Anti-gitr antigen-binding proteins and methods of use thereof

Abstract

Provided herein are antigen-binding proteins (ABPs) that selectively bind to GITR and its isoforms and homologs, and compositions comprising the ABPs. Also provided are methods of using the ABPs, such as therapeutic and diagnostic methods.

1 - 19 . (canceled) 
     
     
         20 . A method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject an effective amount of an isolated antigen binding protein (ABP) that specifically binds human GITR (hGITR; SEQ ID NO: 1) and agonizes GITR expressed on the surface of a target cell, wherein the ABP comprises the following six CDR sequences:
 (a) a CDR-H3 having the sequence X 1 X 2 X 3 X 4 X 5 RGYGDYGGHHAFDI, wherein X 1  is A or V, X 2  is H, D, L, or R, X 3  is E or D, X 4  is R, N, S, or A, and X 5  is V, D or G (SEQ ID NO:141);   (b) a CDR-H2 having the sequence X 1 IX 2 X 3 SGX 4 TYYNPSLKS, wherein X 1  is G, L, or S, X 2  is Y, A, or V, X 3  is E, Y or H, and X 4  is S or K (SEQ ID NO:142);   (c) a CDR-H1 having the sequence X 1 SISSX 2 X 3 X 4 X 5 WX 6 , wherein X 1  is Y or G, X 2  is G, S, or E, X 3  is L, G, S, Y, or A, X 4  is G, A, Y, M, or G, X 5  is V, A, or is absent, and X 6  is S or G (SEQ ID NO:143);   (d) a CDR-L3 having the sequence QQEYX 1 TPPX 2 , wherein X 1  is A or N and X 2  is T or S (SEQ ID NO:144);   (e) a CDR-L2 having the sequence X 1 AX 2 SLX 3 X 4 , wherein X 1  is A or S, X 2  is D or S, X 3  is Q, D, K, or E, and X 4  is S or Y (SEQ ID NO:145); and   (f) a CDR-L1 having the sequence-X 1 AS X 2 SI X 3 X 4 YLN, wherein X 1  is G or R, X 2  is Q or K, X 3  is S, D, or N, and X 4  is S or T (SEQ ID NO:146),
 thereby treating or preventing a cancer in the subject. 
   
     
     
         21 . The method of  claim 20 , wherein the ABP comprises:
 a) a CDR-H3 of SEQ ID NO:13, a CDR-H2 of SEQ ID NO:12, a CDR-H1 of SEQ ID NO:11, a CDR-L3 of SEQ ID NO:16, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:14;   b) a CDR-H3 of SEQ ID NO:23, a CDR-H2 of SEQ ID NO:22, a CDR-H1 of SEQ ID NO:21, a CDR-L3 of SEQ ID NO:17, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:14;   c) a CDR-H3 of SEQ ID NO:30, a CDR-H2 of SEQ ID NO:29, a CDR-H1 of SEQ ID NO:28, a CDR-L3 of SEQ ID NO:17, a CDR-L2 of SEQ ID NO:31, and a CDR-L1 of SEQ ID NO:14;   d) a CDR-H3 of SEQ ID NO:30, a CDR-H2 of SEQ ID NO:29, a CDR-H1 of SEQ ID NO:28, a CDR-L3 of SEQ ID NO:17, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:36;   e) a CDR-H3 of SEQ ID NO:30, a CDR-H2 of SEQ ID NO:29, a CDR-H1 of SEQ ID NO:28, a CDR-L3 of SEQ ID NO:17, a CDR-L2 of SEQ ID NO:41, and a CDR-L1 of SEQ ID NO:14;   f) a CDR-H3 of SEQ ID NO:48, a CDR-H2 of SEQ ID NO:47, a CDR-H1 of SEQ ID NO:46, a CDR-L3 of SEQ ID NO:17, a CDR-L2 of SEQ ID NO:50, and a CDR-L1 of SEQ ID NO:49;   g) a CDR-H3 of SEQ ID NO:48, a CDR-H2 of SEQ ID NO:47, a CDR-H1 of SEQ ID NO:46, a CDR-L3 of SEQ ID NO:56, a CDR-L2 of SEQ ID NO:55, and a CDR-L1 of SEQ ID NO:54;   h) a CDR-H3 of SEQ ID NO:61, a CDR-H2 of SEQ ID NO:60, a CDR-H1 of SEQ ID NO:59, a CDR-L3 of SEQ ID NO:16, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:14;   i) a CDR-H3 of SEQ ID NO:61, a CDR-H2 of SEQ ID NO:47, a CDR-H1 of SEQ ID NO:46, a CDR-L3 of SEQ ID NO:16, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:14; or   j) a CDR-H3 of SEQ ID NO:103, a CDR-H2 of SEQ ID NO:22, a CDR-H1 of SEQ ID NO:21, a CDR-L3 of SEQ ID NO:16, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:14.   
     
