Il-17a/f heterologous polypeptides and therapeutic uses thereof

Abstract

The present invention is directed to a novel naturally occurring human cytokine that is comprised of a heterodimer of interleukin-17 and interleukin-17F designated herein as interleukin 17A/F (IL-17A/F). Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, specific antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention. Further provided herein are methods for treating degenerative cartilaginous disorders and other inflammatory diseases.

What is claimed: 
     
         1 .- 34 . (canceled) 
     
     
         35 . A recombinant IL-17A/F antagonist that binds to an IL-17A/F polypeptide comprising the polypeptide of SEQ ID NO:3 and SEQ ID NO:4 with or without their associated signal peptides, wherein the antagonist is a humanized monoclonal antibody, wherein the antibody is an IgG 1  isotype, and wherein the antibody comprises an amino acid sequence comprising: 
       
         
           
                 
               
                   (SEQ ID NO: 84) 
                 
                   
                     LSCAASGFTXSDYXXXWVRQAPGKGLEWVATITXXGXNTYYXDSVKGRFT 
                   
                 
                     
                 
                     ISXDXXKNXXYLQMNSLRAEDTAVYYCAXXPXYYEGS . 
                 
             
                
                
                
                
               
            
           
         
       
     
     
         36 . The isolated antibody antagonist of  claim 35 , wherein said antibody is a monoclonal antibody, a humanized antibody or a single-chain antibody. 
     
     
         37 . (canceled) 
     
     
         38 . The antagonist of  claim 35  which is labeled and is immobilized on a solid support. 
     
     
         39 . The antagonist of  claim 35 , wherein said antibody is an antibody fragment. 
     
     
         40 .- 55 . (canceled) 
     
     
         56 . A method of treating an immune related disorder in a human subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an antagonist of  claim 35 ,  claim 76 , or  claim 77 , and wherein the immune related disorder is selected from the group consisting of psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis. 
     
     
         57 .- 65 . (canceled) 
     
     
         66 . A method of inhibiting the proliferation of T-lymphocytes, said method comprising contacting T-lymphocytes with an effective amount of an antagonist of IL-17A/F polypeptide of  claim 35 ,  76 ,  77 ,  78 ,  79 , or  80 , wherein the proliferation of T-lymphocytes is inhibited. 
     
     
         67 . (canceled) 
     
     
         68 . A method of decreasing the infiltration of inflammatory cells into a tissue of a mammal, said method comprising administration to said mammal an effective amount of an antagonist of an IL-17A/F polypeptide of  claim 35 ,  76 ,  77 ,  78 ,  79 , or  80 , wherein said infiltration is decreased. 
     
     
         69 . The method of  claim 68 , wherein said inflammatory cells are mononuclear cells, eosinophils or polymorphonuclear neutrophils (PMNs). 
     
     
         70 .- 75 . (canceled) 
     
     
         76 . A recombinant IL-17A/F antagonist that binds to an IL-17A/F polypeptide comprising the polypeptide of SEQ ID NO:3 and SEQ ID NO:4 with or without their associated signal peptides, wherein the antagonist is a humanized monoclonal antibody, wherein the antibody is an IgG 4  isotype, and wherein the antibody comprises an amino sequence acid comprising: 
       
         
           
                 
               
                   (SEQ ID NO: 85) 
                 
                   SCXASGXXXTDYXIHWVRQAPGXGLEWXGVINPXXGXTDYXXXXKGRXTI 
                 
                     
                 
                   XADXSXXTAYXXXXSLRXEDTAVYYCARXXYFTGTGVY. 
                 
             
                
                
                
                
               
            
           
         
       
     
     
         77 . A recombinant IL-17A/F antagonist that binds to an IL-17A/F polypeptide comprising the polypeptide of SEQ ID NO:3 and SEQ ID NO:4 with or without their associated signal peptides, wherein the antagonist is a humanized monoclonal antibody fragment, and wherein the antibody comprises an amino acid sequence comprising: 
       
         
           
                 
               
                   (SEQ ID NO: 86) 
                 
                   LSCAASGXTXXXXGWXRQAPGKXXEXVAXISXSGXDTYYADSVKGRFTIS 
                 
                     
                 
                   XDXXXXTXYLQMNSLXXEDTAVYYCAXRXGLYYVWDSNDY. 
                 
