Fusion proteins

Patent metadata

Field	Value
Publication number	US-12059452-B2
Application number	US-202217577932-A
Country	US
Kind code	B2
Filing date	Jan 18, 2022
Priority date	May 7, 2015
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

The present invention relates to fusion proteins comprising an insulin receptor agonist fused to a human IgG Fc region through the use of a peptide linker, and the use of such fusion proteins in the treatment of diabetes. The fusion protein of the present invention has an extended time action profile and is useful for providing basal glucose control for an extended period of time.

First claim

We claim:

1. A pharmaceutical composition comprising a fusion protein one or more buffering agents, one or more surfactants, and one or more isotonicity agents, wherein the fusion protein comprises:
a) an insulin receptor agonist having the general formula Z 1 —Z 2 —Z 3 , wherein:
i) Z 1 is an insulin B-chain analog, comprising the amino acid sequence:

X 1 X 2 X 3 QHLCGSHLVEALX 4 LVCGERGFX 5 YX 6 X 7 X 8 X 9

wherein X 1 is F, Q or A; X 2 is V or G; X 3 is N, K, D, G, Q, A or E; X 4 is E, Y, Q, or H; X 5 is H or F; X 6 is G, T, S, H, V or is absent; X 7 is G, E, P, K, D, S, H or is absent; X 8 is G, E, K, P, Q, D, H or is absent; X 9 is G, T, S, E, K, A or is absent, provided that the insulin B-chain analog includes at least one modification from the amino acid sequence of the B-chain of a molecule of human insulin at X 4 , X 5 , X 6 , X 7 , X 8 , or X 9 (SEQ ID NO:1);
ii) Z 2 is a first peptide linker comprising 5 to 10 amino acids, wherein at least 5 of said amino acids are G residues; and
iii) Z 3 is an insulin A-chain analog comprising the amino acid sequence:

GIVEQCCTSX 1 CSLX 2 QLENYCX 3 X 4

wherein X 1 is T or I; X 2 is D, Y, Q or E; X 3 is G, N, S or A; and X 4 is any naturally occurring amino acid, or is absent, provided that if X 3 is N, then X 4 must be an amino acid other than G or N (SEQ ID NO:2);
b) a second peptide linker; and
c) a human IgG Fc region;
wherein the C-terminal residue of the insulin receptor agonist is directly fused to the N-terminal residue of the second peptide linker, and the C-terminal residue of the second peptide linker is directly fused to the N-terminal residue of the human IgG Fc region.

2. The pharmaceutical composition of claim 1 wherein the pH ranges from about 5.5 to about 8.0.

3. The pharmaceutical composition of claim 1 , further comprising an additional active ingredient.

4. The pharmaceutical composition of claim 3 , wherein the additional active ingredient is a GLP-1R agonist.

5. The pharmaceutical composition of claim 4 , wherein the GLP-1R agonist is dulaglutide.

Assignees

• Lilly Co Eli

Inventors

• Baldwin David Bruce
• Beals John Michael
• Day Jonathan Wesley
• Dickinson Craig Duane
• Korytko Andrew Ihor
• Lazar Gregory Alan

Classifications

• C07K2319/30

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

• C07K14/001

  by chemical synthesis · CPC title

• A61K38/26

  Glucagons · CPC title

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · 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