Methods of treating fgf21-associated disorders

Abstract

The invention relates to the identification of new polypeptide and protein variants of fibroblast growth factor 21 (FGF21) that have improved pharmaceutical properties. Also disclosed are methods for treating FGF21-associated disorders, including metabolic conditions.

1 . A polypeptide variant having a sequence selected from SEQ ID NO:5-49. 
     
     
         2 . The variant of  claim 1 , wherein the variant further comprises one or more of the following modifications: (a) an amino-terminal truncation of no more than 8 amino acid residues; and (b) a carboxyl-terminal truncation of no more than 12 amino acid residues. 
     
     
         3 . The variant of  claim 1 , wherein the variant is covalently linked to polyethylene glycol (PEG) or polysialic acid. 
     
     
         4 . The variant of  claim 3 , wherein the variant further comprises a branched, 40 kDa PEG group, covalently linked to a cysteine of the variant. 
     
     
         5 . The variant of  claim 1 , wherein the variant is fused to a heterologous amino acid sequence consisting of one of the following: an IgG constant domain or fragment thereof; Human Serum Albumin (HSA); and albumin-binding polypeptides. 
     
     
         6 . The variant of  claim 5 , wherein the heterologous amino acid sequence is fused to the amino-terminal of the variant. 
     
     
         7 . The variant of  claim 5 , wherein the heterologous amino acid sequence is fused to the carboxy-terminal of the variant. 
     
     
         8 . (canceled) 
     
     
         9 . The multimer of  claim 1 , wherein the multimer is a homodimer. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . A method for treating a patient comprising administering to said patient a therapeutically effective amount of a polypeptide variant having a sequence selected from SEQ ID NO:5-49, wherein said patient exhibits one or more of FGF21-associated disorders 
     
     
         16 . The method of  claim 15 , wherein the FGF21-associated disorders consist of one or more of the following: obesity, type 1 and type 2 diabetes mellitus, pancreatitis, dyslipidemia, nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, and other metabolic disorders 
     
     
         17 . The method of  claim 16 , wherein the FGF21-associated disorder consists of type 1 diabetes mellitus. 
     
     
         18 . The method of  claim 16 , wherein the FGF21-associated disorder consists of type 2 diabetes mellitus. 
     
     
         19 . A method for treating a patient comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the polypeptide variant of  claim 1 , wherein said patient exhibits one or more of FGF21-associated disorders. 
     
     
         20 . The method of  claim 19 , wherein said variant further comprises SEQ ID NO:39, with PEGylation at the cysteine residue at position 154. 
     
     
         21 . The method of  claim 20 , wherein the FGF21-associated disorders consist of one or more of the following: obesity, type 1 and type 2 diabetes mellitus, pancreatitis, dyslipidemia, nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, and other metabolic disorders 
     
     
         22 . The method of  claim 21 , wherein the FGF21-associated disorder consists of type 1 diabetes mellitus. 
     
     
         23 . The method of  claim 21 , wherein the FGF21-associated disorder consists of type 2 diabetes mellitus. 
     
     
         24 . A method for reducing one or more of hyperglycemia, hyperinsulinemia, liver lipids, and weight gain in a patient in need, comprising administering to said patient a therapeutically effective amount of polypeptide variant having a sequence selected from SEQ ID NO:5-49. 
     
     
         25 . The method of  claim 24 , wherein the variant further comprises SEQ ID NO:39, with PEGylation at the cysteine residue at position 154.