IP Library › Granted Patent US 12,187,773
Granted Patent B2
US 12,187,773 · App. 17/298,444 · Granted Jan 7, 2025

Modified GIP peptide analogues

Inventors: Alexander Hovard Sparre-Ulrich (Copenhagen N, DK); Bjørn Behrens Sivertsen (Copenhagen S, DK); Ditte Riber (Brønshøj, DK); Mette Marie Rosenkilde (Hellerup, DK)
Assignee: Antag Therapeutics ApS
C07K14/605C07K14/645A61K38/00
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Quick Facts
Patent No.
US 12,187,773
App. No.
17/298,444
Granted
Jan 7, 2025
Kind
B2
Abstract

Disclosed are glucose-dependent insulinotropic peptide (GIP)-derived peptide analogues which are antagonists of the GIP receptor. These GIP peptide analogues are modified by comprising one or more individual amino acid substitutions and are fatty acid conjugated with/without a linker, so to have improved antagonistic activity and improved pharmacokinetic profile.

Claims (182)

1. A glucose-dependent insulinotropic peptide (GIP) analogue selected from the group consisting of:

(a) a GIP analogue consisting of the amino acid sequence of SEQ ID NO: 1:

3   4   5   6   7   8   9  10  11  12  13  14  

X 1  - G - T - F - I - S - D - Y - S - I - A - M -

15  16  17  

   D - R - I   

18  19  20  21  22  23  24  25  26  27  28  29  30  

X 2  - Q - Q - D - F - V - N - W - L - L - A - Q - X 3   

wherein said amino acid residue X 1 is P, G, A, S, or pyroE (pyroglutamic acid),

wherein said amino acid X 2 is K or Orn, and

wherein said amino acid X 3 is R or E,

or a functional variant thereof, wherein said functional variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17 and 19 to 29 of SEQ ID NO: 1,

wherein said amino acid sequence is modified by attaching a fatty acid molecule at the amino acid at position 18 of SEQ ID NO: 1 or said functional variant thereof, and wherein said GIP analogue is an antagonist of GIP receptor (GIPR); and

(b) a GIP analogue consisting of the amino acid sequence of SEQ ID NO: 11:

3   4   5   6   7   8   9  10  11  12  13  14  

X 1  - G - T - F - I - S - D - Y - S - I - A - M -

15  16  17  

   D - R - I   

18  19  20  21  22  23  24  25  26  27  28  29  30  

X 2  - Q - Q - D - F - V - N - W - L - L - A - Q - X 3   

wherein said amino acid X 2 is K or Orn, and

wherein said amino acid X 3 is R or E,

or a functional variant thereof having 1 to 4 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 17 and 19 to 29 of SEQ ID NO: 11,

wherein said peptide amino acid sequence is modified by attaching a fatty acid molecule at the amino acid at position 18 of SEQ ID NO: 11, or a functional variant thereof, and wherein said GIP analogue is an antagonist of GIPR; and

(c) a GIP analogue consisting of the amino acid sequence of SEQ ID NO: 12:

3   4   5   6   7   8   9  10  11  12  13  14  

E - G - T - F - I - S - E - Y - S - I - A - M -

15  16  17  

  E - K - I   

18  19  20  21  22  23  24  25  26  27  28  29  30  

X 2  - Q - Q - E - F - V - Q - W - L - L - A - Q - K   

wherein said amino acid X 2 is K or Orn,

or a functional variant thereof having 1 to 4 individual amino acid substitutions at any one of positions 3 to 30 of SEQ ID NO: 12,

wherein said amino acid sequence is modified by attaching a fatty acid molecule at the amino acid at position 18 of SEQ ID NO: 12, or said functional variant thereof, and wherein said GIP analogue is an antagonist of GIPR.

2. The GIP analogue of claim 1 , wherein the fatty acid molecule is attached to the side chain amino group of the amino acid at position 18 of SEQ ID NO: 1 or said functional variant thereof.

3. The GIP analogue of claim 1 , wherein the amino acid at position 18 of SEQ ID NO: 1 is a lysine, and wherein a fatty acid molecule is attached to the side chain amino group of the lysine at position 18 of SEQ ID NO: 1 or said functional variant thereof.

