Anti-gitr antibodies and uses thereof

Abstract

Provided herein are antibodies, and antigen-binding fragments thereof that specifically bind glucocorticoid-induced tumor necrosis factor receptor (GITR) and methods of using the same, including, e.g., methods of treatment using the same.

What is claimed is: 
     
         1 .- 13 . (canceled) 
     
     
         14 . An isolated antibody or antigen-binding fragment thereof that binds glucocorticoid-induced tumor necrosis factor receptor (GITR), wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence as set forth in Table 1; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence as set forth in Table 1. 
     
     
         15 . The isolated antibody or antigen-binding fragment of  claim 14 , wherein the antibody or antigen-binding fragment comprises an HCVR having an amino acid sequence as set forth in Table 1 and a LCVR having an amino acid sequence as set forth in Table 1. 
     
     
         16 . The isolated antibody or antigen-binding fragment of  claim 14 , wherein the antibody or antigen-binding fragment comprises:
 (i) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 100, 164, 196, 244, 292, 340, and 348;   (ii) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 166, 198, 246, 294, 342, and 350;   (iii) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 104, 168, 200, 248, 296, 344, 352;   (iv) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 108, 172, 204, 252, 300, and 404   (v) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 110 (GAS), 174 (TAS), 206 (AAS), 254 (AAS), 302 (AAS), and 406 (AAS), and   (vi) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID Nos: 112, 176, 208, 256, 304, and 408.   
     
     
         17 . The isolated antibody or antigen-binding fragment of  claim 14 , wherein the antibody or antigen-binding fragment comprises:
 (vii) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 100; an HCDR2 comprising SEQ ID NO: 102; an HCDR3 comprising SEQ ID NO: 104; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 108; an LCDR2 comprising SEQ ID NO: 110 (GAS); and an LCDR3 comprising SEQ ID NO: 112;   (viii) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 164; an HCDR2 comprising SEQ ID NO: 166; an HCDR3 comprising SEQ ID NO: 168; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 172; an LCDR2 comprising SEQ ID NO: 174 (TAS); and an LCDR3 comprising SEQ ID NO: 176;   (ix) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 196; an HCDR2 comprising SEQ ID NO: 198; an HCDR3 comprising SEQ ID NO: 200; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 204; an LCDR2 comprising SEQ ID NO: 206 (AAS); and an LCDR3 comprising SEQ ID NO: 208;   (x) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 244; an HCDR2 comprising SEQ ID NO: 246; an HCDR3 comprising SEQ ID NO: 248; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 252; an LCDR2 comprising SEQ ID NO: 254 (AAS); and an LCDR3 comprising SEQ ID NO: 256;   (xi) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 292; an HCDR2 comprising SEQ ID NO: 294; an HCDR3 comprising SEQ ID NO: 296; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 300; an LCDR2 comprising SEQ ID NO: 302 (AAS); and an LCDR3 comprising SEQ ID NO: 304;   (xii) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 340; an HCDR2 comprising SEQ ID NO: 342; an HCDR3 comprising SEQ ID NO: 344; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 404; an LCDR2 comprising SEQ ID NO: 406 (AAS); and an LCDR3 comprising SEQ ID NO: 408; or   (xiii) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 348; an HCDR2 comprising SEQ ID NO: 350; an HCDR3 comprising SEQ ID NO: 352; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 404; an LCDR2 comprising SEQ ID NO: 406 (AAS); and an LCDR3 comprising SEQ ID NO: 408.   
     
     
         18 .- 19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 14  and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . A method for treating cancer in a subject comprising administering to the subject the composition of  claim 20 . 
     
     
         22 . A method of modulating anti-tumor immune response in a subject comprising administering to the subject the antibody that binds GITR of  claim 14  or antigen-binding fragment thereof. 
     
     
         23 . The method of  claim 22 , further comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to a second T-cell activating receptor. 
     
     
         24 . The method of  claim 23 , wherein the T-cell activating receptor is CD28, OX40, CD137, CD27, or HVEM. 
     
     
         25 . The method of  claim 22 , further comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to a T-cell inhibitory receptor. 
     
     
         26 . The method of  claim 25 , wherein the T-cell inhibitory receptor is CTLA-4, PD-1, TIM-3, BTLA, VISTA, or LAG-3. 
     
     
         27 . The method of  claim 22 , further comprising administering radiation therapy to said subject. 
     
     
         28 . The method of  claim 22 , further comprising administering one or more chemotherapeutic agent. 
     
     
         29 . The method of  claim 26 , wherein the T-cell inhibitory receptor is PD1. 
     
     
         30 . The method of  claim 29 , wherein the antibody that binds to a T-cell inhibitory receptor is REGN 2810. 
     
     
         31 . The method of  claim 22 , wherein the antibody or antigen-binding fragment comprises:
 (i) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 100; an HCDR2 comprising SEQ ID NO: 102; an HCDR3 comprising SEQ ID NO: 104; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 108; an LCDR2 comprising SEQ ID NO: 110 (GAS); and an LCDR3 comprising SEQ ID NO: 112;   (ii) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 164; an HCDR2 comprising SEQ ID NO: 166; an HCDR3 comprising SEQ ID NO: 168; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 172; an LCDR2 comprising SEQ ID NO: 174 (TAS); and an LCDR3 comprising SEQ ID NO: 176;   (iii) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 196; an HCDR2 comprising SEQ ID NO: 198; an HCDR3 comprising SEQ ID NO: 200; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 204; an LCDR2 comprising SEQ ID NO: 206 (AAS); and an LCDR3 comprising SEQ ID NO: 208;   (iv) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 244; an HCDR2 comprising SEQ ID NO: 246; an HCDR3 comprising SEQ ID NO: 248; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 252; an LCDR2 comprising SEQ ID NO: 254 (AAS); and an LCDR3 comprising SEQ ID NO: 256;   (v) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 292; an HCDR2 comprising SEQ ID NO: 294; an HCDR3 comprising SEQ ID NO: 296; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 300; an LCDR2 comprising SEQ ID NO: 302 (AAS); and an LCDR3 comprising SEQ ID NO: 304;   (vi) a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 340; an HCDR2 comprising SEQ ID NO: 342; an HCDR3 comprising SEQ ID NO: 344; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 404; an LCDR2 comprising SEQ ID NO: 406 (AAS); and an LCDR3 comprising SEQ ID NO: 408; or   a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 348; an HCDR2 comprising SEQ ID NO: 350; an HCDR3 comprising SEQ ID NO: 352; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 404; an LCDR2 comprising SEQ ID NO: 406 (AAS); and an LCDR3 comprising SEQ ID NO: 408.