FGF21 mutants multimers and uses thereof
The invention provides a multimer comprising at least a first and a second chain, the first chain comprising the polypeptide of SEQ ID NO:4, wherein the leucine at position 98 is substituted with an arginine; the proline at position 171 is substituted with glycine; and the alanine at position 180 is substituted with glutamic acid; a linker sequence comprising SEQ ID NO:31; and an Fe domain comprising SEQ NO:11; and a second chain comprising the polypeptide of SEQ ID NO:4, wherein the leucine at position 98 is substituted with an arginine; the proline at position 171 is substituted with glycine; and the alanine at position 180 is substituted with glutamic acid; a linker sequence comprising SEQ ID NO:31; and an Fe domain comprising SEQ ID NO:11, nucleic acids encoding the multimer, pharmaceutical compositions comprising the multimer and methods for treating metabolic disorders using such nucleic acids, multimers or pharmaceutical compositions.
1. A multimer comprising at east a first and a second chain,
the first chain comprising:
(a.1) 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.1) a linker sequence comprising SEQ ID NO:31; and
(c.1) an Fc domain comprising SEQ ID NO:11;
and the second chain comprising:
(a.2) 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.2) a linker sequence comprising SEQ ID NO:31; and
(c.2) an Fc domain comprising SEQ ID NO:11.
2. The multimer of claim 1 , wherein the multimer is a dimer.
3. The dimer of claim 2 , wherein the first chain comprises the sequence of SEQ ID NO:47 and the second chain comprises the sequence of SEQ ID NO:47.
4. The dimer of claim 2 , wherein the polypeptide (a.1) or (a.2) comprises:
(a) an amino-terminal truncation of no more than 8 amino add 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.
5. A pharmaceutical composition comprising the dimer of claim 2 and a pharmaceutically acceptable formulation agent.
6. The pharmaceutical composition of claim 5 , wherein the pharmaceutically acceptable formulation agent is a hydrogel.
7. A method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount the pharmaceutical composition of claim 5 .
8. A method of reducing triglyceride levels in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 5 .
9. 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 5 .
10. 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 5 .
11. A method of lowering blood glucose in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 5 .
12. A method of lowering insulin levels in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 5 .
13. The dimer of claim 2 , wherein the polypeptide is covalently linked to one or more polymers.
14. The dimer of claim 13 , wherein the polymer is PEG.
15. A dime comprising a first and a second chain, wherein the first chain is encoded by a nucleic acid sequence comprising SEQ ID NO:46 and the second chain is encoded by a nucleic acid sequence comprising SEQ ID NO:46.
16. The dimer of claim 15 , wherein the first chain is encoded by a nucleic acid molecule comprising nucleotides 1-1272 of SEQ ID NO:46 and the second chain is encoded by a nucleic acid molecule comprising nucleotides 1-1272 of SEQ ID NO:46.
17. A vector comprising a nucleic acid molecule of claim 16 .
18. A host cell comprising the nucleic acid molecule of claim 17 .