Characterization of il-17f and il-17r interactions

Abstract

The invention is related to findings that IL-17F-mediated inflammation of airway passages may be mediated via signaling through IL-17R on the basolateral surface of human respiratory epithelial cells. Thus, the present invention provides isolated and purified IL-17F or IL-17R polynucleotides and polypeptides. The present invention also is directed to novel methods for screening test compounds capable of inhibiting, i.e., decreasing, limiting, blocking, or otherwise reducing, IL-17F bioactivity, and methods for diagnosing, prognosing, and monitoring the progress of, disorders related to IL-17F bioactivity, e.g., disorders related to the effects of IL-17F binding to IL-17R on airway inflammation, e.g., in patients with cystic fibrosis, including pulmonary exacerbations due to bacterial infections in same. The present invention is further directed to novel therapeutics and therapeutic targets and to methods for the intervention (treatment) and prevention of said disorders related to IL-17F bioactivity.

1 . A method of diagnosing a disorder related to IL-17F in a subject, comprising the steps of:
 detecting a test amount of an IL-17F gene product in a sample from the subject; and   comparing the test amount with a normal amount of the IL-17F gene product in a control sample,   whereby a test amount significantly above the normal amount provides a positive indication in the diagnosis of a disorder related to IL-17F.   
     
     
         2 . The method of  claim 1 , wherein the disorder related to IL-17F is airway inflammation. 
     
     
         3 . The method of  claim 2 , wherein the subject is a patient diagnosed with cystic fibrosis. 
     
     
         4 . The method of  claim 3 , wherein the subject is undergoing a pulmonary exacerbation. 
     
     
         5 . The method of  claim 4 , wherein the pulmonary exacerbation is due to an infectious agent. 
     
     
         6 . The method of  claim 1 , wherein the IL-17F gene product is an IL-17F protein. 
     
     
         7 . The method of  claim 6 , wherein the IL-17F protein is detected with an anti-IL-17F antibody. 
     
     
         8 . A method of screening for compounds capable of inhibiting IL-17F binding to IL-17R comprising the steps of:
 contacting a sample containing IL-17F and IL-17R with a compound; and   determining whether the binding of IL-17F to IL-17R in the sample contacted with the test compound is decreased relative to the binding of IL-17F to IL-17R in a sample not contacted with the compound,   whereby a decrease in the binding of IL-17F to IL-17R in the sample contacted with the compound identifies the compound as one that inhibits IL-17F binding to IL-17R.   
     
     
         9 . A method of treating a subject at risk for, or diagnosed with, a disorder related to IL-17F comprising administering to the subject a therapeutically effective amount of an IL-17F antagonist. 
     
     
         10 . The method of  claim 9 , wherein the disorder related to IL-17F is airway inflammation. 
     
     
         11 . The method of  claim 10 , wherein the subject is a patient diagnosed with cystic fibrosis. 
     
     
         12 . The method of  claim 11 , wherein the subject is undergoing a pulmonary exacerbation. 
     
     
         13 . The method of  claim 12 , wherein the pulmonary exacerbation is due to an infectious agent. 
     
     
         14 . The method of  claim 9 , wherein the IL-17F antagonist is selected from the group consisting of an inhibitory anti-IL-17F antibody, an inhibitory anti-IL-17R antibody, soluble IL-17R, a fusion protein containing IL-17R, a fusion protein containing an IL-17F binding fragment of IL-17R, an antagonistic small molecule, an antisense IL-17F nucleic acid molecule, an antisense IL-17R nucleic acid molecule, an siRNA IL-17F nucleic acid molecule, and an siRNA IL-17R nucleic acid molecule. 
     
     
         15 . The method of  claim 9 , further comprising administering to the subject a therapeutically effective amount of at least one additional therapeutic agent. 
     
     
         16 . The method of  claim 15 , wherein the at least one additional therapeutic agent is selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents. 
     
     
         17 . The method of  claim 15 , wherein the at least one additional therapeutic agent is selected from the group consisting of TNF antagonists, anti-TNF agents, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-18 antagonists, IL-22 antagonists, T cell-depleting agents, B cell-depleting agents, cyclosporin, FK-506, CCI-779, etanercept, infliximab, rituximab, adalimumab, prednisolone, azathioprine, gold, sulphasalazine, chloroquine, hydroxychloroquine, minocycline, anakinra, abatacept, methotrexate, leflunomide, rapamycin, rapamycin analogs, Cox-2 inhibitors, cPLA2 inhibitors, NSAIDs, p38 inhibitors, antagonists of B7.1, B7.2, ICOSL, ICOS and/or CD28, and agonists of CTLA4. 
     
     
         18 . A pharmaceutical composition comprising an IL-17F antagonist and a pharmaceutically acceptable carrier. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the IL-17F antagonist is selected from the group consisting of an inhibitory anti-IL-17F antibody, an inhibitory anti-IL-17R antibody, soluble IL-17R, a fusion protein containing IL-17R, a fusion protein containing an IL-17F binding fragment of IL-17R, an antagonistic small molecule, an antisense IL-17F nucleic acid molecule, an antisense IL-17R nucleic acid molecule, an siRNA IL-17F nucleic acid molecule, and an siRNA IL-17R nucleic acid molecule. 
     
     
         20 . A vaccine adjuvant comprising an IL-17F antagonist and a bacterial antigen. 
     
     
         21 . The vaccine adjuvant of  claim 20 , wherein the IL-17F antagonist is selected from the group consisting of an inhibitory anti-IL-17F antibody, an inhibitory IL-17R antibody, soluble IL-17R, a fusion protein containing IL-17R, a fusion protein containing an IL-17F binding fragment of IL-17R, an antagonistic small molecule, an antisense IL-17F nucleic acid molecule, an antisense IL-17R nucleic acid molecule, an siRNA IL-17F nucleic acid molecule, and an siRNA IL-17R nucleic acid molecule.