Il-17a and il-17f antagonists and methods of using the same

Abstract

The present invention relates antagonists of IL-17A and IL-17F. The antagonists of the invention are based on IL-17RC alone or on both IL-17RC and IL-17RA (“IL-17RC/IL-17RA”). Such antagonists serve to block, inhibit, reduce, antagonize or neutralize the activity of IL-17F, IL-17A, or both IL-17A and IL-17F. IL-17A and IL-17F are cytokines that are involved in inflammatory processes and human disease. IL-17RA is a receptor for IL-17A and IL-17RC is a common receptor for both IL-17A and IL-17F. The present invention includes soluble IL-17A and IL-17F anatagonists, as well as methods for using the same.

1 . An isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity with amino acid residues 32-458 of SEQ ID NO:158, wherein the polypeptide binds IL-17A and/or IL-17F.  
     
     
         2 . The isolated polypeptide of  claim 1  wherein the polypeptide comprises amino acid residues 32-458 of SEQ ID NO:158.  
     
     
         3 . The isolated polypeptide of  claim 1  further comprising an immunoglobulin moiety.  
     
     
         4 . The isolated polypeptide of  claim 3  wherein the immunoglobulin moiety is an immunoglobulin heavy chain constant region.  
     
     
         5 . The isolated polypeptide of  claim 3  wherein the immunoglobulin moiety comprises amino acid residues 459-690 of SEQ ID NO:158.  
     
     
         6 . The polypeptide of  claim 3  wherein the immunoglobulin moiety comprises amino acid residues 1-232 of SEQ ID NO:175.  
     
     
         7 . An isolated nucleic acid molecule encoding a polypeptide wherein the encoded polypeptide comprises an amino acid sequence having at least 95% sequence identity with amino acid residues 32-458 of SEQ ID NO:158, and wherein the encoded polypeptide binds IL-17A and/or IL-17F.  
     
     
         8 . The isolated nucleic acid molecule of  claim 7  wherein the encoded polypeptide comprises amino acid residues 32-458 of SEQ ID NO:158.  
     
     
         9 . The isolated nucleic acid molecule of  claim 7  wherein the encoded polypeptide further comprises an immunoglobulin moiety.  
     
     
         10 . The isolated nucleic acid molecule of  claim 9  wherein the immunoglobulin moiety is an immunoglobulin heavy chain constant region.  
     
     
         11 . The isolated nucleic acid molecule of  claim 9  wherein the immunoglobulin moiety comprises amino acid residues 459-690 of SEQ ID NO:158.  
     
     
         12 . The isolated nucleic acid molecule of  claim 11  wherein the nucleic acid molecule comprises nucleotides 94-2070 of SEQ ID NO:157.  
     
     
         13 . The isolated nucleic acid molecule of  claim 9  wherein the immunoglobulin moiety comprises amino acid residues 1-232 of SEQ ID NO:175.  
     
     
         12 . The isolated nucleic acid molecule of  claim 7  wherein the nucleic acid molecule comprises nucleotides 94-1374 of SEQ ID NO:157.  
     
     
         13 . An expression vector comprising the following operably linked elements: 
 a) a transcription promoter;    b) a DNA segment encoding a polypeptide wherein the encoded polypeptide comprises an amino acid sequence having at least 95% sequence identity with amino acid residues 32-458 of SEQ ID NO:158, wherein the encoded polypeptide binds IL-17A and/or IL-17F; and    c) a transcription terminator.    
     
     
         14 . The expression vector of  claim 13  wherein the DNA segment further encodes a secretory signal sequence.  
     
     
         15 . The expression vector of  claim 13  wherein the DNA segment further encodes an immunoglobulin moiety.  
     
     
         16 . The expression vector of  claim 15  wherein the immunoglobulin moiety is an immunoglobulin heavy chain constant region.  
     
     
         17 . A cultured cell comprising the expression vector of  claim 13 , wherein the cell expresses the polypeptide encoded by the DNA segment.  
     
     
         18 . A method of producing a polypeptide comprising: 
 culturing a cell into which has been introduced an expression vector of  claim 13 , wherein the cell expresses the polypeptide encoded by the DNA segment; and    recovering the expressed polypeptide.    
     
     
         19 . A composition comprising: 
 an isolated polypeptide comprising an amino acid sequence having at least 95% sequence identity with amino acid residues 32-458 of SEQ ID NO:158; and    a pharmaceutically acceptable vehicle.    
     
     
         20 . The composition of  claim 19  wherein the polypeptide further comprises an immunoglobulin moiety.  
     
     
         21 . The composition of  claim 20  wherein the immunoglobulin moiety is an immunoglobulin heavy chain constant region.  
     
     
         22 . The composition of  claim 21  wherein the immunoglobulin moiety comprises amino acid residues 1-232 of SEQ ID NO:175.  
     
     
         23 . The composition of  claim 21  wherein the immunoglobulin moiety comprises amino acid residues 459-690 of SEQ ID NO:158.  
     
     
         24 . A method of treating a subject suffering from a disease comprising administering to the subject a polypeptide comprising an amino acid sequence having at least 95% sequence identity with amino acid residues 32-458 of SEQ ID NO:158, wherein the polypeptide binds, blocks, reduces, antagonizes or neutralizes IL-17A and/or IL-17F activity, and wherein the disease is selected from the group consisting of psoriasis, atopic and contact dermatitis, IBD, IBS, colitis, endotoxemia, arthritis, rheumatoid arthritis, Lyme disease arthritis, psoriatic arthritis, adult respiratory disease (ARD), septic shock, multiple organ failure, inflammatory lung injury such as asthma, chronic obstructive pulmonary disease (COPD), airway hyper-responsiveness, chronic bronchitis, allergic asthma, bacterial pneumonia, psoriasis, eczema, and inflammatory bowel disease such as ulcerative colitis and Crohn's disease,  helicobacter pylori  infection, intraabdominal adhesions and/or abscesses as results of peritoneal inflammation (i.e. from infection, injury, etc.), systemic lupus erythematosus (SLE), lupus nephritis, Diabetes Type I, coronary artery disease, stroke, multiple sclerosis, systemic sclerosis, scleroderma, nephrotic syndrome, sepsis, organ allograft rejection, graft vs. host disease (GVHD), transplant rejection (e.g., kidney, lung, and heart), streptococcal cell wall (SCW)-induced arthritis, osteoarthritis, gingivitis/periodontitis, herpetic stromal keratitis, osteoporosis, neuritis, herpetic stromal keratitis, cancers including prostate, renal, colon, ovarian, cervical, leukemia, cancer angiogenesis (such as ovarian cancer, cervical cancer and prostate cancer), B cell lymphoma, T cell lymphoma, cystic fibrosis, restenosis and kawasaki disease.  
     
     
         25 . The method of  claim 24  wherein the polypeptide comprises amino acid residues 32-690 of SEQ ID NO:158.