Fusion proteins and methods of use
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.
1. A method of treating a patient with diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a fusion protein comprising:
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 method of claim 1 , wherein the fusion protein is administered in combination with a GLP-1R agonist.
3. The method of claim 2 , wherein the GLP-1R agonist is dulaglutide.