             
                
                
                
                
               
            
           
         
       
     
     
         78 . A recombinant IL-17A/F antagonist that binds to an IL-17A/F polypeptide comprising the polypeptide of SEQ ID NO:3 and SEQ ID NO:4 with or without their associated signal peptides, wherein the antagonist is a humanized monoclonal antibody, wherein the antibody is an IgG 1  isotype, and wherein the antibody comprises three heavy chain CDR regions: a CDR1 region with an amino acid sequence comprising LSCAASGFTX 1 SDYX 2 X 3 , wherein X 1  and X 3  comprise a non-polar hydrophobic residue, and wherein X 2  comprises a polar hydrophilic residue (SEQ ID NO: 87); a CDR2 region with an amino acid sequence comprising APGKGLEWVATITX 4 X 5 G, wherein X 4  comprises a non-polar residue, and X 5  comprises a polar hydrophilic residue (SEQ ID NO: 88); and a CDR3 region with an amino acid sequence comprising YLQMNSLRAEDTAVYYCAX 6 X 7 PX 8 YYEGSX 9 , wherein X 6  and X 8  comprise a polar hydrophilic residue, and X 7  and X 9  comprise a non-polar hydrophobic residue (SEQ ID NO: 89). 
     
     
         79 . A recombinant IL-17A/F antagonist that binds to an IL-17A/F polypeptide comprising the polypeptide of SEQ ID NO:3 and SEQ ID NO:4 with or without their associated signal peptides, wherein the antagonist is a humanized monoclonal antibody, wherein the antibody is an IgG 4  isotype, and wherein the antibody comprises three heavy chain CDR regions: a CDR1 region with an amino acid sequence comprising ASGX a X b X c TDYX d , wherein X a  comprises a non-polar aromatic residue, wherein X b  comprises a polar, hydrophilic neutral residue, wherein X c  comprises a non-polar hydrophobic residue, and wherein X d  comprises a polar hydrophilic residue (SEQ ID NO: 90); a CDR2 region with an amino acid sequence comprising GLEWX e GVINPX f X g GX h TDY, wherein X e , X f , and X g  comprise a non-polar hydrophobic residue, and wherein X h  comprises a polar, hydrophilic neutral residue (SEQ ID NO: 91); and a CDR3 region with an amino acid sequence comprising EDTAVYYCARX i X j YFTGTGVY, wherein X i  comprises a non-polar hydrophobic residue and X j  comprises a polar hydrophilic residue (SEQ ID NO: 92). 
     
     
         80 . A recombinant IL-17A/F antagonist that binds to an IL-17A/F polypeptide comprising the polypeptide of SEQ ID NO:3 and SEQ ID NO:4 with or without their associated signal peptides, wherein the antagonist is a humanized monoclonal antibody fragment, and wherein the fragment comprises three heavy chain CDR regions: a CDR1 region with an amino acid sequence comprising TX 1′ X 2′ X 3′ X 4′ G, wherein X 1′ , X 3′  and X 4′  comprise a non-polar hydrophobic residue, and X 2′  comprises a polar hydrophilic residue; a CDR2 region with an amino acid sequence comprising EX 5′ VAX 6 ′ISX 7′ SG, wherein X 5′  comprises an aromatic, non-polar hydrophobic residue, and wherein X 6′  and X 7′  comprise a non-polar hydrophobic residue (SEQ ID NO: 93); and a CDR3 region with an amino acid sequence comprising EDTAVYYCAX 8′ RX 9′ GLYYVWDSNDY, wherein X 8′  and X 9′  comprise a polar hydrophilic residue (SEQ ID NO: 94).