin-binding polypeptide-Fc fusion is expressed; and   b) recovering said integrin-binding polypeptide-Fc fusion.   
     
     
         35 . A method for activating the immune system in order to treat cancer in a subject comprising administering to the subject an effective amount of an integrin-binding polypeptide-Fc fusion, wherein said integrin-binding polypeptide-Fc fusion is administered in a therapeutically effective amount, wherein said integrin-binding polypeptide comprises a sequence selected from the group consisting of SEQ ID NO:130 (GCPRPRGDNPPLTCSQDSDCLAGCVCGPNGFCG) and SEQ ID NO:131 (GCPRPRGDNPPLTCKQDSDCLAGCVCGPNGFCG), and wherein said integrin-binding polypeptide is conjugated to an Fc domain. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled)