Novel compositions and methods for the treatment of immune related diseases

Abstract

The present invention relates to compositions and methods of using those compositions for the diagnosis and treatment of immune related diseases.

1 . An isolated T-Cell-Ig and ITIM domain (TIGIT)-like protein (TLP)-interacting agent that specifically interacts with one or more conserved or substantially conserved regions of TLP family members, wherein the TLP-interacting agent is capable of binding to mouse TIGIT and human TIGIT. 
     
     
         2 . The agent of  claim 1 , wherein the agent is an antagonist of the expression and/or activity of a TLP family member, wherein the TLP family member is TIGIT or PVR. 
     
     
         3 . The agent of  claim 2 , wherein the antagonist is an antagonizing antibody or antigen-binding fragment thereof, a small molecule inhibitor, an aptamer, an inhibitory nucleic acid, or an inhibitory polypeptide. 
     
     
         4 . The agent of  claim 1 , wherein the agent is an agonist of the expression and/or activity of a TLP family member, wherein the TLP family member is PVR. 
     
     
         5 . The agent of  claim 4 , wherein the agent is an agonizing antibody or antigen-binding fragment thereof, an agonizing peptide, or a small molecule or protein that activates TIGIT binding to PVR and/or TIGIT intracellular signaling mediated by PVR. 
     
     
         6 . An anti-TIGIT antibody, or antigen-binding fragment thereof, comprising at least one HVR comprising an amino acid sequence at least 90% identical to an HVR set forth in any one of SEQ ID NOs: 23-28 or SEQ ID NOs: 31-36. 
     
     
         7 . The anti-TIGIT antibody, or antigen-binding fragment thereof, of  claim 11 , wherein the antibody light chain comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 21 or 29. 
     
     
         8 . The anti-TIGIT antibody, or antigen-binding fragment thereof, of  claim 11 , wherein the antibody heavy chain comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 22 or 30. 
     
     
         9 . The anti-TIGIT antibody, or antigen-binding fragment thereof, of  claim 12 , wherein (a) the antibody light chain comprises the amino acid sequence set forth in SEQ ID NO: 21 and the antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 22, or (b) the antibody light chain comprises the amino acid sequence set forth in SEQ ID NO: 29 and the antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 30. 
     
     
         10 . The anti-TIGIT antibody, or antigen-binding fragment thereof, of  claim 6 , wherein the antibody is a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, or an immunotoxin. 
     
     
         11 . The anti-TIGIT antibody, or antigen-binding fragment thereof, of  claim 6 , wherein the at least one HVR comprises an amino acid sequence set forth in any one of SEQ ID NOs: 23-28 or 31-36. 
     
     
         12 . The anti-TIGIT antibody, or antigen-binding fragment thereof, of  claim 7 , wherein the antibody heavy chain comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 22 or 30. 
     
     
         13 . The agent of  claim 1 , wherein the one or more conserved or substantially conserved regions of TLP family members comprise one or more of the following structural submotifs selected from the group consisting of:
 (a) V/I 54 -S/T 55 -Q 56 ;   (b) A 67 -X 68 -X 69 -X 70 -X 71 -X 72 -X 73 -G 74 , wherein X is any amino acid; and   (c) T 112 -F/Y 113 -P 114 -X 115 -G 116 , wherein X is any amino acid.   
     
     
         14 . The agent of  claim 2 , wherein the antagonist specifically binds TIGIT and blocks TIGIT interaction with PVR. 
     
     
         15 . The agent of  claim 14 , wherein the antagonist inhibits intracellular signaling through the ERK pathway mediated by TIGIT binding to PVR.