Treatment of Obesity and Obesity-Related Disorders

Abstract

The present invention relates to glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) antagonist GIP peptides in combination with glucagon-like peptide-1 (GLP-1) receptor agonists, such as GLP-1 peptides, for use in the treatment of obesity and obesity-related disorders, and GIPR antagonist GIP peptides for treating a subset of obesity-related disorders.

Description

[Technical field]

[0001] The present disclosure relates to glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) antagonist GIP peptides in combination with glucagon-like peptide-1 (GLP-1) agonists such as GLP-1 peptides for use in the treatment of obesity and obesity-related disorders, and GIPR antagonist GIP peptides for treating a subset of obesity-related disorders. [Background technology]

[0002] Gut peptides and adipokines are important signaling molecules involved in the control of whole-body energy homeostasis. These circulating hormones regulate various biological responses such as hunger, satiety, and glucose uptake. In vivo experiments have established that these hormones also regulate bone metabolism, while the relationship between these hormones and bone mass has been observed in human clinical studies.

[0003] Incretins are gastrointestinal hormones that help regulate carbohydrate metabolism in response to feeding. The two main incretins are glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), both of which are secreted by intestinal epithelial cells. Intestinal glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 upon nutrient ingestion.

[0004] Glucose-dependent insulinotropic peptide (GIP) is a hormone secreted from intestinal K cells after a meal. 1 GIP, like its sister hormone glucagon-like peptide 1 (GLP-1), is a potent insulin secretagogue. 2 In contrast to the glucagon secretion suppression effect of GLP-1, 3,4 , GIP has been shown to exhibit glucagon-releasing properties under certain conditions ( 3,5~13 Interest in understanding the biology of GIP has been fuelled by the association between rodent GIPR (GIP receptor) and adiposity. 14~21In humans, the role of GIP in fat metabolism is relatively less clear, with the demonstration of GIPR expression in adipose tissue. 22 , Association between high BMI and elevated GIP levels 22、23 Increased adipose tissue blood flow and triacylglycerol (TAG) deposition after GIP administration under conditions of high insulin and high glucose 24 Decreased basal and postprandial GIP levels in diet-treated obese children 25 and elevated fasting GIP levels in healthy young men consuming a high-fat diet 26 There is also evidence that GIPR antagonists play a key role in the development of anti-obesity drugs.

[0005] Examples of promising GIPR antagonist GIP peptides are disclosed in PCT / EP2020 / 084487.

[0006] GLP-1 is a 31 amino acid peptide derived from the proglucagon gene. It is secreted by intestinal L cells and released in response to food ingestion to induce insulin secretion from pancreatic β cells. In addition to its incretin effect, GLP-1 also reduces glucagon secretion, delays gastric emptying, and reduces caloric intake. GLP-1 exerts its effects by activation of the GLP-1 receptor, which belongs to the B class G protein-coupled receptors. The function of GLP-1 is limited by its rapid degradation by the DPP-IV enzyme, resulting in a half-life of approximately 2 minutes.

[0007] In recent years, long-acting GLP-1 receptor agonists, such as exenatide, liraglutide, dulaglutide, and semaglutide, have been developed and are being used clinically to improve glycemic control in patients with type 2 diabetes. In addition, GLP-1 receptor agonists promote weight loss and lowering of blood pressure and plasma cholesterol levels in patients.

[0008] Irwin et al. 2009 (Diabetes Obes Metab 2009 Jun;11(6):603-10) discloses that daily intraperitoneal injections of the GLP-1 agonist (d-Ala8)GLP-1 or the GIPR antagonist GIP peptide (Pro3)GIP restore glycemic control to normal levels and significantly improve glucose tolerance in mice compared to high-fat controls. However, food intake and body weight were not affected. Furthermore, Irwin et al. 2009 discloses that a combination therapy consisting of the GLP-1 agonist (d-Ala8)GLP-1 and the GIPR antagonist GIP peptide (Pro3)GIP appears to offer little benefit over either monotherapy, and that body weight and food intake were not affected when the two compounds were administered together.

