FGF21 polypeptides comprising two or more mutations
The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.
1. An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:4, wherein the polypeptide comprises (a) an arginine residue at position 98 of SEQ ID NO:4; and (b) a glycine residue at position 171 of SEQ ID NO:4.
2. A fusion polypeptide comprising the polypeptide of claim 1 linked to a heterologous polypeptide.
3. The fusion polypeptide of claim 2 , wherein the heterologous polypeptide is an Fc polypeptide.
4. The fusion polypeptide of claim 3 , wherein the Fc polypeptide comprises the amino acid sequence of SEQ ID NO:13.
5. The fusion polypeptide of claim 4 , wherein the polypeptide is joined to the Fc polypeptide by a linker.
6. The fusion polypeptide of claim 5 wherein the linker is GGGGGSGGGSGGGGS (SEQ ID NO:23).
7. The fusion polypeptide of claim 6 , wherein the fusion polypeptide comprises the amino acid sequence of SEQ ID NO:38.
8. A multimer comprising two or more copies of the fusion polypeptide of claim 7 .
9. A pharmaceutical composition comprising the fusion polypeptide of claim 7 and a pharmaceutically acceptable formulation agent.
10. The fusion polypeptide of claim 5 wherein the linker is GGGGSGGGGSGGGGS (SEQ ID NO:31).
11. The fusion polypeptide of claim 10 , wherein the fusion polypeptide comprises the amino acid sequence of SEQ ID NO:36.
12. A multimer comprising two or more copies of the fusion polypeptide of claim 11 .
13. A pharmaceutical composition comprising the fusion polypeptide of claim 11 and a pharmaceutically acceptable formulation agent.
14. The isolated polypeptide of claim 1 , further comprising a mutation at position 180.
15. A fusion polypeptide encoded by nucleotides 1-1272 of SEQ ID NO:37.