Anti-tigit antibodies and their use as therapeutics and diagnostics

Abstract

Provided are antibodies that specifically bind to TIGIT (T cell immunoreceptor with Ig and ITIM domains, WUCAM or Vstm3) and inhibit Tigit-mediated cellular signaling and activities in immune cells. The anti-TIGIT antibodies can be used to treat or diagnose cancer, infectious diseases or other pathological disorders that may be modulated by Tigit-mediated functions.

1 . A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof, which is capable of binding to human Tigit, comprising:
 (a) a heavy chain variable region (VH) comprising heavy chain complementarity determining region (CDR)1, CDR2, and CDR3 comprising amino acid sequences of SEQ ID NOs: 3, 13, and 5, respectively; and   (b) a light chain variable region (VL) comprising light chain CDR1, CDR2, and CDR3 comprising amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively;   wherein the composition is in a liquid solution form.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the antibody or fragment thereof is a humanized antibody molecule. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 14, and a light chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 16. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the antibody or fragment thereof comprises a heavy chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 19, and a light chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 21. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the antibody or fragment thereof comprises:
 (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 14, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 16; or   (b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 19, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 21.   
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the antibody or fragment thereof comprises one or more of:
 (a) a heavy chain variable domain with a T to A mutation at position 24 of SEQ ID NO 14;   (b) a heavy chain variable domain with a I to V mutation at position 37 of SEQ ID NO 14;   (c) a light chain variable domain with a V to I mutation at position 58 of SEQ ID NO 16.   
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the antigen-binding fragment is a Fab, F(ab′)2, Fv, or a single chain Fv(ScFv). 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the antibody comprises a heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4 or a variant thereof, and a light chain constant region of the type of kappa or lambda or a variant thereof. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the composition is suitable for parenteral administration. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the composition is suitable for intravenous administration. 
     
     
         11 . The pharmaceutical composition of  claim 1 , further comprising second therapeutic agent. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the second therapeutic agent is selected from a chemotherapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy. 
     
     
         13 . A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof, which is capable of binding to human Tigit, comprising:
 (a) a heavy chain variable region (VH) comprising heavy chain complementarity determining region (CDR)1, CDR2, and CDR3 comprising amino acid sequences of SEQ ID NOs: 3, 13, and 5, respectively; and   (b) a light chain variable region (VL) comprising light chain CDR1, CDR2, and CDR3 comprising amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively;   wherein the composition is an injectable or infusion solution.   
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the antibody or fragment thereof is a humanized antibody molecule. 
     
     
         15 . The pharmaceutical composition of  claim 13 , wherein the antibody or fragment thereof comprises a heavy chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 14, and a light chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 16. 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the antibody or fragment thereof comprises a heavy chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 19, and a light chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 21. 
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the antibody or fragment thereof comprises:
 (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 14, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 16; or   (b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 19, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 21.   
     
     
         18 . The pharmaceutical composition of  claim 13 , wherein the antibody or fragment thereof comprises one or more of:
 (a) a heavy chain variable domain with a T to A mutation at position 24 of SEQ ID NO 14;   (b) a heavy chain variable domain with a I to V mutation at position 37 of SEQ ID NO 14;   (c) a light chain variable domain with a V to I mutation at position 58 of SEQ ID NO 16.   
     
     
         19 . The pharmaceutical composition of  claim 13 , wherein the antigen-binding fragment is a Fab, F(ab′)2, Fv, or a single chain Fv(ScFv). 
     
     
         20 . The pharmaceutical composition of  claim 13 , wherein the antibody comprises a heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4 or a variant thereof, and a light chain constant region of the type of kappa or lambda or a variant thereof. 
     
     
         21 . The pharmaceutical composition of  claim 13 , wherein the composition is suitable for intravenous injection or intravenous infusion. 
     
     
         22 . The pharmaceutical composition of  claim 13 , further comprising second therapeutic agent. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the second therapeutic agent is selected from a chemotherapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.