Interferon antagonists, antibodies thereto, and associated methods of use

Abstract

Described are compositions and methods useful for modulating the immune system of a subject. Also included are diagnostic methods for monitoring an immunologic condition. In particular the invention relates to antagonists of interferon proteins and associated methods of use as well as methods to develop neutralizing antibodies against IFN antagonists to treat viral infections.

1 . A therapeutic composition comprising: a therapeutically effective amount of an isolated polypeptide having IFN I and IFN III antagonist activity; and at least one of a pharmaceutically acceptable carrier, excipient, or adjuvant. 
     
     
         2 . The therapeutic of  claim 1 , wherein the polypeptide has at least 30% sequence identity to SEQ ID NO. 1 or portion thereof. 
     
     
         3 . The therapeutic of  claim 1 , wherein the polypeptide is a fusion protein comprising at least one other polypeptide portion located at either of the amino terminus, the carboxy terminus, or both, and wherein the polypeptide portions are disposed in a single, contiguous polypeptide chain. 
     
     
         4 . The therapeutic of  claim 3 , wherein the fusion protein comprises a polypeptide portion comprising SEQ ID NO. 1 or a portion thereof and a second polypeptide portion comprising SEQ ID NO. 5 or portion thereof. 
     
     
         5 . An isolated nucleic acid molecule comprising a first polynucleotide component having at least 30% sequence homology to SEQ ID. NO. 2 or portion thereof, and at least one additional polynucleotide component contiguous with the first, wherein the additional polynucleotide component is disposed at the 5′ end or the 3′ end of the nucleic acid, and wherein both are contained within a single open reading frame. 
     
     
         6 . A fusion protein encoded by the isolated nucleic acid of  claim 5 . 
     
     
         7 . The isolated nucleic acid of  claim 6 , wherein the at least one other polynucleotide portion encodes at least one member selected from group consisting of a fluorescent protein, a FLAG tag, an HA tag, a HIS tag, a TAT polypeptide, GST peptide, a second Y136 peptide, an IL receptor, an IL receptor like protein, portions and combinations thereof. 
     
     
         8 . A vector comprising at least one transcription regulatory sequence, and the nucleic acid of  claim 5 . 
     
     
         9 . The vector of  claim 8 , further comprising a promoter operably-linked to said nucleic acid molecule. 
     
     
         10 . The vector of  claim 9 , wherein the isolated nucleic acid further disposed within an expression cassette. 
     
     
         11 . An isolated cell comprising the vector of  claim 8 . 
     
     
         12 . The cell of  claim 11 , wherein the cell is a eukaryotic cell. 
     
     
         13 . The cell of  claim 12 , wherein the cell is a prokaryotic cell. 
     
     
         14 . A method for inhibiting the activity of an interferon comprising administering to a subject an effective amount of a polypeptide having at least 30% sequence identity to SEQ ID NO. 1 or portion thereof. 
     
     
         15 . The method of  claim 14 , wherein the interferon is at least one of a type I interferon, a type III interferon or a combination of both. 
     
     
         16 . The method of  claim 14 , wherein the interferon inhibition ameliorates symptoms associated with a immunological conditions 
     
     
         17 . The method of  claim 16 , wherein the immunological condition is selected from the group consisting of an autoimmune diseases, SLE, acute allograft rejections, septic shock, and viral infection. 
     
     
         18 . The therapeutic of  claim 1 , wherein the polypeptide is an antagonist of at least one of a type I interferon protein, a type III interferon protein or a combination of both. 
     
     
         19 . An antibody capable of binding immunospecifically to a polypeptide having an amino acid sequence SEQ ID NO. 1 or portion thereof. 
     
     
         20 . The antibody of  claim 19 , wherein the antibody is at least one of a chimeric antibody, antibody fragment or humanized antibody. 
     
     
         21 . A method for treating a viral infection comprising administering to a subject in need thereof an effective amount of the antibody of  claim 19 . 
     
     
         22 . A method of preventing a viral infection comprising administering a prophylactic amount of the antibody of  claim 19 . 
     
     
         23 . A method of screening for Y136 agonist or antagonist agents comprising providing at least one of a type I interferon, type III interferon or a combination thereof, and a polypeptide having an amino acid sequence with at least 30% homology to SEQ ID NO. 1 or portion thereof; providing a library of test agents; combining the interferon and polypeptide of SEQ ID NO. 1 before or after exposure to treatment with the test agent; measuring the ability of the test agent to promote or inhibit the formation of IFN-Y136 protein complexes; and comparing the complex-forming ability of a treated sample versus an untreated sample. 
     
     
         24 . A composition comprising a nucleic acid molecule that forms a small inhibitory RNA and that down regulates expression of a nucleic acid of SEQ ID NO. 1 via RNA-interference, wherein the nucleic acid molecule is from about 10 to about 100 nucleotides in length; and wherein the inhibitory nucleic acid molecule comprises a nucleotide sequence having sufficient complementarity to an RNA transcribed from the Y136 gene for the inhibitory nucleic acid molecule to cause, directly or indirectly, cleavage of said RNA via RNA-interference.