4. The GIP analogue of claim 1 , wherein said functional variant has 1 individual amino acid substitution, or 2 individual amino acid substitutions, or 3 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17, and 19 to 29 of SEQ ID NO: 1.

5. The GIP analogue of claim 1 , wherein said fatty acid molecule is attached to the epsilon-amino group of the amino acid residue K at position 18 of SEQ ID NO: 1, or said functional variant thereof.

6. The GIP analogue of claim 1 , wherein said GIP analogue has an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R ,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R ,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R ,

(SEQ ID NO: 17)

pyroE GTFISDYSIAMD R I K QQDFVNWLLAQ R ,

(SEQ ID NO: 20)

EGTFISDYSIAMD R I K QQDFVNWLLAQ R , and

(SEQ ID NO: 29)

EGTFIS E YSIAM E KI K QQ E FV Q WLLAQK,

or a functional variant thereof comprising 1 to 2 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17, and 19 to 29.

7. The GIP analogue of claim 1 , wherein said GIP analogue is C-terminally amidated (—NH 2 ) or C-terminally carboxylated (—COOH).

8. The GIP analogue of claim 1 , wherein said fatty acid molecule is a straight-chain fatty acid or a branched fatty acid.

9. The GIP analogue of claim 1 , wherein said fatty acid molecule is (i) a monoacyl fatty acid molecule or (ii) a diacyl fatty acid molecule.

10. The GIP analogue of claim 1 , wherein said fatty acid molecule comprises an acyl group of the formula CH 3 (CH 2 ) n CO—, wherein n is an integer of 4 to 24.

11. The GIP analogue of claim 1 , wherein said fatty acid molecule comprises an acyl group selected from the group consisting of COOH—CH 3 (CH 2 ) 14 CO—, COOH—CH 3 (CH 2 ) 16 CO—, COOH—CH 3 (CH 2 ) 18 CO—, and COOH—CH 3 (CH 2 ) 20 CO—.

12. The GIP analogue of claim 1 , wherein said fatty acid molecule is attached to the epsilon amino group of the side chain of the lysine residue at position 18 of said GIP analogue, directly or via a linker.

13. The GIP analogue of claim 12 , wherein said linker comprises one or more moieties individually selected from the group consisting of:

a. α-amino acid, γ-amino acid, or ω-amino acid,

b. one or more amino acids selected from the group consisting of succinic acid, Lys,

c. γ-aminobutanoyl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparagyl), β-Ala (β-alanyl), or a dipeptide comprising Gly at the N-terminus, and/or

d. [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer of 1 to 50.

14. The GIP analogue of claim 1 , wherein the GIP analogue is selected from the group consisting of:

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -NH 2 -C16-diacid/K18,

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -C16-diacid/K18,

(SEQ ID NO: 14)

PGTFISDYSIAMD R I K QQDFVNWLLAQ R -(γ-Glu)-C16-diacid/

K18,

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -NH 2 -(γ-Glu)-C16-

diacid/K18,

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -( AEEAc +γ-Glu)-C16-

diacid/K18,

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -NH 2 -( AEEAc +γ-Glu)-

C16-diacid/K18,

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc +γ-Glu)-

C16-diacid/K18,

(SEQ ID NO: 14)

P GTFISDYSIAMD R I K QQDFVNWLLAQ R -NH 2 -(2x AEEAc +γ-

Glu)-C16-diacid/K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R -C16-diacid/K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R -NH 2 -C16-diacid/K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R -(γ-Glu)-C16-diacid 

/K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -(γ-Glu)-C16-

diacid, /K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R -( AEEAc -γ-Glu)-

C16-diacid /K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -( AEEAc -γ-Glu)-

C16-diacid /K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R -(2 AEEAc -γ-Glu-)C16-

diacid /K18,

(SEQ ID NO: 15)

G GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -(2x AEEAc -γ-

Glu-)C16-diacid/K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -C16-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -C16-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -C18-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -(γ-Glu)-C16-diacid 

/K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -(γ-Glu)-C16-

diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -( AEEAc -γ-Glu)-C16-

diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -( AEEAc -γ-Glu)-

C16-diacid/K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc -γ-Glu)-

C16-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R - NH 2 -(2x AEEAc G-γ-

Glu)-C16-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc -γ-Glu)-

C18-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -( AEEAc -γ-Glu)-

C16-diacid /K18,

(SEQ ID NO: 16)

