Methods of treating il-tif associated inflammatory or immune diseases using antibodies against soluble zcytor 11 cytokine receptors

Abstract

Novel polypeptide combinations, polynucleotides encoding the polypeptides, and related compositions and methods are disclosed for soluble zcytor11 receptors that may be used as novel cytokine antagonists, and within methods for detecting ligands that stimulate the proliferation and/or development of hematopoietic, lymphoid and myeloid cells in vitro and in vivo. Ligand-binding receptor polypeptides and antibodies can also be used to block TIF activity in vitro and in vivo, and may be used in conjunction with TIF and other cytokines to selectively stimulate the immune system. The present invention also includes methods for producing the protein, uses therefor and antibodies thereto.

1 . A method of producing an antibody to soluble cytokine receptor polypeptide comprising:
 inoculating an animal with a soluble cytokine receptor polypeptide selected from the group consisting of:   (a) a polypeptide comprising a homodimeric soluble cytokine receptor complex;   (b) a polypeptide comprising a soluble cytokine receptor heterodimeric, or multimeric receptor complex comprising a soluble Class I or Class II cytokine receptor polypeptide;   (c) a polypeptide comprising a soluble cytokine receptor heterodimeric or multimeric receptor complex comprising a soluble CRF2-4 receptor polypeptide (SEQ ID NO: 33);   (d) a polypeptide comprising a soluble cytokine receptor heterodimeric or multimeric receptor complex comprising a soluble IL-10 receptor polypeptide (SEQ ID NO: 34)   (e) a polypeptide comprising a soluble cytokine receptor heterodimeric or multimeric receptor complex comprising a soluble DIRS1 receptor polypeptide (SEQ ID NO: 35); and   isolating the antibody from the animal.   
     
     
         2 . An antibody produced by the method of  claim 1 , which specifically binds to a homodimeric, heterodimeric, or multimeric receptor complex comprising a soluble cytokine receptor polypeptide. 
     
     
         3 . The antibody of  claim 2 , wherein the antibody is a monoclonal antibody. 
     
     
         4 . The antibody which specifically binds to a homodimeric, heterodimeric or multimeric receptor complex, wherein at least one of the soluble receptor subunits of the receptor complex comprises a soluble cytokine receptor polypeptide comprising a sequence of amino acid residues as set forth in SEQ ID NO: 3. 
     
     
         5 . An isolated polynucleotide that encodes a soluble cytokine receptor polypeptide comprising a sequence of amino acid residues that is at least 90% identical to the amino acid sequence as shown in SEQ ID NO:3, or at least 90% identical to the amino acid sequence as shown in SEQ ID NO: 3, and wherein the soluble cytokine receptor polypeptide encoded by the polynucleotide sequence hinders or antagonizes IL-TIF (SEQ ID NO:8). 
     
     
         6 . An isolated polynucleotide according to  claim 5 , wherein the soluble cytokine receptor polypeptide encoded by the polynucleotide forms a homodimeric, heterodimeric, or multimeric receptor complex, optionally further comprising a soluble Class I or Class II cytokine receptor. 
     
     
         7 . The isolated polynucleotide according to  claim 6 , wherein the soluble cytokine receptor polypeptide encoded by the polynucleotide forms a heterodimeric or multimeric receptor complex further comprising a soluble CRF2-4 receptor polypeptide (SEQ ID NO:33) or a soluble IL-10 receptor polypeptide (SEQ ID NO:34). or a soluble DIRS I receptor polypeptide (SEQ 10 NO:35). 
     
     
         8 . The isolated polynucleotide of  claim 5 , wherein the polynucleotide encodes a soluble cytokine receptor polypeptide comprising a sequence of amino acid residues as set forth in SEQ ID NO:3, wherein the soluble cytokine receptor polypeptide encoded by the polynucleotide forms a heterodimeric or multimeric receptor complex. 
     
     
         9 . The isolated polynucleotide of  claim 8 , wherein the soluble cytokine receptor polypeptide further encodes an intracellular domain. 
     
     
         10 . An expression vector comprising the polynucleotide of  claim 5 . 
     
     
         11 . The expression vector of  claim 10 , further comprising a second DNA segment that encodes a soluble CRF2-4 receptor polypeptide (SEQ ID NO:33), a soluble IL-10 receptor polypeptide (SEQ ID NO:34), or a soluble DIRS I receptor polypeptide (SEQ ID NO:35). 
     
     
         12 . A host cell comprising the expression vector of  claim 10 . 
     
     
         13 . The host cell of  claim 12 , wherein the cell expresses a heterodimeric or multimeric soluble receptor polypeptide encoded by the polynucleotide of  claim 5 . 
     
     
         14 . The host cell of  claim 13 , wherein the cell secretes a soluble cytokine receptor polypeptide heterodimer or multimeric complex. 
     
     
         15 . The host cell of  claim 14 , wherein the cell secretes a soluble cytokine receptor polypeptide heterodimer or multimeric complex that binds IL-TIF or antagonizes ILTIF activity. 
     
     
         16 . A method of treating an inflammatory or immune disease involving IL-TIF activity in a mammal, wherein said disease is selected from rheumatoid arthritis, psoriasis, and atopic disease, the method comprising:
 administering to said mammal an effective amount of an antagonist of IL-TIF, wherein said antagonist is a soluble cytokine receptor complex comprising
 (i) a first receptor subunit comprising the sequence of amino acid residues shown in SEQ ID NO:3 and 
 (ii) a second receptor subunit comprising a soluble CRF2-4 receptor polypeptide; 
 wherein the soluble cytokine receptor complex binds IL-TIF; and wherein IL-TIF activity in the mammal is reduced, thereby treating the disease. 
   
     
     
         17 . The method of  claim 16 , wherein the disease is rheumatoid arthritis. 
     
     
         18 . The method of  claim 16 , wherein the disease is psoriasis. 
     
     
         19 . The method of  claim 16 , wherein the soluble cytokine receptor complex further comprises an immunoglobulin heavy chain constant region. 
     
     
         20 . The method of  claim 19 , wherein the immunoglobulin heavy chain constant region is an Fc fragment.