[0009] West et al.2021(PLOS One 2021 Mar 31;16(3)) discloses the administration of the GIPR antagonist GIP peptides, GIPA-1:mouse GIP(3-30)NH2, or GIPA-2 (ΝαΑc-K10[γΕγΕ-C16]-Arg18-hGIP(5-42), alone or in combination with the GLP-1 agonist liraglutide, to fat-fed or lean mice. GIPA-2 was found to be a more potent antagonist than GIPA-1 in mice and suppressed glucose-stimulated insulin secretion. However, chronic administration of GIPA-1 or GIPA-2 alone had no effect on absolute body weight or cumulative food intake compared to vehicle controls. As expected, liraglutide reduced both body weight and food intake, but no additive effects were observed by combining liraglutide with either of the GIPR antagonists on these parameters. Summary of the Invention

[0010] The present inventors have found that acylated GIPR antagonist GIP peptides derived from native hGIP(3-30) containing amino acid substitutions D9E, A13Aib, D15E, H18K, D21E, and / or N24E, as well as C-terminal extensions, with high solubility, physical stability, and / or excellent antagonistic properties, when used alone and especially in combination with the GLP-1 receptor agonist liraglutide, are surprisingly effective in reducing body weight, reducing food intake, reducing fasting blood glucose, reducing fasting blood insulin concentrations, reducing insulin resistance and improving insulin sensitivity, reducing fasting blood triglyceride levels, and reducing fasting blood cholesterol levels in monkey obesity models, meaning that these carefully optimized GIPR antagonist GIP peptides are particularly effective when administered in combination with GLP-1 receptor agonists, especially in the treatment of obesity and obesity-related disorders, such as dyslipidemia.

[0011] The in vivo data presented herein demonstrates for the first time that the therapies disclosed herein, including combination therapies, result in improved weight loss, improved reduction in food intake, improved reduction in fasting blood glucose levels, improved reduction in fasting blood insulin levels, improved reduction in insulin resistance, improved reduction in fasting blood triglyceride levels, improved reduction in fasting blood cholesterol levels, and improved reduction in fasting blood low-density lipoprotein (LDL) cholesterol levels compared to either monotherapy, with at least apparent additive effects on these parameters.

[0012] Thus, in one aspect, the disclosure provides a method for the production of a medicament for the treatment of a pulmonary fibrosis, comprising administering to a subject a subject the amino acid sequence SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2- E-K-I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO:1 in that the amino acid sequence of the variant contains one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; For use in a method for the treatment of obesity, obesity-related disorders and / or dyslipidemia, The methods provide a peptide that includes one or more steps of co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0013] In another aspect, the disclosure provides a GIPR antagonist GIP peptide as disclosed herein for use in a method of inhibiting or reducing one or more of: i) food intake; ii) body weight; iii) fasting blood glucose levels; iv) fasting blood insulin levels; v) insulin resistance; vi) fasting blood triglyceride levels; vii) fasting cholesterol levels; viii) fasting blood low-density lipoprotein (LDL) cholesterol levels, the method comprising one or more steps of co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0014] In another aspect, the disclosure provides a GIPR antagonist GIP peptide as disclosed herein for use in a method for treating dyslipidemia, the method comprising one or more steps of co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0015] A further aspect of the disclosure provides a composition comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, either separately or together, The GIPR antagonist GIP peptide has the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2- E-K-I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions; The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof.

[0016] A further aspect of the present disclosure provides a kit of parts comprising a GIPR antagonist GIP peptide as defined herein and a GLP-1 receptor agonist as defined herein.

[0017] In one embodiment, the composition comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, separately or together, or the kit of parts comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, is for use in a method of treating one or more of obesity, obesity-related disorders and dyslipidemia, and / or in a method of inhibiting or reducing one or more of i) food intake, ii) body weight, iii) fasting blood glucose levels, iv) fasting blood insulin levels, v) insulin resistance, vi) fasting blood triglyceride levels, vii) fasting blood cholesterol levels, and viii) fasting blood low-density lipoprotein (LDL) cholesterol levels.

[0018] Furthermore, the inventors have found that the optimized GIPR antagonist GIP peptides of the present disclosure are particularly effective in improving a number of parameters, including lowering fasting blood levels of insulin, lowering insulin resistance, and improving insulin sensitivity, lowering fasting blood levels of triglycerides, and lowering fasting blood levels of low-density lipoprotein (LDL) cholesterol, which occur independently of the observed effects on weight loss and obesity.This demonstrates that the optimized GIPR antagonist GIP peptides of the present disclosure have a dual effect on insulin sensitivity and blood lipids, directly and indirectly through reduced food intake and weight loss.