S GTFISDYSIAMD R I K QQDFVNWLLAQ R -(3x AEEAc -γ-Glu)-

C18-diacid /K18,

(SEQ ID NO: 17)

pyroE GTFISDYSIAMD R I K QQDFVNWLLAQ R -C16-diacid /K18,

(SEQ ID NO: 17)

pyroE GTFISDYSIAMD R I K QQDFVNWLLAQ R -C18-diacid /K18,

(SEQ ID NO: 17)

pyroE GTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc -γ-

Glu)-C16-diacid/K18,

(SEQ ID NO: 17)

pyroEGTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc -γ-

Glu)-C18-diacid/K18,

(SEQ ID NO: 17)

pyroEGTFISDYSIAMD R I K QQDFVNWLLAQ R -(3x AEEAc -γ-

Glu)-C16-diacid/K18,

(SEQ ID NO: 17)

pyroEGTFISDYSIAMD R I K QQDFVNWLLAQ R -(3x AEEAc -γ-

Glu)-C18-diacid/K18,

(SEQ ID NO: 20)

TFISDYSIALD R I K QQDFVNWLLAQ R -( AEEAc +γ-Glu)-C16-

diacid/K18,

(SEQ ID NO: 20)

EGTFISDYSIAMD R I K QQDFVNWLLAQ R -(AEEAc +γ-Glu)-C18-

diacid/K18,

(SEQ ID NO: 20)

EGTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc G+γ-Glu)-

C16-diacid/K18,

(SEQ ID NO: 20)

EGTFISDYSIAMD R I K QQDFVNWLLAQ R -(2x AEEAc +γ-Glu)-

C18-diacid/K18,

(SEQ ID NO: 20)

EGTFISDYSIAMD R I K QQDFVNWLLAQ R -(3x AEEAc +γ-Glu)-

C16-diacid/K18,

(SEQ ID NO: 20)

EGTFISDYSIAMD R I K QQDFVNWLLAQ R -(3x AEEAc +γ-Glu)-

C18-diacid/K18,

and

(SEQ ID NO: 29)

EGTFIS E YSIAMEKI K QQ E FV Q WLLAQK(NH 2 )- 2xPEG+yGlu-

C18-diacid/K18

or said variant thereof having 1 or 2 individual amino acid substitutions at any one of the amino acid residues at positions 4 to 15, 17, and 19 to 29.

15. A method of inhibiting or reducing one or more of i) GIP-induced glucagon secretion, ii) GIP-induced insulin secretion, iii) GIP-induced somatostatin secretion, iv) GIP-induced glucose uptake, v) GIP-induced fatty acid synthesis and/or fatty acid incorporation, vi) high or increased expression or activity of a GIPR, vii) post-prandial GIP release, viii) serum levels of free fatty acids and/or triglycerides, ix) GIP-induced appetite increases, x) GIP-induced reduction in energy expenditure, xi) GIP-induced increase in absorption of nutrients from the gut, xii) GIP-induced decrease in GLP-1's appetite suppressive effect, xiii) GIP-induced leptin resistance, wherein the method comprises administering a therapeutically effective amount of a GIP analogue according to claim 1 to an individual in need thereof.

16. A method of treating a condition selected from metabolic syndrome, obesity, over-weight, an obesity-related disorder, pre-diabetes (impaired fasting glucose), diabetes mellitus (type 1 or type 2), a diabetes-related disorder, insulin resistance, elevated fasting glucose (hyperglycemia), elevated fasting serum triglyceride level (VLDL triglyceride), low high-density lipoprotein (HDL) levels, a fatty acid metabolism disorder, a cardiovascular disease, elevated blood pressure, and atherosclerosis, wherein the method comprises administering a therapeutically effective amount of a GIP analogue according to claim 1 to an individual in need thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2021
From: SPARRE-ULRICH, ALEXANDER HOVARD; SIVERTSEN, BJØRN BEHRENS; RIBER, DITTE; ROSENKILDE, METTE MARIE
To: ANTAG THERAPEUTICS APS
Reel/Frame 056389/0397 →
Priority Claims (2)
EP 18209896 · Dec 3, 2018 · regional
EP 19176739 · May 27, 2019 · regional
Continuity (1)
Related Publication 20220025010A1 · Jan 27, 2022
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