     
         22 . The method of  claim 21 , wherein:
 a) the ABP of  claim 21  a) comprises a V H  sequence of SEQ ID NO:9 and a V L  sequence of SEQ ID NO:10;   b) the ABP of  claim 21  b) comprises a V H  sequence of SEQ ID NO:19 and a V L  sequence of SEQ ID NO:20;   c) the ABP of  claim 21  c) comprises a V H  sequence of SEQ ID NO:26 and a V L  sequence of SEQ ID NO:27;   d) the ABP of  claim 21  d) comprises a V H  sequence of SEQ ID NO:26 or SEQ ID NO:34 and a V L  sequence of SEQ ID NO:35;   e) the ABP of  claim 21  e) comprises a V H  sequence of SEQ ID NO:26 and a V L  sequence of SEQ ID NO:40;   f) the ABP of  claim 21  f) comprises a V H  sequence of SEQ ID NO:44 and a V L  sequence of SEQ ID NO:45;   g) the ABP of  claim 21  g) comprises a V H  sequence of SEQ ID NO:44 and a V L  sequence of SEQ ID NO:53;   h) the ABP of  claim 21  h) comprises a V H  sequence of SEQ ID NO:58 and a V L  sequence of SEQ ID NO:10;   i) the ABP of  claim 21  i) comprises a V H  sequence of SEQ ID NO:104 and a V L  sequence of SEQ ID NO:10; and   j) the ABP of  claim 21  j) comprises a V H  sequence of SEQ ID NO:105 and a V L  sequence of SEQ ID NO:10.   
     
     
         23 . The method of  claim 22 , wherein:
 a) the ABP of  claim 22  a) comprises a heavy chain of SEQ ID NO:7 and a light chain of SEQ ID NO:8;   b) the ABP of  claim 22  b) comprises a heavy chain of SEQ ID NO:221 and a light chain of SEQ ID NO:18;   c) the ABP of  claim 22  c) comprises a heavy chain of SEQ ID NO:24 and a light chain of SEQ ID NO:25;   d) the ABP of  claim 22  d) comprises (i) a heavy chain of SEQ ID NO:32 and a light chain of SEQ ID NO:33, or (ii) a heavy chain of SEQ ID NO:37 and a light chain of SEQ ID NO:33;   e) the ABP of  claim 22  e) comprises (i) a heavy chain of SEQ ID NO:38 and a light chain of SEQ ID NO:39;   f) the ABP of  claim 22  f) comprises (i) a heavy chain of SEQ ID NO:42 and a light chain of SEQ ID NO:43;   g) the ABP of  claim 22  g) comprises (i) a heavy chain of SEQ ID NO:51 and a light chain of SEQ ID NO:52;   h) the ABP of  claim 22  h) comprises (i) a heavy chain of SEQ ID NO:57 and a light chain of SEQ ID NO:8, or (ii) a heavy chain of SEQ ID NO:220 and a light chain of SEQ ID NO:8;   i) the ABP of  claim 22  i) comprises (i) a heavy chain of SEQ ID NO:114 and a light chain of SEQ ID NO:8, or (ii) a heavy chain of SEQ ID NO:120 and a light chain of SEQ ID NO:8; or (iii) a heavy chain of SEQ ID NO:122 and a light chain of SEQ ID NO:8; or   j) the ABP of  claim 22  j) comprises (i) a heavy chain of SEQ ID NO:115 and a light chain of SEQ ID NO:8, or (ii) a heavy chain of SEQ ID NO:121 and a light chain of SEQ ID NO:8; or (iii) a heavy chain of SEQ ID NO:123 and a light chain of SEQ ID NO:8.   
     
