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.

1 - 22 . (canceled) 
     
     
         23 . An isolated polypeptide having at least 80% amino acid sequence identity to:
 (a) the amino acid sequence of an IL-17A/F polypeptide comprising SEQ ID NO:3 and SEQ ID NO:4; or   (b) the amino acid sequence of an IL-17A/F polypeptide comprising SEQ ID NO:3 and SEQ ID NO:4 lacking its associated signal peptides.   
     
     
         24 . The isolated polypeptide of  claim 23 , wherein said IL-17 A/F polypeptide comprises a heterodimeric complex comprising SEQ ID NO:3 and SEQ ID NO:4. 
     
     
         25 . The isolated polypeptide of  claim 24 , wherein said heterodimeric complex comprises two interchain disulfide linkages between SEQ ID NO:3 and SEQ ID NO:4. 
     
     
         26 . The isolated polypeptide of  claim 23  having at least 95% amino acid sequence identity to:
 (a) the amino acid sequence of an IL-17A/F polypeptide comprising SEQ ID NO:3 and SEQ ID NO:4; or 
 (b) the amino acid sequence of an IL-17A/F polypeptide comprising SEQ ID NO:3 and SEQ ID NO:4 lacking its associated signal peptides. 
 
     
     
         27 . A composition of matter comprising (a) the isolated polypeptide of  claim 23 , (b) an agonist of said polypeptide, (c) an antagonist of said polypeptide, or (d) an antibody that binds to said polypeptide, in combination with a carrier. 
     
     
         28 . An isolated antibody which binds to a polypeptide according to  claim 23 . 
     
     
         29 . The isolated antibody of  claim 28 , wherein said antibody is a monoclonal antibody, which preferably has nonhuman complementarity determining region (CDR) residues and human framework region (FR) residues. 
     
     
         30 . The isolated antibody of  claim 28 , wherein said antibody is a human antibody. 
     
     
         31 . The isolated antibody of  claim 28 , wherein said antibody is an antibody fragment, a monoclonal antibody, a single-chain antibody, or an anti-idiotypic antibody. 
     
     
         32 . The isolated antibody of  claim 31 , wherein the antibody fragment or single-chain antibody comprises a Fab fragment selected from the group consisting of the amino acid sequence shown in  FIG. 6  as SEQ ID NO:9, SEQ ID NO: 10; SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, and SEQ ID NO:42, wherein said Fab fragment further comprises three heavy chain variable regions containing CDR-H1 consisting of amino acid residues 7 to 16 of SEQ ID NOs:9-42, CDR-H2 consisting of amino acid residues 30 to 46 of SEQ ID NOs:9-42, and CDR-H3 consisting of amino acid residue 78 to at least amino acid residue 96 of SEQ ID NOs:9-42, wherein said isolated Fab fragment is capable of binding IL-17A/F. 
     
     
         33 . An isolated nucleic acid molecule selected from the group consisting of the nucleotide sequence of SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75 and SEQ ID NO:76, wherein said nucleic acid molecule encodes the Fab fragment shown as SEQ ID NO:9, SEQ ID NO:10; SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, or SEQ ID NO:42, wherein said Fab fragment is capable of binding to IL-17 A/F. 
     
     
         34 . The composition of matter of  claim 27  which is useful for the treatment of an immune related disease in a mammal. 
     
     
         35 . The composition of matter of  claim 27 , wherein (a), (b) or (d) is capable of (i) increasing the proliferation of T-lymphocytes in a mammal, or (ii) increasing infiltration of inflammatory cells into a tissue of a mammal. 
     
     
         36 . An article of manufacture, comprising: a container; a label on said container; and a composition of matter according to  claim 27  contained within said container, wherein label on said container indicates that said composition of matter can be used for treating an immune related disease. 
     
     
         37 . A method of treating an immune related disorder in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of (a) a polypeptide of  claim 23 , (b) an agonist of said polypeptide, (c) an antagonist of said polypeptide, or (d) an antibody that binds to said polypeptide. 
     
     
         38 . The method of  claim 37 , wherein the immune related disorder is systemic lupus erythematosis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, a spondyloarthropathy, systemic sclerosis, an idiopathic inflammatory myopathy, Sjögren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus, immune-mediated renal disease, a demyelinating disease of the central or peripheral nervous system, idiopathic demyelinating polyneuropathy, Guillain-Barr{acute over (ε)} syndrome, a chronic inflammatory demyelinating polyneuropathy, a hepatobiliary disease, infectious or autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive enteropathy, Whipple's disease, an autoimmune or immune-mediated skin disease, a bullous skin disease, erythema multiforme, contact dermatitis, psoriasis, an allergic disease, asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity, urticaria, an immunologic disease of the lung, eosinophilic pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, a transplantation associated disease, graft rejection or graft-versus-host-disease. 
     
     
         39 . A vector comprising the nucleic acid molecule of  claim 33 . 
     
     
         40 . The vector of  claim 39  operably linked to control sequences recognized by a host cell transformed with the vector. 
     
     
         41 . A host cell comprising the vector of  claim 39 . 
     
     
         42 . The host cell of  claim 41 , wherein said cell is a CHO cell, an  E. coli  cell, a yeast cell or a Baculovirus infected insect cell. 
     
     
         43 . A process for producing an antibody according to  claim 28  comprising culturing the host cell of  claim 41  under conditions suitable for expression of said antibody and recovering said antibody from the cell culture.