[0019] Thus, one aspect of the present disclosure is the amino acid sequence SEQ ID NO:1 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant contains one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; The present invention relates to a peptide for use in a method for inhibiting or reducing one or more of: i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and viii) fasting blood low-density lipoprotein (LDL) cholesterol level.

[0020] Another aspect of the disclosure is the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant contains one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; The present invention relates to a peptide for use in a method for treating obesity, obesity-related disorders and / or dyslipidemia. [Brief description of the drawings]

[0021] [Figure 1A] GIPR antagonists alone and in combination with the GLP-1R agonist liraglutide significantly reduced energy intake and body weight and improved insulin resistance and blood lipid profile in HFD-induced obese male cynomolgus monkeys. Cynomolgus monkeys (Macaca fascicularis) were fed an HFD consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, 150 g of apples in the afternoon from 14:00 to 15:00, and 100 g of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was available ad libitum. Monkeys were treated for 42 days with vehicle (placebo), liraglutide (once daily SC injection with a dose escalation regimen up to 0.03 mg / kg over 7 days), compound 1 (540 nmol / kg, once daily SC injection), a combination of compound 1 and liraglutide (same dosing and frequency), compound 2 (1440 nmol / kg for the first 3 days and 540 nmol / kg, once daily SC injection for the remaining 39 days), or a combination of compound 2 and liraglutide (same dosing and frequency). Cumulative energy intake. Values ​​are expressed as mean ± SEM, n = 9-10 per group. [Figure 1B]GIPR antagonists alone and in combination with the GLP-1R agonist liraglutide significantly reduced energy intake and body weight and improved insulin resistance and blood lipid profile in HFD-induced obese male cynomolgus monkeys. Cynomolgus monkeys (Macaca fascicularis) were fed an HFD consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, 150 g of apples in the afternoon from 14:00 to 15:00, and 100 g of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was available ad libitum. Monkeys were treated for 42 days with vehicle (placebo), liraglutide (once daily SC injection with a dose escalation regimen up to 0.03 mg / kg over 7 days), compound 1 (540 nmol / kg, once daily SC injection), a combination of compound 1 and liraglutide (same dosing and frequency), compound 2 (1440 nmol / kg for the first 3 days and 540 nmol / kg for the remaining 39 days, once daily SC injection), or a combination of compound 2 and liraglutide (same dosing and frequency). Percentage change in body weight. Values ​​are expressed as mean ± SEM, n = 9-10 per group. [Figure 1C]GIPR antagonists alone and in combination with the GLP-1R agonist liraglutide significantly reduced energy intake and body weight and improved insulin resistance and blood lipid profile in HFD-induced obese male cynomolgus monkeys. Cynomolgus monkeys (Macaca fascicularis) were fed an HFD consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, 150 g of apples in the afternoon from 14:00 to 15:00, and 100 g of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was available ad libitum. Monkeys were treated for 42 days with vehicle (placebo), liraglutide (once daily SC injection with a dose escalation regimen up to 0.03 mg / kg over 7 days), compound 1 (540 nmol / kg, once daily SC injection), a combination of compound 1 and liraglutide (same dosing and frequency), compound 2 (1440 nmol / kg for the first 3 days and 540 nmol / kg, once daily SC injection for the remaining 39 days), or a combination of compound 2 and liraglutide (same dosing and frequency). Homeostatic model assessment of insulin resistance. Values ​​are expressed as mean ± SEM, n = 9-10 per group. [Figure 1D]GIPR antagonists alone and in combination with the GLP-1R agonist liraglutide significantly reduced energy intake and body weight and improved insulin resistance and blood lipid profile in HFD-induced obese male cynomolgus monkeys. Cynomolgus monkeys (Macaca fascicularis) were fed an HFD consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, 150 g of apples in the afternoon from 14:00 to 15:00, and 100 g of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was available ad libitum. Monkeys were treated for 42 days with vehicle (placebo), liraglutide (once daily SC injection with a dose escalation regimen up to 0.03 mg / kg over 7 days), compound 1 (540 nmol / kg, once daily SC injection), a combination of compound 1 and liraglutide (same dosing and frequency), compound 2 (1440 nmol / kg for the first 3 days and 540 nmol / kg, once daily SC injection for the remaining 39 days), or a combination of compound 2 and liraglutide (same dosing and frequency) to measure fasting triglycerides. Values ​​are expressed as mean ± SEM, n = 9-10 per group. [Figure 1E]GIPR antagonists alone and in combination with the GLP-1R agonist liraglutide significantly reduced energy intake and body weight and improved insulin resistance and blood lipid profile in HFD-induced obese male cynomolgus monkeys. Cynomolgus monkeys (Macaca fascicularis) were fed an HFD consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, 150 g of apples in the afternoon from 14:00 to 15:00, and 100 g of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was available ad libitum. Monkeys were treated for 42 days with vehicle (placebo), liraglutide (once daily SC injection with a dose escalation regimen up to 0.03 mg / kg over 7 days), compound 1 (540 nmol / kg, once daily SC injection), a combination of compound 1 and liraglutide (same dosing and frequency), compound 2 (1440 nmol / kg for the first 3 days and 540 nmol / kg, once daily SC injection for the remaining 39 days), or a combination of compound 2 and liraglutide (same dosing and frequency) to measure fasting low-density lipoprotein cholesterol. Values ​​are expressed as mean ± SEM, n = 9-10 per group. [Figure 1F]GIPR antagonists alone and in combination with the GLP-1R agonist liraglutide significantly reduced energy intake and body weight and improved insulin resistance and blood lipid profile in HFD-induced obese male cynomolgus monkeys. Cynomolgus monkeys (Macaca fascicularis) were fed an HFD consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, 150 g of apples in the afternoon from 14:00 to 15:00, and 100 g of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was available ad libitum. Monkeys were treated for 42 days with vehicle (placebo), liraglutide (once daily SC injection with a dose escalation regimen up to 0.03 mg / kg over 7 days), compound 1 (540 nmol / kg, once daily SC injection), the combination of compound 1 and liraglutide (same dosing and frequency), compound 2 (1440 nmol / kg for the first 3 days and 540 nmol / kg, once daily SC injection for the remaining 39 days), or the combination of compound 2 and liraglutide (same dosing and frequency). Change from baseline in fasting low-density lipoprotein cholesterol. Values ​​are expressed as mean ± SEM, n = 9-10 per group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition The term "agonist" in this context refers to a peptide, or an analog thereof, that is capable of binding to a receptor and activating a downstream signaling cascade from the receptor.

