Gitr ligand and gitr ligand-related molecules and antibodies and uses thereof

Abstract

The present invention provides novel isolated and purified polynucleotides and polypeptides related to a novel ligand for glucocorticoid-induced TNF receptor (GITR). The invention also provides antibodies to the GITR ligand (GITRL). The present invention also is directed to novel methods for diagnosing, prognosing, monitoring the progress of, and treating disorders arising from disregulation of the immune system (e.g., autoimmune disorders, inflammatory diseases, and transplant rejection, and cancers and infectious diseases) using GITRL and/or modulators of GITRL. The present invention is further directed to novel therapeutics and therapeutic targets and to methods of screening and assessing test compounds for the intervention (treatment) and prevention of said disorders arising from disregulation of the immune system, as related to GITRL and GITR.

1 . An isolated nucleic acid molecule having 90% sequence identity to the nucleotide sequence of SEQ ID NO:3. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . An isolated nucleic acid molecule that specifically hybridizes under highly stringent conditions to the nucleotide sequence set forth in SEQ ID NO:3, or the complement thereto. 
     
     
         5 . An isolated nucleic acid molecule that encodes a protein comprising the amino acid sequence of SEQ ID NO:2 or an active fragment of the amino acid sequence of SEQ ID NO:2, wherein the protein or the active fragment thereof is capable of binding GITR. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . A nonhuman transgenic animal in which a transgene in the somatic and germ cells contains DNA comprising the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3. 
     
     
         9 . (canceled) 
     
     
         10 . An isolated protein having 60% sequence identity to the amino acid sequence of SEQ ID NO:2, or an active fragment thereof, wherein the protein or the active fragment thereof is capable of binding GITR. 
     
     
         11 . An isolated nucleic acid molecule comprising a nucleotide sequence complementary to the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3, or a fragment thereof, wherein expression of the nucleic acid molecule in a cell results in decreased production of GITRL. 
     
     
         12 . (canceled) 
     
     
         13 . An antisense oligonucleotide complementary to an mRNA corresponding to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3, or a fragment thereof, wherein the oligonucleotide inhibits expression of GITRL. 
     
     
         14 . An siRNA molecule corresponding to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:3, or a fragment thereof, wherein the siRNA molecule inhibits expression of GITRL. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A method of screening for test compounds capable of inhibiting the interaction of GITRL with GITR comprising the steps of:
 contacting a sample containing GITRL and GITR with the compound; and   determining whether the interaction of GITRL with GITR in the sample is decreased relative to the interaction of GITRL with GITR in a sample not contacted with the compound,   
       whereby a decrease in the interaction of GITRL with GITR in the sample contacted with the compound identifies the compound as one that inhibits the interaction of GITRL with GITR. 
     
     
         19 . A method of screening for test compounds capable of enhancing or mimicking the interaction of GITRL with GITR comprising the steps of:
 contacting a sample containing GITRL and GITR with the compound; and   determining whether the interaction of GITRL with GITR in the sample is increased relative to the interaction of GITRL with GITR in a sample not contacted with the compound,   
       whereby an increase in the interaction of GITRL with GITR in the sample contacted with the compound identifies the compound as one that enhances or mimics the interaction of GITRL with GITR. 
     
     
         20 . A method for diagnosing an autoimmune disorder, an inflammatory disease, or transplant rejection in a subject comprising the steps of:
 detecting a test amount of a GITRL gene product in a sample from the subject; and   comparing the test amount with a normal amount of the GITRL gene product in a control sample,   
       whereby a test amount significantly above the normal amount provides a positive indication in the diagnosis of an autoimmune disorder, an inflammatory disease, or transplant rejection. 
     
     
         21 . A method for diagnosing cancer or an infectious disease in a subject comprising the steps of:
 detecting a test amount of a GITRL gene product in a sample from the subject; and   comparing the test amount with a normal amount of the GITRL gene product in a control sample,   
       whereby a test amount significantly below the normal amount provides a positive indication in the diagnosis of cancer or an infectious disease. 
     
     
         22 - 26 . (canceled) 
     
     
         27 . A method of treating a subject at risk for, or diagnosed with, cancer or an infectious disease comprising administering to the subject a GITR agonist. 
     
     
         28 - 29 . (canceled) 
     
     
         30 . A method of inducing proliferation of a cell population containing effector T cells comprising administering a GITR agonist to the cell population. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method of inhibiting proliferation of a cell population containing effector T cells comprising administering a GITR antagonist to the cell population. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . A method of blocking suppression of a cell population including effector T cells in the presence of CD4 + CD25 +  regulatory T cells comprising administering a GITR agonist to the cell population. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . A method of suppressing of a cell population including effector T cells in the presence of CD4 + CD25 +  regulatory T cells comprising administering a GITR antagonist to the cell population. 
     
     
         41 - 43 . (canceled) 
     
     
         44 . A method of treating cancer or an infectious disease in a subject, the method comprising the steps of obtaining a population of effector T cells, treating the population with a GITR agonist, and administering the treated population to the subject afflicted with cancer or an infectious disease. 
     
     
         45 - 46 . (canceled) 
     
     
         47 . A pharmaceutical composition comprising a GITR agonist and a pharmaceutically acceptable carrier. 
     
     
         48 . (canceled) 
     
     
         49 . A pharmaceutical composition comprising a GITR antagonist and a pharmaceutically acceptable carrier. 
     
     
         50 . (canceled) 
     
     
         51 . A vaccine adjuvant comprising a GITR agonist and an antigen selected from the group consisting of a viral antigen, a bacterial antigen, a fungal antigen, a parasitic antigen, a cancer antigen, a tumor-associated antigen, and fragments thereof. 
     
     
         52 - 54 . (canceled)