Methods of treating non-alcoholic steatohepatitis using FGF21 mutants

Patent metadata

Field	Value
Publication number	US-11840558-B2
Application number	US-202117357444-A
Country	US
Kind code	B2
Filing date	Jun 24, 2021
Priority date	Jun 4, 2008
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

Abstract

The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.

First claim

What is claimed is:

1. A method of treating non-alcoholic steatohepatitis (NASH) comprising administering to a human patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide comprising
(i) the amino acid sequence of SEQ ID NO: 4 comprising:
(a) a substitution of an arginine, cysteine, glutamic acid, glutamine, lysine, or threonine residue for the leucine residue at position 98; or
(b) a substitution of an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, lysine, serine, threonine, tryptophan, or tyrosine residue for the proline residue at position 171.

2. The method of claim 1 , wherein the polypeptide comprises a glycine or a serine at position 171.

3. The method of claim 1 , wherein the polypeptide comprises a glycine at position 171.

4. The method of claim 1 , wherein the polypeptide further comprises (c) a phenylalanine, proline, alanine, serine or glycine at position 179; (d) a glutamic acid, glycine, proline, or serine at position 180; (e) a lysine, glycine, threonine, alanine, leucine, or proline at position 181; or (f) a combination of any of (c)-(f).

5. The method of claim 4 , wherein the polypeptide comprises a glutamic acid at position 180.

6. The method of claim 5 , wherein the polypeptide comprises a glycine at position 171.

7. The method of claim 5 , wherein the polypeptide is fused to a heterologous amino acid sequence.

8. The method of claim 7 , wherein the polypeptide is fused to the heterologous amino acid sequence via a linker.

9. The method claim 8 , wherein the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 31).

10. The method of claim 9 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.

11. The method of claim 10 , wherein the IgG constant domain comprises the amino acid sequence of SEQ ID NO:13.

12. The method of claim 4 , wherein the polypeptide is fused to a heterologous amino acid sequence.

13. The method of claim 12 , wherein the polypeptide is fused to the heterologous amino acid sequence via a linker.

14. The method claim 13 , wherein the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 31).

15. The method of claim 14 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.

16. The method of claim 15 , wherein the IgG constant domain comprises the amino acid sequence of SEQ ID NO:13.

17. The method of claim 1 , wherein the polypeptide is covalently linked to one or more polymers.

18. The method of claim 17 , wherein the polypeptide is covalently linked to PEG.

19. The method of claim 1 , wherein the polypeptide is fused to a heterologous amino acid sequence.

20. The method of claim 19 , wherein the polypeptide is fused to the heterologous amino acid sequence via a linker.

21. The method claim 20 , wherein the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 31).

22. The method of claim 20 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.

23. The method of claim 22 , wherein the IgG constant domain comprises the amino acid sequence of SEQ ID NO:13.

Assignees

• Amgen Inc

Inventors

• Belouski Edward John
• Ellison Murielle Marie
• Hamburger Agnes Eva
• Hecht Randy Ira
• Li Yue-Sheng
• Michaels Mark Leo
• Sun Jeonghoon
• Xu Jing

Classifications

• C07K14/05 Primary

  Epstein-Barr virus · CPC title

• A61K38/1825

  Fibroblast growth factor [FGF] · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/18

  against material from animals or humans · CPC title