Combination therapies employing gitr binding molecules

Abstract

The present invention provides combination therapies that employ a GITR binding molecule in combination with one or more additional agents.

1 .- 64 . (canceled) 
     
     
         65 . A method for treating a subject having a tumor, the method comprising administering to the subject:
 a) a GITR-binding antibody comprising a heavy chain and a light chain, or an antigen-binding fragment thereof, wherein the GITR-binding antibody or the antigen-binding fragment acts as a GITR agonist;   b) a chemotherapeutic agent; and   c) an anti-CTLA-4 antibody, or an antigen-binding fragment.   
     
     
         66 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding fragment comprises: the heavy chain complementarity determining regions (CDRs) set forth in SEQ ID NOs.: 1, 2, and 4 or in SEQ ID NOs.: 1, 3, and 4; and the light chain CDRs set forth in SEQ ID NOs.: 5, 6, and 7. 
     
     
         67 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding fragment comprises human heavy chain framework regions. 
     
     
         68 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding fragment comprises human light chain framework regions. 
     
     
         69 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding fragment is humanized. 
     
     
         70 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding fragment is a chimeric antibody or a chimeric antigen-binding fragment. 
     
     
         71 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding fragment comprises human heavy chain and human light chain framework regions, except that one or more human framework amino acid residues is backmutated to a corresponding murine amino acid residue. 
     
     
         72 . The method of  claim 65 , wherein the GITR agonist activity of the GITR-binding antibody or the antigen-binding fragment comprises increasing T cell effector responses. 
     
     
         73 . The method of  claim 65 , wherein the chemotherapeutic agent is an antimetabolite, an agent that affects microtubule formation, an alkylating agent, or a cytotoxic antibiotic. 
     
     
         74 . The method of  claim 73 , wherein the chemotherapeutic agent is an antimetabolite. 
     
     
         75 . The method of  claim 74 , wherein the antimetabolite is selected from the group consisting of Aminopterin, Methotrexate, Pemetrexed, Raltitrexed, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine, Capecitabine, Cytarabine, Fluorouracil, Floxuridine, and Gemcitabine. 
     
     
         76 . The method of  claim 75 , wherein the antimetabolite is Gemcitabine. 
     
     
         77 . The method of  claim 65 , wherein the GITR-binding antibody or antigen-binding, acts synergistically with the chemotherapeutic agent and the CTLA-4-binding antibody or antigen-binding fragment. 
     
     
         78 . The method of  claim 65 , wherein the method results in one or more of the following: inhibition of tumor growth; reduction in tumor size; reduction in the number of tumors; and decreased tumor burden in the subject. 
     
     
         79 . The method of  claim 65 , wherein the method prolongs survival of the subject. 
     
     
         80 . A method for treating a subject having a tumor, the method comprising administering to the subject:
 a) a GITR-binding antibody comprising a heavy chain and a light chain, or GITR-binding fragment thereof, wherein the GITR-binding antibody or the antigen-binding fragment acts as a GITR agonist, and wherein the GITR-binding antibody or antigen-binding fragment comprises: the heavy chain complementarity determining regions (CDRs) set forth in SEQ ID NOs.: 1, 2, and 4 or in SEQ ID NOs.: 1, 3, and 4; and the light chain CDRs set forth in SEQ ID NOs.: 5, 6, and 7;   b) Gemcitabine; and   c) an anti-CTLA-4 antibody, or a CTLA-4-binding fragment thereof.   
     
     
         81 . The method of  claim 80 , wherein the GITR-binding antibody or antigen-binding fragment comprises human framework regions. 
     
     
         82 . The method of  claim 80 , wherein the GITR-binding antibody or antigen-binding fragment is humanized. 
     
     
         83 . The method of  claim 80 , wherein the GITR-binding antibody or antigen-binding fragment is a chimeric antibody or a chimeric antigen-binding fragment. 
     
     
         84 . A kit for treating a subject having a tumor, the kit comprising:
 a) a GITR-binding antibody comprising a heavy chain and a light chain, or GITR-binding fragment thereof, wherein the GITR-binding antibody or the antigen-binding fragment acts as a GITR agonist, and wherein the GITR-binding antibody or antigen-binding fragment comprises: the heavy chain complementarity determining regions (CDRs) set forth in SEQ ID NOs.: 1, 2, and 4 or in SEQ ID NOs.: 1, 3, and 4; and the light chain CDRs set forth in SEQ ID NOs.: 5, 6, and 7;   b) Gemcitabine; and   c) an anti-CTLA-4 antibody, or a CTLA-4-binding fragment thereof.