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 polypeptide comprising an amino acid sequence comprising one or more of the following amino acids: an alanine at an amino acid position corresponding to amino acid position 67 of human TIGIT, a glycine at an amino acid position corresponding to amino acid position 74 of human TIGIT, a proline at an amino acid position corresponding to amino acid position 114 of human TIGIT, and a glycine at an amino acid position corresponding to amino acid position 116 of human TIGIT. 
     
     
         2 . The polypeptide of  claim 1 , wherein the polypeptide is not PVR, PVRL1, PVRL2, PVRL3, PVRL4, TIGIT, CD96, or CD226. 
     
     
         3 . The polypeptide of  claim 2 , wherein the polypeptide further comprises one or more of: an amino acid selected from valine, isoleucine, and leucine at an amino acid position corresponding to amino acid position 54 of human TIGIT, an amino acid selected from serine and threonine at an amino acid position corresponding to amino acid position 55 of human TIGIT, a glutamine at an amino acid position corresponding to amino acid position 56 of human TIGIT, a threonine at an amino acid position corresponding to amino acid position 112 of human TIGIT, and an amino acid selected from phenylalanine and tyrosine at an amino acid position corresponding to amino acid position 113 of human TIGIT. 
     
     
         4 . The polypeptide of  claim 2 , wherein the polypeptide further comprises one or more structural submotifs selected from the following:
 a. an amino acid selected from valine and isoleucine at amino acid position 54-an amino acid selected from serine and threonine at amino acid position 55-a glutamine at amino acid position 56;   b. an alanine at position 67-any amino acid at each of amino acid positions 68-73-a glycine at amino acid position 74; and   c. a threonine at amino acid position 112-an amino acid selected from phenylalanine and tyrosine at amino acid position 113-a proline at amino acid position 114-any amino acid at amino acid position 115-a glycine at amino acid position 116, and   
       wherein the numbering of the amino acid positions corresponds to the amino acid positions of human TIGIT. 
     
     
         5 . A method of determining whether a test polypeptide is a member of the TLP family of polypeptides comprising aligning the amino acid sequence of the test polypeptide with an amino acid sequence of one or more members of the TLP family of polypeptides and assessing the presence or absence in the test polypeptide amino acid sequence of any of the amino acids as set forth in  claim 1 . 
     
     
         6 . A method for identifying one or more members of the TLP protein family by identifying proteins in one or more sequence databases whose amino acid sequences comprise at least one of the amino acids as set forth in  claim 1 . 
     
     
         7 . An isolated agent that specifically interacts with one or more conserved or substantially conserved regions of the TLP family members of  claim 1 . 
     
     
         8 . The agent of  claim 7 , wherein the agent is an antagonist of the expression and/or activity of a TLP family member. 
     
     
         9 . The agent of  claim 8 , wherein the antagonist is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. 
     
     
         10 . The agent of  claim 7 , wherein the agent is an agonist of the expression and/or activity of a TLP family member. 
     
     
         11 . The agent of  claim 10 , wherein the agent is selected from an agonizing antibody or antigen-binding fragment thereof, an agonizing peptide, and a small molecule or protein that activates TIGIT binding to PVR and/or TIGIT intracellular signaling mediated by PVR. 
     
     
         12 . A method of identifying or detecting one or more TLP family members by contacting a putative TLP family member polypeptide with the agent of  claim 7  and determining the binding of the agent to the putative TLP family member. 
     
     
         13 . A method of determining whether a test immune cell is an activated or normal T reg , memory T cell, NK cell, or T Fh  cell, comprising assessing the level of expression of TIGIT in the test immune cell and comparing it to the level of expression of TIGIT in a known activated or normal T reg , memory T cell, NK cell, or T Fh  cell, or by comparing the level of expression of TIGIT in the test immune cell to known standard TIGIT expression value(s). 
     
     
         14 . A method for modulating immune system function and/or activity comprising modulating the binding of TIGIT to one or more of PVR, PVRL3, and PVRL2. 
     
     
         15 . An anti-TIGIT antibody or a fragment thereof comprising at least one HVR comprising an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 23-28 or SEQ ID NOs: 31-36. 
     
     
         16 . The anti-TIGIT antibody or antigen-binding fragment thereof of  claim 15 , wherein the antibody light chain comprises the amino acid sequence set forth in SEQ ID NOs: 21 or 29. 
     
