Anti-pcsk9-glp-1 fusions and methods for use

Patent metadata

Field	Value
Publication number	US-2016369010-A1
Application number	US-201515117985-A
Country	US
Kind code	A1
Filing date	Feb 20, 2015
Priority date	Feb 21, 2014
Publication date	Dec 22, 2016
Grant date	—

Abstract

This application provides anti-PCSK9˜GLP-1 fusions and methods for use.

First claim

What is claimed is:

1 . A dual active fusion molecule for the treatment of diabetes comprising an anti-PCSK9 antibody stably fused to a GLP-1 peptide, wherein the anti-PCSK9 antibody binds a PCSK9 polypeptide and the GLP-1 peptide binds a GLP-1 receptor.

2 . The fusion molecule of claim 1 wherein the GLP-1 peptide is fused to the PCSK9 antibody via a linker peptide.

3 . The fusion molecule of claim 2 wherein the linker peptide is fused to the C-terminus of the GLP-1 peptide.

4 . The fusion molecule of any one of claims 1 - 3 , wherein the GLP-1 peptide comprises the amino acid sequence of SEQ ID NO: 36.

5 . The fusion molecule of any one of claims 1 - 3 , wherein the GLP-1 peptide comprises the amino acid sequence of SEQ ID NO: 3.

6 . The fusion molecule of claim 5 wherein the Cys18 of the GLP-1 peptide forms a disulfide bridge with the C terminus of the GLP-1 peptide.

7 . The fusion molecule of any one of claims 1 - 6 , wherein said fusion molecule controls glucose and/or reduces LDL in an animal.

8 . The fusion molecule of claim 7 , wherein the animal is a human.

9 . A dual active fusion molecule for the treatment of diabetes comprising an anti-PCSK9 antibody stably fused to a GLP-1 peptide comprising the amino acid sequence of SEQ ID NO: 3, wherein the C-terminus of the GLP-1 peptide is fused via a peptide linker to the anti-PCSK9 antibody, and wherein the anti-PCSK9 antibody binds a PCSK9 polypeptide and the GLP-1 peptide binds a GLP-1 receptor.

10 . The dual active fusion molecule of claim 9 , wherein the GLP-1 peptide is fused via a peptide linker to the light chain of the anti-PCSK9 antibody.

11 . The dual active fusion molecule of claim 9 , wherein the GLP-1 peptide is fused via a peptide linker to the heavy chain of the anti-PCSK9 antibody.

12 . A dual active fusion molecule comprising an antibody stably fused to a GLP-1 peptide comprising the amino acid sequence of SEQ ID NO: 3, wherein the C-terminus of the GLP-1 peptide is fused via a peptide linker to the antibody, and wherein the antibody binds a target polypeptide and the GLP-1 peptide binds a GLP-1 receptor.

13 . The dual active fusion molecule of claim 12 , wherein the antibody is an anti-PCSK9 antibody.

14 . The dual active fusion molecule of claim 13 , wherein the GLP-1 peptide is fused via a peptide linker to the light chain of the anti-PCSK9 antibody.

15 . The dual active fusion molecule of claim 13 , wherein the GLP-1 peptide is fused via a peptide linker to the heavy chain of the anti-PCSK9 antibody.

16 . The dual active fusion molecule of claim 10 or 14 , wherein the light chain of the anti-PCSK9 antibody is at least 90% identical to the amino acid sequence of SEQ ID NO: 2.

17 . The dual active fusion molecule of claim 16 , wherein the light chain of the anti-PCSK9 antibody comprises the amino acid sequence of SEQ ID NO: 2.

18 . The dual active fusion molecule of claim 11 or 15 , wherein the heavy chain of the anti-PCSK9 antibody is at least 90% identical to the amino acid sequence of SEQ ID NO: 1.

19 . The dual active fusion molecule of claim 18 , wherein the heavy chain of the anti-PCSK9 antibody comprises the amino acid sequence of SEQ ID NO: 1.

20 . The dual active fusion molecule of any one of claims 12 - 19 wherein the peptide linker comprises the amino acid sequence of SEQ ID NO: 4.

21 . The dual active fusion molecule of any one of claims 12 - 20 , wherein the dual active fusion molecule is for the treatment of diabetes.

22 . The dual active fusion molecule of any one of claims 12 - 21 , wherein the Cys18 of the GLP-1 peptide forms a disulfide bridge with the C terminus of the GLP-1 peptide.

23 . The dual active fusion molecule of any one of claims 12 - 22 , wherein the dual active fusion molecule controls glucose and/or reduces LDL in an animal.

24 . The dual active fusion molecule of claim 23 , wherein the animal is a human.

25 . A dual active fusion molecule for the treatment of diabetes comprising an anti-PCSK9 antibody stably fused to a GLP-1 peptide that has reduced potency at the human GLP-1 receptor compared to a GLP-1 peptide comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 29, wherein the C-terminus of the GLP-1 peptide is fused via a peptide linker to the anti-PCSK9 antibody, and wherein the anti-PCSK9 antibody binds a PCSK9 polypeptide and the GLP-1 peptide binds a GLP-1 receptor.

26 . The dual active fusion molecule of claim 25 , wherein the GLP-1 peptide comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 29 is fused using a linker comprising SEQ ID NO:4 to the amino acid sequence comprising SEQ ID NO: 416.

27 . The dual active fusion molecule of claim 25 or 26 , wherein the potency at the human GLP-1 receptor is reduced by 30 to 60 fold compared to a GLP-1 peptide comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 29.

28 . A method of treating Type 2 Diabetes comprising administering to a subject in need thereof, a fusion molecule of any one of claims 1 - 27 .

29 . A method of controlling glucose in a subject comprising administering to a subject in need thereof, a fusion molecule of any one of claims 1 - 27 .

30 . A method of reducing low density lipoprotein (LDL) in a subject comprising administering to a subject in need thereof, a fusion molecule of any one of claims 1 - 27 .

31 . A method of controlling glucose and reducing LDL in a subject comprising administering to a subject in need thereof, a fusion molecule of any one of claims 1 - 27 .

32 . A method of promoting weight loss, controlling glucose and reducing LDL in a subject comprising administering to a subject in need thereof, a fusion molecule of any one of claims 1 - 27 .

33 . The method of any one of claims 28 - 32 , wherein the subject has Type 2 diabetes.

34 . The method of any one of claims 28 - 32 , wherein the subject has metabolic syndrome.

35 . An isolated polynucleotide encoding the fusion molecule of any one of claims to 27 .

36 . A vector comprising the polynucleotide of claim 35 .

37 . A host cell comprising the polynucleotide of claim 35 or the vector of claim 36 .

38 . A method of making the fusion molecule of any one of claims to 27 , comprising culturing the host cell of claim 35 under conditions allowing expression of the fusion molecule, and recovering the fusion molecule.

39 . A pharmaceutical composition comprising the fusion molecule of any one of claims 1 to 27 , and a carrier.

40 . A kit comprising the composition of claim 39 .

Assignees

• Medimmune Llc
• Medimmune Ltd

Inventors

• Celeste Anthony
• Chodorge Matthieu
• Buchanan Andrew
• Rondinone Cristina
• Grimsby Joseph
• Ravn Peter
• Seaman Jonathan
• Fairman David

Classifications

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title