Methods of treating metabolic disorders with dual function fibroblast growth factor 21 proteins
The present invention relates to the identification of dual function fusion proteins comprising fibroblast growth factor 21 (FGF21) and Exenatide, Exendin-4, or GLP-1. Also disclosed are methods for treating metabolic, cardiovascular, and endocrine conditions related to glucose and/or lipid homeostasis.
1. A method of treating a metabolic disorder by administering to a subject in need thereof a dual function fusion protein, wherein the dual function fusion protein comprises a GLP-1 receptor agonist, an FGF21 receptor agonist, and an Fc domain attached to each other via a GS linker, having an orientation of N-terminus-GLP-1 receptor agonist-linker-Fc domain-linker-FGF21 receptor agonist-C-terminus; and wherein the metabolic disorder is obesity, type 2 diabetes mellitus, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, or hyperglycemia.
2. The method of claim 1 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:36.
3. The method of claim 1 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:134.
4. The method of claim 1 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:135.
5. The method of claim 1 , wherein the GLP-1 receptor agonist is selected from wild-type GLP-1, Exendin-4, GLP-1 variants, and Exendin-4 analogues.
6. The method of claim 1 , wherein the FGF21 receptor agonist is selected from FGF21 variants comprising the following amino acid sequences:
(a)
(SEQ ID NO: 185)
DSSPLLQFGG QVRQRYLYTD DAQETEAHLE IREDGTVGGA
AHQSPESLLE LKALKPGVIQ ILGVKTSRFL CQKPDGALYG
SLHFDPEACS FRELLLEDGY NVYQSEAHGL PLHLPGNRSP
HCDPAPQGPA RFLPLPGLPP ALPEPPGILA PQPPDVGSSD
PLAMVGPSQG RSPSYAS;
(b)
(SEQ ID NO: 186)
DSSPLLQFGG QVRQRYLYTD DAQETEAHLE IREDGTVGGA
AHQSPESLLE LKALKPGVIQ ILGVKTSRFL CQKPDGALYG
SLHFDPEACS FRELLLEDGY NVYQSEAHGL PLHLPGNRSP
HCDPAPQGPA RFLPLPGLPP ALPEPPGILA PQPPDVGSSD
PLAMVGGSQG RSPSYAS;
(c)
(SEQ ID NO: 187)
D SSPLLQFGGQ VRQRYLYTDD ACQTEAHLEI REDGTVGGAA
DQSPESLLQL KALKPGVIQI LGVKTSRFLC QRPDGTLYGS
LHFDPEACSF RELLLEDGYN VYQSEAHGLP LHLPCNRSPH
RDPASRGPAR FLPLPGLPPA LPEPPGILAP QPPDVGSSDP
LAMVGGSQAR SPSYAS;
and
(d)
(SEQ ID NO: 188)
D SSPLLQFGGQ VRQRYLYTDD ACQTEAHLEI REDGTVGGAA
DQSPESLLQL KALKPGVIQI LGVKTSRFLC QKPDGALYGS
LHFDPEACSF RELLLEDGYN VYQSEAHGLP LHLPCNRSPH
RDPASRGPAR FLPLPGLPPA LPEPPGILAP QPPDVGSSDP
LAMVGGSQAR SPSYAS.
7. The method of claim 1 , wherein the metabolic disorder is obesity.
8. The method of claim 1 , wherein the metabolic disorder is type 2 diabetes mellitus.
9. The method of claim 1 , wherein the metabolic disorder is dyslipidemia.
10. The method of claim 1 , wherein the metabolic disorder is nonalcoholic fatty liver disease (NAFLD).
11. The method of claim 1 , wherein the metabolic disorder is nonalcoholic steatohepatitis (NASH).
12. The method of claim 1 , wherein the metabolic disorder is insulin resistance.
13. The method of claim 1 , wherein the metabolic disorder is hyperinsulinemia.
14. The method of claim 1 , wherein the metabolic disorder is glucose intolerance.
15. The method of claim 1 , wherein the metabolic disorder is hyperglycemia.