     
         17 . The anti-TIGIT antibody or antigen-binding fragment thereof of  claim 15 , wherein the antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NOs: 22 or 30. 
     
     
         18 . The anti-TIGIT antibody or antigen-binding fragment thereof of  claim 15 , wherein the antibody light chain comprises the amino acid sequence set forth in SEQ ID NOs: 21 or 29 and the antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NOs: 22 or 30. 
     
     
         19 . The anti-TIGIT antibody or antigen-binding fragment thereof of  claim 15 , wherein the antibody is selected from a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, and an immunotoxin. 
     
     
         20 . The anti-TIGIT antibody or antigen-binding fragment thereof of  claim 15 , wherein the at least one HVR is at least 90% identical to an HVR set forth in any of SEQ ID NOs: 23-28 or 31-36. 
     
     
         21 . The anti-TIGIT antibody or fragment thereof of  claim 15 , wherein the light chain and/or heavy chain comprise amino acid sequences at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 21 or 29, or 22 or 30, respectively. 
     
     
         22 . A method of modulating a CD226-PVR interaction and/or a CD96-PVR interaction comprising administering at least one of TIGIT, an agonist of TIGIT expression and/or activity, or an antagonist of TIGIT expression and/or activity in vivo or in vitro. 
     
     
         23 . The method of  claim 22 , wherein TIGIT or an agonist of TIGIT expression and/or activity is administered and the CD226-PVR interaction and/or the CD96-PVR interaction is inhibited. 
     
     
         24 . The method of  claim 22 , wherein an antagonist of TIGIT expression and/or activity is administered and the CD226-PVR interaction and/or the CD96-PVR interaction is stimulated. 
     
     
         25 . A method of modulating immune cell function and/or activity by modulating TIGIT and/or PVR expression and/or activity, or by modulating the intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         26 . The method of  claim 25 , wherein the modulating is decreasing or inhibiting proliferation of one or more immune cells or proinflammatory cytokine release by one or more immune cells by treating the cells in vitro or in vivo with TIGIT, an agonist of TIGIT expression and/or activity, an agonist of PVR expression and/or activity, or by stimulating intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         27 . The method of  claim 25 , wherein the modulating is increasing or stimulating proliferation of one or more immune cells or proinflammatory cytokine release by one or more immune cells by treating the cells in vitro or in vivo with an antagonist of TIGIT expression and/or activity, an antagonist of PVR expression and/or activity, or by inhibiting intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         28 . A method of inhibiting an immune response by administering in vitro or in vivo TIGIT, an agonist of TIGIT expression and/or activity, an agonist of PVR expression and/or activity, or by stimulating intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         29 . A method of increasing or stimulating an immune response by administering in vitro or in vivo an antagonist of TIGIT expression and/or activity, an antagonist of PVR expression and/or activity, or by inhibiting intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         30 . A method of modulating the type and/or amount of cytokine production from an immune cell by modulating TIGIT or PVR expression and/or activity in vitro or in vivo. 
     
     
         31 . The method of  claim 30 , wherein proinflammatory cytokine production is stimulated and/or increased by administration of an antagonist of TIGIT expression and/or activity, an antagonist of PVR expression and/or activity, or by inhibiting intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         32 . The method of  claim 30 , wherein proinflammatory cytokine production is inhibited by administration of an agonist of TIGIT expression and/or activity, an agonist of PVR expression and/or activity, or by stimulating intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         33 . A method of stimulating ERK phosphorylation and/or intracellular signaling through the ERK pathway in one or more immune cells comprising treating the one or more immune cells with TIGIT, an agonist of TIGIT expression and/or activity, or an agonist of PVR expression and/or activity. 
     
     
         34 . A method of diagnosing or assessing the severity of an immune-related disease relating to aberrant immune cell response in a subject comprising assessing the expression and/or activity of TIGIT in a sample from the subject and comparing the expression and/or activity of TIGIT to a reference amount of TIGIT expression and/or activity or the amount of TIGIT expression and/or activity in a sample from a normal subject. 
     
     
         35 . (canceled) 
     
     
         36 . A method of preventing treating and/or lessening the severity of an immune-related disease relating to aberrant immune cell response in a subject comprising modulating the expression and/or activity of TIGIT in the subject. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 36 , wherein the immune-related disease is selected from psoriasis, arthritis, inflammatory bowel disease or cancer.