Granted Patent B2

US 12,297,250 · App. 17/298,512 · Granted May 13, 2025

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

C07K14/605A61K38/22C07K14/645A61K38/00

Abstract

Claims (45)

1. A glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO: 81:

(SEQ ID NO: 81)

3   4   5   6   7   8   9   10  11  12  13    14  15  16  17

E - G - T - F - I - S - E - Y - S - I - Aib - L - E - K - I

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

K - Q - Q - E - F - V - E - W - L - L - A - Q - K - Z,

wherein said amino acid sequence is modified by attaching a fatty acid molecule at one or more amino acid residue, directly or via a linker, at any one of positions 3 to 29 of SEQ ID NO: 81,

wherein Z is a peptide of one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: 2) or wherein Z is a peptide of one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: 3),

wherein said amino acid sequence is optionally C-terminally amidated (—NH2) or C-terminally carboxylated (—COOH), and

wherein said GIP analogue is an antagonist of GIPR.

2. The GIP analogue according to claim 1 ,

wherein said GIP analogue inhibits GIPR activity of at least 80%, and/or

wherein inhibition of GIPR activity is determined as a decrease in intracellular cAMP, and/or

wherein said GIP analogue has a GIPR antagonistic potency corresponding to an IC50 value of 50 nM or less than 50 nM.

3. The GIP analogue according to claim 1 , wherein Z consists of one or more consecutive amino acid residues of:

(a) the C-terminus of Exendin-4(30-39) (PSSGAPPPS; SEQ ID NO: 4; CE31-39); or

(b) the C-terminus of Exendin-4(29-39) (GPSSGAPPPS; SEQ ID NO: 5; CE30-39).

4. The GIP analogue according to claim 1 , wherein Z is a peptide selected from:

a glycine, a proline, GP, PS, PSS, GPS, GPSS (SEQ ID NO: 6), PSSG (SEQ ID NO: 12), PSSGA (SEQ ID NO: 13), GPSSG (SEQ ID NO: 7), GPSSGA (SEQ ID NO: 8), PSSGAP (SEQ ID NO: 14), PSSGAPP (SEQ ID NO: 15), GPSSGAP (SEQ ID NO: 9), GPSSGAPP (SEQ ID NO: 10), PSSGAPPP (SEQ ID NO: 16), PSSGAPPPS (SEQ ID NO: 4), GPSSGAPPP (SEQ ID NO: 11), GPSSGAPPPS (SEQ ID NO: 5),

GK, GKK, GKKN (SEQ ID NO: 17), GKKND (SEQ ID NO: 18), GKKNDW (SEQ ID NO: 19), GRKNDW (SEQ ID NO: 20), GKRNDW (SEQ ID NO: 21), GRRNDW (SEQ ID NO: 22), GKKKDW (SEQ ID NO: 28), GKKNDK (SEQ ID NO: 29), GKKNDWK (SEQ ID NO: 23), GKKNDWKH (SEQ ID NO: 24), GKKNDWKHN (SEQ ID NO: 25), GKKNDWKHNI (SEQ ID NO: 26), GKKNDWKHNIT (SEQ ID NO: 27), and GKKNDWKHNITQ (SEQ ID NO: 2).

5. The GIP analogue according to claim 1 , wherein said fatty acid molecule is attached to an amino acid residue at any one of positions 11 to 21 of SEQ ID NO: 81.

6. The GIP analogue according to claim 1 , wherein a fatty acid molecule is attached to the side chain amino group of the K amino acid residue at position 18 of SEQ ID NO: 81.

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

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

9. The GIP analogue according to claim 1 , wherein:

a) said fatty acid molecule is a monoacyl fatty acid molecule comprising one fatty acid;

b) said fatty acid molecule is a diacyl fatty acid molecule;

c) said fatty acid molecule comprises an acyl group of the formula CH 3 (CH 2 ) n CO—, wherein n is in an integer of 4 to 24; or

d) said fatty acid molecule comprises an acyl group selected from COOH(CH 2 ) 14 CO—, COOH(CH 2 ) 16 CO—, COOH(CH 2 ) 18 CO— and COOH(CH 2 ) 20 CO—.

10. The GIP analogue according to claim 1 , wherein said GIP analogue is modified by attaching a fatty acid molecule at an amino acid residue via a linker, wherein said linker comprises one or more moieties individually selected from:

a) α-amino acid, γ-amino acid, and ω-amino acid;

b) one or more amino acids selected from Lys, Glu, and Asp;

c) one or more of γ-aminobutanoyl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparagyl), β-Ala (β-alanyl) and Gly;

d) [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer of 1 to 50, or an integer of 1-4, 1-3, or 1-2; and

(e) succinic acid.

11. The GIP analogue according to claim 1 , wherein the GIP analogue is

EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid/18K; SEQ ID NO: 174 GIP(3-30)+Cex(31-39).

12. The GIP analogue according to claim 1 , wherein said GIP analogue is

EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid/18K; SEQ ID NO: 174 GIP(3-30)+Cex(31-39).

13. The GIP analogue according to claim 1 , wherein said GIP analogue is EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid/18K; SEQ ID NO: 174 GIP(3-30)+Cex(31-39), wherein said GIP analogue is C-terminally carboxylated.

14. The GIP analogue according to claim 1 , wherein said GIP analogue is EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid/18K; SEQ ID NO: 174 GIP(3-30)+Cex(31-39), wherein said GIP analogue is C-terminally amidated.

15. A method of treating obesity in a subject, wherein said method comprises administering to the subject the GIP analogue

EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid/18K; SEQ ID NO: 174 GIP(3-30)+Cex(31-39), wherein said GIP analogue is C-terminally carboxylated.

16. A method of 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, and v) GIP-induced leptin resistance in a subject, wherein said method comprising administering a GIP analogue according to claim 1 to the subject.

17. A method of treating a condition in a subject, wherein said method comprises administering a GIP analogue according to claim 1 to the subject, wherein the condition is selected from the group consisting of obesity, pre-diabetes, type 2 diabetes, insulin resistance, elevated fasting glucose, and hyperglycemia.

Assignments (1)

Priority Claims (2)

Continuity (1)

References Cited (119)