Gdf15 fusion proteins and uses thereof

Abstract

Fusion proteins containing a half-life extension protein, a linker, and a GDF15 protein are described. Also described are nucleic acids encoding the fusion proteins, recombinant cells thereof, compositions comprising the fusion proteins, and methods of using the fusion proteins for treating or preventing metabolic diseases, disorders or conditions.

We claim: 
     
         1 . A fusion protein comprising:
 a. a half-life extension protein,   b. a linker, and   c. a GDF15 protein;   wherein the fusion protein is arranged from N-terminus to C-terminus in the order (a)-(b)-(c).   
     
     
         2 . The fusion protein of  claim 1 , wherein the GDF15 protein comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 6, 7, 8, 9, 10 or 11. 
     
     
         3 . The fusion protein of  claim 1 , wherein the half-life extension protein is human serum albumin (HSA) or a functional variant thereof. 
     
     
         4 . The fusion protein of  claim 3 , wherein the half-life extension protein comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 1. 
     
     
         5 . The fusion protein of  claim 1 , wherein the linker comprises the sequence (GGGGS)n, wherein n is 2 to 20. 
     
     
         6 . The fusion protein of  claim 1 , wherein the linker comprises the sequence (AP)n or (EAAAK)n, wherein n is 2 to 20. 
     
     
         7 . The fusion protein of  claim 1 , wherein the linker comprises the amino acid sequence selected from the group consisting of (GGGGA)n, (PGGGS)n, (AGGGS)n or GGS-(EGKSSGSGSESKST)n-GGS wherein n is 2 to 20. 
     
     
         8 . A fusion protein comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 5, 25-30, 36-37, 40, 48, 55-56, 59-60, 64-75, 92, 113, 115, 117, 119, 121, 123, 125, or 127. 
     
     
         9 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding the fusion protein of  claim 1 . 
     
     
         10 . A vector comprising a nucleic acid molecule encoding the fusion protein of  claim 1 . 
     
     
         11 . A method of producing the fusion protein of  claim 1 , comprising:
 (1) culturing a host cell comprising a nucleic acid molecule encoding the fusion protein under a condition that the fusion protein is produced; and   (2) recovering the fusion protein produced by the host cell.   
     
     
         12 . A pharmaceutical composition comprising the fusion protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating or preventing a metabolic disorder, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of  claim 12 . 
     
     
         14 . The method of  claim 13  wherein the metabolic disorder is selected from the group consisting of a metabolic disorder selected from the group consisting of type 2 diabetes, elevated glucose levels, elevated insulin levels, obesity, dyslipidemia, diabetic nephropathy; myocardial ischemic injury, congestive heart failure, and rheumatoid arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a fusion protein comprising the amino acid sequence of SEQ ID NO: 60 or NO: 92, and a pharmaceutically acceptable carrier. 
     
     
         15 . A dimer comprising two polypeptide chains, wherein each chain comprises from N-terminus to C-terminus an HSA region, a linker, and a GDF15 region; wherein the HSA region comprises an ammo acid sequence having at least 90% identity to SEQ ID NOs: 1, 2, or 3, and wherein the GDF15 region comprises an amino acid sequence having at least 90% identity to SEQ ID NOs: 6, 7, 8, 9, 10, or 11. 
     
     
         16 . The dimer of  claim 15 , wherein the two polypeptide chains are linked by disulfide bonds. 
     
     
         17 . The dimer of  claim 15 , wherein the HSA region and the GDF15 region are joined by a polypeptide linker. 
     
     
         18 . The dimer of  claim 15 , wherein the polypeptide linker comprises the sequence (GGGGS)n, wherein n is 2 to 20. 
     
     
         19 . The dimer of  claim 15 , wherein the polypeptide linker comprises the sequence (AP)n or (EAAAK)n, wherein n is 2 to 20. 
     
     
         20 . The dimer of  claims 17 , wherein the linker comprises the amino acid sequence selected from the group consisting of (GGGGA)n, (PGGGS)n, (AGGGS)n or GGS-(EGKSSGSGSESKST)n-GGS wherein n is 2 to 20.