Icos binding proteins

Abstract

The present invention relates to an ICOS binding protein or antigen binding portion thereof that is an agonist to human ICOS and does not induce complement, ADCC, or CDC when placed in contact with a T cell in vivo and methods of treating cancer, infectious disease and/or sepsis with said ICOS binding protein or antigen binding portion thereof. Further the ICOS binding proteins or antigen binding portions thereof of the present invention are capable of activating a T cell when placed in contact with said T cell; stimulating T cell proliferation when placed in contact with said T cell and/or inducing cytokine production when placed in contact with said T cell. The present invention relates to ICOS binding proteins or antigen binding portions thereof comprising one or more of: SEQ ID NO: 1; SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; and/or SEQ ID NO:6.

1 . A method of treating a cancer in a human in need thereof, which method comprises administering an ICOS binding protein or antigen binding portion thereof to said human, wherein the ICOS binding protein or antigen binding portion thereof cross-competes for binding to human ICOS with a reference antibody or antigen binding portion thereof comprising a V H  domain comprising an amino acid sequence set forth in SEQ ID NO:7; and a V L  domain comprising the amino acid sequence set forth in SEQ ID NO:8, and administering an anti-OX40 antibody or antigen binding portion thereof to said human. 
     
     
         2 . The method of  claim 1  wherein the ICOS binding protein or antigen binding portion thereof binds to human ICOS with
 (i) an association rate constant (k on ) of at least 1×10 5  M −1  s −1 ; and a dissociation rate constant (k off ) of less than 6×10 −5  s −1 ; or 
 (ii) a dissociation constant (KD) of less than about 100 nM, 
 
       wherein the affinity is measured by BIAcore. 
     
     
         3 . The method of  claim 1  wherein said cancer is selected from colorectal cancer (CRC), esophageal, cervical, bladder, breast, head and neck, ovarian, melanoma, renal cell carcinoma (RCC), EC squamous cell, non-small cell lung carcinoma, mesothelioma, and prostate cancer. 
     
     
         4 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof comprises one or more of: CDRH1 as set forth in SEQ ID NO: 1; CDRH2 as set forth in SEQ ID NO:2; CDRH3 as set forth in SEQ ID NO:3; CDRL1 as set forth in SEQ ID NO:4; CDRL2 as set forth in SEQ ID NO:5 and/or CDRL3 as set forth in SEQ ID NO:6 or a direct equivalent of each CDR wherein a direct equivalent has no more than two amino acid substitutions in said CDR. 
     
     
         5 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof of  claim 1  comprising a V H  domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7 and/or a V L  domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO:8 wherein said ICOS binding protein specifically binds to human ICOS. 
     
     
         6 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof is an ICOS agonist. 
     
     
         7 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof of any one of  claims 1  to  4  wherein the ICOS binding protein comprises a heavy chain variable region comprising SEQ ID NO:1; SEQ ID NO:2; and SEQ ID NO:3 and wherein said ICOS binding protein comprises a light chain variable region comprising SEQ ID NO:4; SEQ ID NO:5, and SEQ ID NO:6. 
     
     
         8 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof of any one of  claims 1  to  5  comprising a V H  domain comprising the amino acid sequence set forth in SEQ ID NO:7 and a V L  domain comprising the amino acid sequence as set forth in SEQ ID NO:8. 
     
     
         9 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof of any one of  claims 1  to  6  wherein said ICOS binding protein or antigen binding portion thereof comprises a scaffold selected from human IgG1 isotype or variant thereof and human IgG4 isotype or variant thereof. 
     
     
         10 . The method of  claim 1 , wherein the ICOS binding protein or antigen binding portion thereof of any one of  claims 1  to  7  wherein said ICOS binding protein or antigen binding portion thereof comprises an hIgG4PE scaffold. 
     
     
         11 . The method of  claim 1 , wherein the ICOS binding protein is a monoclonal antibody. 
     
     
         12 . The method of  claim 11 , wherein the monoclonal antibody is humanized. 
     
     
         13 . The method of  claim 11 , wherein the monoclonal antibody is fully human. 
     
     
         14 . The method of  claim 11 , wherein the monoclonal antibody comprises heavy chain CDRs having the amino acid sequences set forth in SEQ ID NO:1; SEQ ID NO:2; and SEQ ID NO:3 and light chain CDRs having the amino acid sequences set forth in SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6. 
     
     
         15 . The method of  claim 11 , wherein the monoclonal antibody is an agonist to human ICOS and comprises an IgG4 isotype scaffold or a variant thereof. 
     
     
         16 . The method of  claim 11 , wherein the monoclonal antibody comprises a hIgG4PE scaffold. 
     
     
         17 . The method of  claim 1  further comprising administering at least one, anti-neoplastic agent, at least one third immuno-modulatory agent, and/or at least one immunostimulatory adjuvant to said human. 
     
     
         18 . A pharmaceutical composition comprising an ICOS binding protein or antigen binding portion thereof to said human, wherein the ICOS binding protein or antigen binding portion thereof cross-competes for binding to human ICOS with a reference antibody or antigen binding portion thereof comprising a V H  domain comprising an amino acid sequence set forth in SEQ ID NO:7; and a V L  domain comprising the amino acid sequence set forth in SEQ ID NO:8, and administering an anti-OX40 antibody or antigen binding portion thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the ICOS binding protein is a humanized monoclonal antibody comprising a V H  domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7; and a V L  domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO:8 wherein said antibody specifically binds to human ICOS. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the ICOS binding protein comprises heavy chain CDRs having the amino acid sequences set forth in SEQ ID NO: 1; SEQ ID NO:2; and SEQ ID NO:3 and light chain CDRs having the amino acid sequences set forth in SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6.