FGF21 mutants and uses thereof
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. A polypeptide comprising:
(a) the polypeptide of SEQ ID NO:4, wherein
(i) the leucine at position 98 is substituted with an arginine;
(ii) the proline at position 171 is substituted with glycine; and
(iii) the alanine at position 180 is substituted with glutamic acid;
(b) a linker sequence comprising SEQ ID NO:31; and
(c) an Fc domain comprising SEQ ID NO:11.
2. A polypeptide comprising the sequence of SEQ ID NO:47.
3. A pharmaceutical composition comprising the isolated polypeptide of claim 1 or 2 and a pharmaceutically acceptable formulation agent.
4. The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable formulation agent is a hydrogel.
5. A method of lowering blood glucose in a patient suffering from a metabolic disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
6. The method of claim 5 , wherein the metabolic disorder is type 2 diabetes.
7. The method of claim 5 , wherein the metabolic disorder is obesity.
8. A method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount the pharmaceutical composition of claim 3 .
9. A method of reducing fasting triglyceride levels in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
10. A method of elevating HDL-cholesterol levels in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
11. A method of improving glucose tolerance in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 3 .
12. The polypeptide of claim 1 or 2 , wherein the polypeptide of SEQ ID NO:4 comprises:
(a) an amino-terminal truncation of no more than 8 amino acid residues, wherein the polypeptide is capable of lowering blood glucose in a mammal;
(b) a carboxyl-terminal truncation of no more than 12 amino acid residues, wherein the polypeptide is capable of lowering blood glucose in a mammal; or
(c) an amino-terminal truncation of no more than 8 amino acid residues and a carboxyl-terminal truncation of no more than 12 amino acid residues, wherein the polypeptide is capable of lowering blood glucose in a mammal.
13. The polypeptide of claim 1 or 2 , wherein the polypeptide is covalently linked to one or more polymers.
14. The polypeptide of claim 13 , wherein the polymer is PEG.
15. A polypeptide encoded by the nucleic acid sequence of SEQ ID NO:46.
16. A nucleic acid encoding
(a) the polypeptide of SEQ ID NO:4, wherein
(i) the leucine at position 98 is substituted with an arginine;
(ii) the proline at position 171 is substituted with glycine; and
(iii) the alanine at position 180 is substituted with glutamic acid;
(b) a linker sequence comprising SEQ ID NO:31; and
(c) an Fc domain comprising SEQ ID NO:11.
17. The nucleic acid of claim 16 , wherein the nucleic acid comprises SEQ ID NO:46.
18. A vector comprising the nucleic acid molecule of claim 17 .
19. A host cell comprising the nucleic acid molecule of claim 18 .
20. A nucleic acid encoding the polypeptide of SEQ ID NO:47.
21. A nucleic acid comprising nucleotides 1-1272 of SEQ ID NO:46.