Fusion proteins for treating metabolic disorders

Patent metadata

Field	Value
Publication number	US-2016193297-A1
Application number	US-201614987338-A
Country	US
Kind code	A1
Filing date	Jan 4, 2016
Priority date	Sep 26, 2011
Publication date	Jul 7, 2016
Grant date	—

Abstract

The invention relates to the identification of fusion proteins comprising polypeptide and protein variants of fibroblast growth factor 21 (FGF21) with improved pharmaceutical properties. Also disclosed are methods for treating FGF21-associated disorders, including metabolic conditions.

First claim

What is claimed is:

1 . A method for treating a patient suffering from one or more disorders selected from the group consisting of: obesity, type 1 and type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, diabetic complications, gastroparesis, and disorders associated with severe inactivating mutations in the insulin receptor, said method comprising administering to said patient a therapeutically effective amount of a fusion protein comprising an FGF21 variant and an Fc region, wherein the FGF21 variant comprises the following mutations: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

2 . The method of claim 1 , wherein said disorder is type 2 diabetes mellitus.

3 . The method of claim 1 , wherein said disorder is insulin resistance.

4 . The method of claim 1 , wherein said disorder is hyperglycemia.

5 . The method of claim 1 , wherein the FGF21 variant further comprises the amino acid sequence of SEQ ID NO:11.

6 . The method of claim 1 , wherein the fusion protein is administered in combination with one or more oral anti-diabetic agents.

7 . The method of claim 1 , wherein the FGF21 variant is a mature hFGF21 protein comprising the following mutations: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

8 . The method of claim 1 , wherein the FGF21 variant comprises a disulfide bond between C103 and C121, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

9 . The method of claim 1 , wherein the FGF21 variant comprises one or more engineered disulfide bonds between Gln55Cys and a cysteine residue at one of Cys103, Cys121, Gly148Cys, Asn149Cys, Lys150Cys, Ser141Cys, Pro152Cys, His153Cys, Arg154Cys, Asp155Cys, Pro156Cys, Ala157Cys, Pro158Cys, Arg159Cys, Gly160Cys, Pro161Cus, Ala162Cys, and Arg163Cys.

10 . The method of claim 1 , wherein the FGF21 variant comprises one or more engineered disulfide bonds between Gly148Cys and a cysteine residue at one of Cys103, Cys121, Arg47Cys, Tyr48Cys, Leu49Cys, Tyr50Cys, Thr51Cys, Asp52Cys, Asp53Cys, Ala54Cys, Gln55Cys, Gln56Cys, Thr57Cys, Glu58Cys, Gly160Cys, Pro161Cys, Ala162Cys, Arg163Cys, and Phe164Cys.

11 . The method of claim 1 , wherein the FGF21 variant an engineered disulfide bond between Gln55Cys-Gly148Cys.

12 . The method of claim 1 , wherein the Fc region is linked to the FGF21 variant via a linker.

13 . The method of claim 12 , wherein the linker is 1 to 20 amino acids in length.

14 . The method of claim 12 , wherein the linker comprises glycine and serine residues.

15 . The method of claim 1 , wherein the Fc region of the fusion protein is a modified Fc fragment.

16 . The method of claim 15 , wherein the modified Fc fragment is a LALA-Fc fragment.

17 . A method for treating a patient suffering from one or more disorders selected from the group consisting of: obesity, type 1 and type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, diabetic complications, gastroparesis, and disorders associated with severe inactivating mutations in the insulin receptor, said method comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a fusion protein comprising an FGF21 variant and an Fc region, wherein the FGF21 variant comprises the following mutations: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

18 . The method of claim 17 , wherein said disorder is type 2 diabetes mellitus.

19 . The method of claim 17 , wherein said disorder is insulin resistance.

20 . The method of claim 17 , wherein said disorder is hyperglycemia.

21 . The method of claim 17 , wherein the FGF21 variant further comprises the amino acid sequence of SEQ ID NO:11.

22 . The method of claim 17 , wherein the fusion protein is administered in combination with one or more oral anti-diabetic agents.

23 . A method for treating a patient suffering from one or more disorders selected from the group consisting of: pancreatitis, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), acute myocardial infarction, hypertension, cardiovascular disease, atherosclerosis, peripheral arterial disease, stroke, heart failure, coronary heart disease, kidney disease, and neuropathy, said method comprising administering to said patient a therapeutically effective amount of a fusion protein comprising an FGF21 variant and an Fc region, wherein the FGF21 variant comprises the following mutations: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

24 . The method of claim 23 , wherein said disorder is nonalcoholic fatty liver disease (NAFLD).

25 . The method of claim 23 , wherein said disorder is nonalcoholic steatohepatitis (NASH).

26 . The method of claim 23 , wherein the FGF21 variant further comprises the amino acid sequence of SEQ ID NO:11.

27 . The method of claim 23 , wherein the FGF21 variant is a mature hFGF21 protein comprising the following mutations: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

28 . The method of claim 23 , wherein the FGF21 variant comprises a disulfide bond between C103 and C121, positions referring to the amino acid position of the full length hFGF21 sequence SEQ ID NO:1.

29 . The method of claim 23 , wherein the FGF21 variant comprises one or more engineered disulfide bonds between Gln55Cys and a cysteine residue at one of Cys103, Cys121, Gly148Cys, Asn149Cys, Lys150Cys, Ser141Cys, Pro152Cys, His153Cys, Arg154Cys, Asp155Cys, Pro156Cys, Ala157Cys, Pro158Cys, Arg159Cys, Gly160Cys, Pro161Cus, Ala162Cys, and Arg163Cys.

30 . The method of claim 23 , wherein the FGF21 variant comprises one or more engineered disulfide bonds between Gly148Cys and a cysteine residue at one of Cys103, Cys121, Arg47Cys, Tyr48Cys, Leu49Cys, Tyr50Cys, Thr51Cys, Asp52Cys, Asp53Cys, Ala54Cys, Gln55Cys, Gln56Cys, Thr57Cys, Glu58Cys, Gly160Cys, Pro161Cys, Ala162Cys, Arg163Cys, and Phe164Cys.

31 . The method of claim 23 , wherein the FGF21 variant an engineered disulfide bond between Gln55Cys-Gly148Cys.

32 . The method of claim 23 , wherein the Fc region is linked to the FGF21 variant via a linker.

33 . The method of claim 32 , wherein the linker is 1 to 20 amino acids in length.

34 . The method of claim 32 , wherein the linker comprises glycine and serine residues.

35 . The method of claim 23 , wherein the Fc region of the fusion protein is a modified Fc fragment.

36 . The method of claim 35 , wherein the modified Fc fragment is a LALA-Fc fragment.

37 . A method for treating a patient suffering from one or more dis

Assignees

• Boeltcher Brian R
• Caplan Shari Lynn
• Daniels Douglas S
• Hamamatsu Norio
• Licht Stuart
• Weldon Stephen Craig
• Novartis Ag

Inventors

• Boeltcher Brian R
• Caplan Shari Lynn
• Daniels Douglas S
• Hamamatsu Norio
• Licht Stuart
• Weldon Stephen Craig

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title