Fibroblast growth factor-21-fc fusion proteins

Patent metadata

Field	Value
Publication number	US-2024261372-A1
Application number	US-202418435440-A
Country	US
Kind code	A1
Filing date	Feb 7, 2024
Priority date	Sep 26, 2011
Publication date	Aug 8, 2024
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

1 - 9 . (canceled)

10 . A fusion protein comprising a fibroblast growth factor 21 (FGF21) variant and an Fc region, wherein the FGF21 variant comprises:
the amino acid sequence of SEQ ID NO: 3 with an N-terminal truncation of 1, 2, 3, 4, 5, 6, 7, or 8 amino acid residues; and the following mutations relative to SEQ ID NO:1: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A.

11 . The fusion protein of claim 10 , wherein the FGF21 variant comprises an N-terminal truncation of 4 amino acid residues.

12 . The fusion protein of claim 10 , wherein the FGF21 variant is fused to the Fc region via the N-terminus.

13 . The fusion protein of claim 10 , wherein the FGF21 variant is fused to the Fc region via a linker.

14 . The fusion protein of claim 13 , wherein the linker comprises a GS amino acid linker.

15 . The fusion protein of claim 10 , wherein the Fc region is a modified Fc fragment with a LALA mutation.

16 . The fusion protein of claim 10 , wherein the FGF21 variant comprises at least one disulfide bond engineered between GIn55Cys and a cysteine residue at one of Cys 103, Cys121, Gly148Cys, Asn149Cys, Lys150Cys, Ser141Cys, Pro152Cys, His153Cys, Arg154Cys, Asp 155Cys, Pro156Cys, Ala157Cys, Pro158Cys, Arg159Cys, Gly160Cys, Pro161Cus, Ala162Cys, and Arg 163Cys relative to SEQ ID NO: 1.

17 . The fusion protein of claim 10 , wherein the FGF21 variant comprises at least one disulfide bond engineered 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 relative to SEQ ID NO: 1.

18 . The fusion protein of claim 17 , wherein the FGF21 variant comprises an engineered disulfide bond of Gln55Cys-Gly148Cys relative to SEQ ID NO: 1.

19 . A fusion protein comprising a fibroblast growth factor 21 (FGF21) variant and an Fc region, wherein the fusion protein consists of the amino acid sequence of SEQ ID NO: 11.

20 . A nucleic acid coding for a fusion protein comprising a fibroblast growth factor 21 (FGF21) variant and an Fc region, wherein the FGF21 variant comprises:
the amino acid sequence of SEQ ID NO: 3 with an N-terminal truncation of 1, 2, 3, 4, 5, 6, 7, or 8 amino acid residues; and the following mutations relative to SEQ ID NO:1: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A.

21 . The nucleic acid of claim 20 , wherein the FGF21 variant comprises an N-terminal truncation of 4 amino acid residues.

22 . The nucleic acid of claim 20 , wherein the FGF21 variant is fused to the Fc region via the N-terminus.

23 . The nucleic acid of claim 22 , wherein the FGF21 variant is fused to the Fc region via a linker.

24 . The nucleic acid of claim 20 , wherein the linker comprises a GS amino acid linker.

25 . The nucleic acid of claim 20 , wherein the Fc region is a modified Fc fragment with a LALA mutation.

26 . The nucleic acid of claim 20 , wherein the FGF21 variant comprises at least one disulfide bond engineered between Gln55Cys and a cysteine residue at one of Cys103, Cys121, Gly148Cys, Asn149Cys, Lys150Cys, Ser141Cys, Pro152Cys, His 153Cys, Arg154Cys, Asp155Cys, Pro156Cys, Ala157Cys, Pro158Cys, Arg159Cys, Gly160Cys, Pro161Cus, Ala162Cys, and Arg 163Cys relative to SEQ ID NO: 1.

27 . The nucleic acid of claim 20 , wherein the FGF21 variant comprises at least one disulfide bond engineered 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 relative to SEQ ID NO: 1.

28 . The nucleic acid of claim 27 , wherein the FGF21 variant comprises an engineered disulfide bond of Gln55Cys-Gly148Cys relative to SEQ ID NO: 1.

29 . A nucleic acid coding for a fusion protein comprising a fibroblast growth factor 21 (FGF21) variant and an Fc region, wherein the fusion protein consists of the amino acid sequence of SEQ ID NO: 11.

Assignees

• Novartis Ag

Inventors

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

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K14/50 Primary

  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

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title