Growth differentiation factor 15 (gdf-15) constructs

Abstract

Constructs comprising GDF15, and mutants thereof are provided. In various embodiments the constructs comprising GDF15, and mutants thereof, can be of use in the treatment or ameliorating a metabolic disorder. In various embodiments the metabolic disease or disorder is type 2 diabetes, obesity, dyslipidemia, elevated glucose levels, elevated insulin levels and diabetic nephropathy.

1 .- 26 . (canceled) 
     
     
         27 . A fusion protein comprising a growth differentiation factor 15 (GDF15) region joined to a human serum albumin (HSA) polypeptide. 
     
     
         28 . The fusion protein of  claim 27 , wherein the HSA polypeptide comprises the amino acid sequence of SEQ ID NO: 110. 
     
     
         29 . The fusion protein of  claim 27  or  28 , wherein the GDF15 region is joined via a polypeptide linker to the HSA polypeptide. 
     
     
         30 . The fusion protein of  claim 29 , wherein the polypeptide linker comprises the amino acid sequence of SEQ ID NO: 18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125, or 128. 
     
     
         31 . The fusion protein of  claim 30 , wherein the polypeptide linker comprises the amino acid sequence of SEQ ID NO: 18, 113, 116, 119, 122, 125 or 128. 
     
     
         32 . The fusion protein of  claim 27 , wherein the GDF15 region comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO: 4, 8, or 12. 
     
     
         33 . The fusion protein of  claim 27 , wherein the GDF15 region comprises an amino acid sequence of SEQ ID NO: 4, 8, 12, 25, 52 or 55. 
     
     
         34 . The fusion protein of  claim 32 , wherein the GDF15 region comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO: 12 and comprises a mutation at position 3. 
     
     
         35 . The fusion protein of  claim 34 , wherein the mutation at position 3 is a N3Q mutation. 
     
     
         36 . The fusion protein of  claim 28 , wherein the fusion protein comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO. 112, 115, 118, 121, 124, 127, or 130. 
     
     
         37 . The fusion protein of  claim 27 , further comprising a second HSA polypeptide. 
     
     
         38 . The fusion protein of  claim 37 , wherein the second HSA sequence comprises an amino acid sequence of SEQ ID NO: 110. 
     
     
         39 . A dimer comprising (i) a first protein comprising a fusion protein of  claim 27 , and (ii) a second protein comprising a GDF 15 region. 
     
     
         40 . The dimer of  claim 39 , where the GDF15 region of the first protein or the second protein comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO: 4, 8, or 12. 
     
     
         41 . The dimer of  claim 40 , where the GDF15 region of the first protein or the second protein comprises an amino acid sequence of SEQ ID NO: 4, 8, 12, 25, 52 or 55. 
     
     
         42 . The dimer of  claim 39  wherein the GDF15 region of the first protein or the second protein comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO: 12 and comprises a mutation at position 3. 
     
     
         43 . The dimer of  claim 42 , wherein the mutation at position 3 of the first protein or the second protein is a N3Q mutation. 
     
     
         44 . The dimer of  claim 39 , wherein the second protein further comprises a human serum albumin (HSA) polypeptide. 
     
     
         45 . The dimer of  claim 39 , wherein the first protein and the second protein are associated via a disulfide bond. 
     
     
         46 . A method for treating a metabolic disorder in a subject comprising administering to the subject the fusion protein of  claim 27 . 
     
     
         47 . The method of  claim 46 , wherein the disorder is diabetes, obesity, dyslipidemia or diabetic nephropathy. 
     
     
         48 . A method for reducing food intake, body weight, insulin levels, triglyceride levels, cholesterol levels or glucose levels in a subject comprising administering a fusion protein of  claim 27 .