Compositions and Methods of Use for Treating Metabolic Disorders

Abstract

Methods of treating individuals with a glucose metabolism disorder and/or a body weight disorder, and compositions associated therewith, are provided.

1 .- 52 . (canceled) 
     
     
         53 . A polypeptide comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:3, and further comprising one or more of the substitutions of D5T, L17N, Q40N, P70N, Q90N, G95N, and L98N, wherein the polypeptide binds to a GDF15 receptor. 
     
     
         54 . The polypeptide of  claim 53 , wherein polypeptide comprises an amino acid sequence selected from a group consisting of SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:38, SEQ ID NO:43, SEQ ID NO:4, 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, and SEQ ID NO:52. 
     
     
         55 . The polypeptide of  claim 53 , wherein the polypeptide is fused to a half-life extending moiety. 
     
     
         56 . The polypeptide of  claim 55 , wherein the half-life extending moiety is an Fc polypeptide, a maltose binding protein or a fragment thereof, an albumin binding domain, an albumin, an albumin variant, or an albumin fragment. 
     
     
         57 . The polypeptide of  claim 56 , wherein the half-life extending moiety is the albumin, albumin variant, or albumin fragment that is human serum albumin, a human serum albumin variant, or a human serum albumin fragment, respectively, or bovine serum albumin, a bovine serum albumin variant, or a bovine serum albumin fragment, respectively, or cyno serum albumin, a cyno serum albumin variant, or a cyno serum albumin fragment, respectively. 
     
     
         58 . The polypeptide of  claim 55 , wherein the half-life extending moiety is fused to the polypeptides at the carboxyl terminus or the amino terminus of the polypeptide. 
     
     
         59 . The polypeptide of  claim 58 , wherein the half-life extending moiety is fused to the polypeptide at the amino terminus. 
     
     
         60 . The polypeptide of  claim 55 , wherein the half-life extending moiety is fused to the polypeptide via a linker. 
     
     
         61 . The polypeptide of  claim 60 , wherein the linker is a cleavable linker. 
     
     
         62 . The polypeptide of  claim 61 , wherein the cleavable linker is cleaved by a protease. 
     
     
         63 . The polypeptide of  claim 60 , wherein the linker is a non-cleavable linker. 
     
     
         64 . The polypeptide of  claim 53 , wherein the polypeptide is N-glycosylated. 
     
     
         65 . A dimer comprising the polypeptide of  claim 53 . 
     
     
         66 . A polynucleotide encoding the polypeptide of  claim 53 . 
     
     
         67 . A vector comprising the polynucleotide of  claim 66 . 
     
     
         68 . An isolated cell comprising the polynucleotide of  claim 66 . 
     
     
         69 . A method of making a dimer of a polypeptide, the method comprising:
 (a) culturing the cell of  claim 68  under conditions that result in the expression of the dimer, and   (b) isolating the dimer.   
     
     
         70 . A pharmaceutical composition, comprising the dimer of  claim 65 , and a pharmaceutically acceptable diluent, carrier or excipient. 
     
     
         71 . A method of treating glucose metabolism disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the dimer of  claim 65 . 
     
     
         72 . The method of  claim 71 , wherein the glucose metabolism disorder is diabetes mellitus, or any other disorders characterized by insulin resistance, decreased insulin production, hyperinsulinemia, hyperglycemia, or glucose intolerance. 
     
     
         73 . A method of treating a body weight disorder in a mammalian subject, comprising administering to the subject a therapeutically effective amount of the dimer of  claim 65 . 
     
     
         74 . The method of  claim 73 , wherein the body weight disorder is obesity. 
     
     
         75 . A dimer comprising the polypeptide of  claim 54 . 
     
     
         76 . A pharmaceutical composition, comprising the dimer of  claim 75 , and a pharmaceutically acceptable diluent, carrier or excipient.