Dual function proteins for treating metabolic disorders

Patent metadata

Field	Value
Publication number	US-2017166621-A1
Application number	US-201615248712-A
Country	US
Kind code	A1
Filing date	Aug 26, 2016
Priority date	Sep 26, 2011
Publication date	Jun 15, 2017
Grant date	—

Abstract

The present invention relates to the identification of new proteins comprising fibroblast growth factor 21 (FGF21) and other metabolic regulators, including variants thereof, known to improve metabolic profiles in subjects to whom they are administered. Also disclosed are methods for treating FGF21-associated disorders, GLP-1-associated disorders, and Exendin-4-associated disorders, including metabolic conditions.

First claim

1 - 6 . (canceled)

7 . A method of treating a metabolic disorder by administering to a subject in need a dual function fusion protein comprising a GLP-1 receptor agonist and an FGF21 receptor agonist.

8 . The method of claim 7 , wherein said dual function fusion protein improves metabolic parameters in subjects over the administration of individual GLP-1 receptor agonists and FGF21 receptor agonists in combination.

9 . The method of claim 7 , wherein said dual function fusion protein further comprises variant 208, variant 209, variant 211, variant 214, variant 272, variant 277, or variant 311.

10 . The method of claim 7 , wherein the dual function fusion protein comprises a GLP-1 receptor agonist peptide, a FGF21 variant, and an Fc domain.

11 . The method of claim 7 , wherein the dual function fusion protein comprises comprising a GLP-1 receptor agonist, a FGF21 variant, and an Fc domain, attached to each other via a linker, and having an orientation of N-terminus-GLP-1 receptor agonist-linker-Fc domain-linker-FGF21 variant-C-terminus

12 . The method of claim 7 , wherein the FGF21 variant is variant 101.

13 . The method of claim 11 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:36.

14 . The method of claim 11 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:134.

15 . The method of claim 11 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:135.

16 . The method of claim 7 , wherein the GLP-1 receptor agonist is selected from wild-type GLP-1, Exendin-4, GLP-1 variants, and Exendin-4 analogues.

17 . The dual function fusion protein of claim 11 , 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.

18 . The method of claim 7 , wherein the metabolic disorder is obesity, type 2 diabetes mellitus, pancreatitis, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, or hyperglycemia.

19 . The method of claim 11 , wherein the metabolic disorder is obesity, type 2 diabetes mellitus, pancreatitis, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, or hyperglycemia.

20 . A method of treating an endocrine disorder or a cardiovascular disorder by administering to a subject in need thereof a dual function fusion protein comprising a GLP-1 receptor agonist and an FGF21 receptor agonist.

21 . The method of claim 20 , wherein the dual function fusion protein comprises the amino acid sequence of SEQ ID NO:36, SEQ ID NO:134, or SEQ ID NO:135.

Assignees

• Boettcher Brian R
• Caplan Shari Lynn
• Cellitti Susan E
• Daniels Douglas S
• Hamamatsu Norio
• Geierstanger Bernhard Hubert
• Licht Stuart
• Loew Andreas
• Weldon Stephen Craig
• Novartis Ag

Inventors

• Boettcher Brian R
• Caplan Shari Lynn
• Cellitti Susan E
• Daniels Douglas S
• Hamamatsu Norio
• Geierstanger Bernhard Hubert
• Licht Stuart
• Loew Andreas
• Weldon Stephen Craig

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07K14/575

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695) · CPC title

• C07K14/50 Primary

  Fibroblast growth factor [FGF] · CPC title