Dual function fibroblast growth factor 21 proteins

Patent metadata

Field	Value
Publication number	US-9458214-B2
Application number	US-201213626207-A
Country	US
Kind code	B2
Filing date	Sep 25, 2012
Priority date	Sep 26, 2011
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

The present invention relates to dual function fusions proteins comprising fibroblast growth factor 21 (FGF21) and Exenatide, Exendin-4, or GLP-1. Also disclosed are methods for treating FGF21-associated disorders, GLP-1-associated disorders, and Exendin-4-associated disorders, including metabolic conditions.

First claim

What is claimed is:

1. A dual function fusion protein comprising a GLP-1 receptor agonist, a FGF21 receptor agonist, and an Fc domain, attached to each other via a GS linker, and having an orientation of N-terminus-GLP-1 receptor agonist-linker-Fc domain-linker-FGF21 receptor agonist-C-terminus.

2. The dual function fusion protein of claim 1 , wherein said protein comprises the amino acid sequence of SEQ ID NO:36.

3. The dual function fusion protein of claim 1 , wherein said protein comprises the amino acid sequence of SEQ ID NO:134.

4. The dual function fusion protein of claim 1 , wherein said protein comprises the amino acid sequence of SEQ ID NO:135.

5. The dual function fusion protein of claim 1 , wherein the GLP-1 receptor agonist is selected from wild-type GLP-1, Exendin-4, GLP-1 variants, and Exendin-4 analogues.

6. The dual function fusion protein of claim 5 , wherein the GLP-1 receptor agonist is selected from Exendin-4 and Exendin-4 analogues.

7. The dual function fusion protein of claim 1 , wherein the FGF21 receptor agonist is selected from wild-type FGF21, FGF21 fragments, and FGF21 variants.

8. The dual function fusion protein of claim 7 , wherein the FGF21 receptor agonist is selected from FGF21 variants comprising the following amino acid sequences:
(a) DSSPLLQFGG QVRQRYLYTD DAQETEAHLE IREDGTVGGA AHQSPESLLE LKALKPGVIQ ILGVKTSRFL CQKPDGALYG SLHFDPEACS FRELLLEDGY NVYQSEAHGL PLHLPGNRSP HCDPAPQGPA RFLPLPGLPP ALPEPPGILA PQPPDVGSSD PLAMVGPSQG RSPSYAS (SEQ ID NO: 185);
(b) DSSPLLQFGG QVRQRYLYTD DAQETEAHLE IREDGTVGGA AHQSPESLLE LKALKPGVIQ ILGVKTSRFL CQKPDGALYG SLHFDPEACS FRELLLEDGY NVYQSEAHGL PLHLPGNRSP HCDPAPQGPA RFLPLPGLPP ALPEPPGILA PQPPDVGSSD PLAMVGGSQG RSPSYAS (SEQ ID NO: 186);
(c) D SSPLLQFGGQ VRQRYLYTDD ACQTEAHLEI REDGTVGGAA DQSPESLLQL KALKPGVIQI LGVKTSRFLC QRPDGTLYGS LHFDPEACSF RELLLEDGYN VYQSEAHGLP LHLPCNRSPH RDPASRGPAR FLPLPGLPPA LPEPPGILAP QPPDVGSSDP LAMVGGSQAR SPSYAS (SEQ ID NO: 187); and
(d) D SSPLLQFGGQ VRQRYLYTDD ACQTEAHLEI REDGTVGGAA DQSPESLLQL KALKPGVIQI LGVKTSRFLC QKPDGALYGS LHFDPEACSF RELLLEDGYN VYQSEAHGLP LHLPCNRSPH RDPASRGPAR FLPLPGLPPA LPEPPGILAP QPPDVGSSDP LAMVGGSQAR SPSYAS (SEQ ID NO: 188).

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a dual function fusion protein comprising a GLP-1 receptor agonist, a FGF21 receptor agonist, and an Fc domain, attached to each other via a GS linker, and having an orientation of N-terminus-GLP-1 receptor agonist-linker-Fc domain-linker-FGF21 receptor agonist-C-terminus.

10. The pharmaceutical composition of claim 9 , wherein the GLP-1 receptor agonist is selected from wild-type GLP-1, Exendin-4, GLP-1 variants, and Exendin-4 analogues.

11. The pharmaceutical composition of claim 10 , wherein the GLP-1 receptor agonist is selected from Exendin-4 and Exendin-4 analogues.

12. The pharmaceutical composition of claim 9 , wherein the FGF21 receptor agonist is selected from wild-type FGF21, FGF21 fragments, and FGF21 variants.

13. The pharmaceutical composition of claim 12 , wherein the FGF21 receptor agonist is selected from FGF21 variants comprising the following amino acid sequences:
(a) DSSPLLQFGG QVRQRYLYTD DAQETEAHLE IREDGTVGGA AHQSPESLLE LKALKPGVIQ ILGVKTSRFL CQKPDGALYG SLHFDPEACS FRELLLEDGY NVYQSEAHGL PLHLPGNRSP HCDPAPQGPA RFLPLPGLPP ALPEPPGILA PQPPDVGSSD PLAMVGPSQG RSPSYAS (SEQ ID NO: 185);
(b) DSSPLLQFGG QVRQRYLYTD DAQETEAHLE IREDGTVGGA AHQSPESLLE LKALKPGVIQ ILGVKTSRFL CQKPDGALYG SLHFDPEACS FRELLLEDGY NVYQSEAHGL PLHLPGNRSP HCDPAPQGPA RFLPLPGLPP ALPEPPGILA PQPPDVGSSD PLAMVGGSQG RSPSYAS (SEQ ID NO: 186);
(c) D SSPLLQFGGQ VRQRYLYTDD ACQTEAHLEI REDGTVGGAA DQSPESLLQL KALKPGVIQI LGVKTSRFLC QRPDGTLYGS LHFDPEACSF RELLLEDGYN VYQSEAHGLP LHLPCNRSPH RDPASRGPAR FLPLPGLPPA LPEPPGILAP QPPDVGSSDP LAMVGGSQAR SPSYAS (SEQ ID NO: 187); and
(d) D SSPLLQFGGQ VRQRYLYTDD ACQTEAHLEI REDGTVGGAA DQSPESLLQL KALKPGVIQI LGVKTSRFLC QKPDGALYGS LHFDPEACSF RELLLEDGYN VYQSEAHGLP LHLPCNRSPH RDPASRGPAR FLPLPGLPPA LPEPPGILAP QPPDVGSSDP LAMVGGSQAR SPSYAS (SEQ ID NO: 188).

14. The pharmaceutical composition of claim 9 , wherein said protein comprises the amino acid sequence of SEQ ID NO:36.

15. The pharmaceutical composition of claim 9 , wherein said protein comprises the amino acid sequence of SEQ ID NO:134.

16. The pharmaceutical composition of claim 9 , wherein said protein comprises the amino acid sequence of SEQ ID NO:135.

Assignees

• Novartis Ag
• Irm Llc

Inventors

• Boettcher Brian R
• Caplan Shari L
• Daniels Douglas S
• Hamamatsu Norio
• Licht Stuart
• Weldon Stephen Craig
• Cellitti Susan E
• Geierstranger Bernhard Hubert
• Loew Andreas

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

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

• C07K14/50 Primary

  Fibroblast growth factor [FGF] · CPC title

• C07K2319/75

  containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones · CPC title