FGF21-FC fusion proteins for treating metabolic disorders

Patent metadata

Field	Value
Publication number	US-10076554-B2
Application number	US-201614987338-A
Country	US
Kind code	B2
Filing date	Jan 4, 2016
Priority date	Sep 26, 2011
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

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 obesity, 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, wherein said method reduces body weight in the patient.

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

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

4. 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.

5. 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.

6. 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.

7. 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.

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

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

10. The method of claim 9 , wherein the linker is 1 to 20 amino acids in length.

11. The method of claim 9 , wherein the linker comprises glycine and serine residues.

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

13. The method of claim 12 , wherein the modified Fc fragment is a LALA-Fc fragment.

14. A method for treating a patient suffering from type 2 diabetes mellitus, insulin resistance, hyperinsulinemia, glucose intolerance, or hyperglycemia, 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, wherein said method lowers blood glucose, lowers insulin levels, improves glucose tolerance or improves insulin sensitivities in the patient.

15. The method of claim 14 , wherein the FGF21 variant further comprises the amino acid sequence of SEQ ID NO:11.

16. The method of claim 14 , wherein the fusion protein is administered in combination with one or more oral anti-diabetic agents.

17. A method for treating a patient suffering from metabolic syndrome, said method comprising administering to said patient a therapeutically effective amount of a fusion protein comprising the amino acid sequence of SEQ ID NO:11, wherein said method achieves one or more of the following: lowers blood glucose, lowers insulin levels, lowers triglyceride levels, lowers cholesterol levels, reduces liver lipid levels, reduces liver triglyceride levels, reduces body weight, improves glucose tolerance or improves insulin sensitivities in the patient.

18. The method of claim 17 , wherein the patient additionally has nonalcoholic fatty liver disease (NAFLD).

19. The method of claim 17 , wherein the patient additionally has nonalcoholic steatohepatitis (NASH).

20. The method of claim 17 , wherein the patient has a blood sugar level of at least 110 milligrams per deciliter (mg/dl) after fasting.

21. The method of claim 17 , wherein the patient has a triglyceride level of at least 150 mg/dL in the bloodstream.

22. The method of claim 17 , wherein the patient has HDL level of less than 40 mg/dl.

23. The method of claim 17 , wherein the patient has blood pressure of 130/85 mmHg or higher.

24. The method of claim 17 , wherein the patient has at least three of the following signs: (i) abdominal fat characterized by a 40-inch waist or greater in men; (ii) blood sugar level of at least 110 milligrams per deciliter (mg/dl) after fasting; (iii) triglyceride level of at least 150 mg/dL in the bloodstream; (iv) HDL level of less than 40 mg/dl; and (v) blood pressure of 130/85 mmHg or higher.

25. The method of claim 17 , wherein the patient is suffering from obesity.

26. The method of claim 17 , wherein the patient has type 2 diabetes mellitus.

27. A method for treating a patient suffering from metabolic syndrome, 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 the amino acid sequence of SEQ ID NO:11, wherein said method achieves one or more of the following: lowers blood glucose, lowers insulin levels, lowers triglyceride levels, lowers cholesterol levels, reduces liver lipid levels, reduces liver triglyceride levels, reduces body weight, improves glucose tolerance or improves insulin sensitivities in the patient.

28. The method of claim 27 , wherein the patient additionally has nonalcoholic fatty liver disease (NAFLD).

29. The method of claim 27 , wherein the patient additionally has nonalcoholic steatohepatitis (NASH).

30. The method of claim 27 , wherein the patient has a triglyceride level of at least 150 mg/dL in the bloodstream.

31. The method of claim 27 , wherein the patient has HDL level of less than 40 mg/dl.

32. The method of claim 27 , wherein the patient has blood pressure of 130/85 mmHg or higher.

33. The method of claim 27 , wherein the patient has at least three of the following signs: (i) abdominal fat characterized by a 40-inch waist or greater in men; (ii) blood sugar level of at least 110 milligrams per deciliter (mg/dl) after fasting; (iii) triglyceride level of at least 150 mg/dL in the bloodstream; (iv) HDL level of less than 40 mg/dl; and (v) blood pressure of 130/85 mmHg or higher.

34. The method of claim 27 , wherein the patient is suffering from obesity.

35. The method of claim 27 , wherein the patient has type 2 diabetes mellitus.

Assignees

• Novartis Ag

Inventors

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

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

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

• A61P3/00

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