FGF21 Mutants and Uses Thereof

Patent metadata

Field	Value
Publication number	US-2019023757-A1
Application number	US-201815996232-A
Country	US
Kind code	A1
Filing date	Jun 1, 2018
Priority date	Jun 4, 2008
Publication date	Jan 24, 2019
Grant date	—

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

1 - 50 . (canceled)

51 . 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, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, proline, or serine residue for the glycine residue at position 170; or (c) 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; or (d) a combination of any of (a)-(c); or
(ii) an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 4 comprising any of the substitutions of (a)-(d).

52 . The method of claim 51 , wherein the polypeptide comprises a glycine or a serine at position 171.

53 . The method of claim 51 , wherein the polypeptide comprises a glycine at position 171.

54 . The method of claim 51 , wherein the polypeptide further comprises (e) a phenylalanine, proline, alanine, serine or glycine at position 179; (f) a glutamic acid, glycine, proline, or serine at position 180; (g) a lysine, glycine, threonine, alanine, leucine, or proline at position 181; or (h) a combination of any of (e)-(g).

55 . The method of claim 54 , wherein the polypeptide comprises a glutamic acid at position 180.

56 . The method of claim 55 , wherein the polypeptide comprises a glycine at position 171.

57 . The method of claim 54 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:4 comprising a substitution of an arginine residue for the leucine residue at position 98; a substitution of a glycine residue for the proline residue at position 171; and a substitution of a glutamic acid residue for the alanine residue at position 180.

58 . The method of claim 51 , wherein the polypeptide comprises 1 to 10 amino acid residues fused to the C-terminus of the polypeptide.

59 . The method of claim 51 , wherein the polypeptide comprises: (a) an amino-terminal truncation of no more than 8 amino acid residues, wherein the polypeptide is capable of lowering blood glucose in a mammal; (b) a carboxyl-terminal truncation of no more than 10 amino acid residues, wherein the polypeptide is capable of lowering blood glucose in a mammal; or (c) an amino-terminal truncation of no more than 8 amino acid residues and a carboxyl-terminal truncation of no more than 12 amino acid residues, wherein the polypeptide is capable of lowering blood glucose in a mammal.

60 . The method of claim 51 , wherein the polypeptide is covalently linked to one or more polymers.

61 . The method of claim 60 , wherein the polypeptide is covalently linked to PEG.

62 . The method of claim 57 , wherein the polypeptide is covalently linked to one or more polymers.

63 . The method of claim 62 , wherein the polypeptide is covalently linked to PEG.

64 . The method of claim 51 , wherein the polypeptide is fused to a heterologous amino acid sequence.

65 . The method of claim 64 , wherein the polypeptide is fused to the heterologous amino acid sequence via a linker.

66 . The method claim 65 , wherein the linker comprises GGGGGSGGGSGGGGS (SEQ ID NO: 23).

67 . The method claim 65 , wherein the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 31).

68 . The method of claim 65 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.

69 . The method of claim 68 , wherein the IgG constant domain comprises the amino acid sequence of SEQ ID NO:13.

70 . The method of claim 67 , wherein the polypeptide is fused to a heterologous amino acid sequence.

71 . The method of claim 70 , wherein the polypeptide is fused to the heterologous amino acid sequence via a linker.

72 . The method claim 70 , wherein the linker comprises GGGGGSGGGSGGGGS (SEQ ID NO: 23).

73 . The method claim 70 , wherein the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 31).

74 . The method of claim 71 , wherein the heterologous amino acid sequence is an IgG constant domain or fragment thereof.

75 . The method of claim 74 , 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• C07K14/50 Primary

  Fibroblast growth factor [FGF] · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C12N5/10

  Cells modified by introduction of foreign genetic material · CPC title