     
         24 . The method of  claim 20 , wherein
 (a) the CDR-H3 has a sequence selected from the group consisting of SEQ ID NOs: 13, 23, 30, 48, 61 and 103;   (b) the CDR-H2 has a sequence selected from the group consisting of SEQ ID NOs: 12, 22, 29, 47, and 60;   (c) the CDR-H1 has a sequence selected from the group consisting of SEQ ID NOs: 11, 21, 28, 46, and 59;   (d) the CDR-L3 has a sequence selected from the group consisting of SEQ ID NOs: 16, 17, and 56;   (e) the CDR-L2 has a sequence selected from the group consisting of SEQ ID NOs: 15, 31, 41, 50, and 55; and   (f) the CDR-L1 has a sequence selected from the group consisting of SEQ ID NOs: 14, 36, 49, and 54.   
     
     
         25 . The method of  claim 20 , wherein the ABP comprises: a CDR-H3 of SEQ ID NO:13, a CDR-H2 of SEQ ID NO:12, a CDR-H1 of SEQ ID NO:11, a CDR-L3 of SEQ ID NO:16, a CDR-L2 of SEQ ID NO:15, and a CDR-L1 of SEQ ID NO:14. 
     
     
         26 . The method of  claim 20 , wherein the ABP comprises a V H  sequence of SEQ ID NO:9 and a V L  sequence of SEQ ID NO:10. 
     
     
         27 . The method of  claim 20 , wherein the method induces or enhances an immune response to a cancer-associated antigen. 
     
     
         28 . The method of  claim 20 , wherein the ABP is administered in an amount sufficient to (a) reduce the suppression of effector T cells by regulatory T cells; (b) activate effector T cells; (c) reduce the number of regulatory T cells in a tissue or systemically; (d) induce or enhance proliferation of effector T cells; (e) inhibit the rate of tumor growth; (f) induce tumor regression; or (g) combinations thereof. 
     
     
         29 . The method of  claim 20 , wherein the cancer is a solid cancer. 
     
     
         30 . The method of  claim 20 , wherein the cancer is a hematological cancer. 
     
     
         31 . The method of  claim 20 , further comprising administering to the subject one or more additional therapeutic agents. 
     
     
         32 . The method of  claim 31 , wherein the additional therapeutic agent is selected from the group consisting of radiation, a cytotoxic agent, a chemotherapeutic agent, a cytostatic agent, an anti-hormonal agent, an EGFR inhibitor, an immunostimulatory agent, an anti-angiogenic agent, and combinations thereof. 
     
     
         33 . The method of  claim 31 , wherein the additional therapeutic agent is an immunostimulatory agent. 
     
     
         34 . The method of  claim 33 , wherein the immunostimulatory agent comprises an agent that blocks signaling of an inhibitory receptor expressed by an immune cell or a ligand thereof. 
     
     
         35 . The method of  claim 34 , wherein the inhibitory receptor expressed by an immune cell or ligand thereof is selected from the group consisting of CTLA-4, PD-1, PD-L1, NRP-1, LAG-3, Tim3, TIGIT, neuritin, BTLA, KIR, and combinations thereof. 
     
     
         36 . The method of  claim 33 , wherein the immunostimulatory agent comprises an agonist to a stimulatory receptor expressed by an immune cell. 
     
     
         37 . The method of  claim 36 , wherein the stimulatory receptor expressed by an immune cell is selected from the group consisting of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, CD83 ligand, and combinations thereof. 
     
     
         38 . The method of  claim 36 , wherein the stimulatory receptor expressed by an immune cell is selected from the group consisting of OX40, ICOS, CD27, CD28, 4-1BB, CD40, and combinations thereof. 
     
     
         39 . The method of  claim 33 , wherein the immunostimulatory agent comprises:
 (a) a cytokine;   (b) an oncolytic virus;   (c) a T cell expressing a chimeric antigen receptor, a bi- or multi-specific T cell directed antibody;   (d) an anti-TGF-β antibody, a TGF-β trap, or a combination thereof;   (e) a vaccine to a cancer-associated antigen; or   (f) a combination thereof.   
     
     
         40 . The method of  claim 39 , wherein the cytokine is selected from the group consisting of IL-2, IL-5, IL-7, IL-12, IL-15, IL-21, and combinations thereof. 
     
     
         41 . The method of  claim 39 , wherein the oncolytic virus is selected from the group consisting of herpes simplex virus, vesicular stomatitis virus, adenovirus, Newcastle disease virus, vaccinia virus, a maraba virus, and combinations thereof.