[0023] The term "antagonist" in this context refers to a GIPR antagonist GIP peptide as defined herein that can bind to a receptor and block or reduce the agonist-mediated response of the receptor. Antagonists usually do not induce a biological response by themselves upon binding to a receptor. Antagonists have affinity but no potency for the receptor they recognize, and their binding to the receptor inhibits the function of agonists or inverse agonists at the receptor. Antagonists mediate their effects by binding to the active (orthosteric) or allosteric sites of the receptor, or they may interact at a unique binding site that is not normally involved in the biological control of the receptor's activity. Antagonist activity can be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, which in turn depends on the nature of the antagonist-receptor binding. Most drug antagonists typically achieve their efficacy by competing with endogenous ligands or substrates at the structurally defined binding sites of the receptor. Antagonists can be competitive, non-competitive, uncompetitive, silent antagonists, partial agonists or inverse agonists.

[0024] As used herein, the term "glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) antagonist" refers to a compound, such as a peptide, that can bind to the GIPR and block or reduce an agonist-mediated response of the GIPR.

[0025] The term "GLP-1 receptor agonist" as used herein refers to a compound, such as a peptide or small molecule drug, that can bind to the GLP-1R and activate or enhance an agonist-mediated response of the GLP-1R.

[0026] The term "individual" refers to a vertebrate, particularly a member of the mammalian species, preferably a primate, including a human. As used herein, "subject" and "individual" may be used interchangeably.

[0027] An "amino acid residue" can be a natural or unnatural amino acid residue linked by a peptide bond or a bond other than a peptide bond. The amino acid residue can be in the D or L configuration. An amino acid residue comprises an amino terminal portion (NH2) and a carboxy terminal portion (COOH) separated by a central portion comprising a carbon atom or a chain of carbon atoms, at least one of which comprises at least one side chain or functional group. NH2 refers to the amino group present at the amino terminus of an amino acid or peptide, and COOH refers to the carboxy group present at the carboxy terminus of an amino acid or peptide. The general term amino acid includes both natural and unnatural amino acids. The natural amino acids of standard nomenclature as listed in J. Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.FR section 1.822(b)(2) belong to the group of amino acids listed as Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N, and C. Non-naturally occurring amino acids are not directly listed above and include, but are not limited to, modified amino acid residues, L-amino acid residues, and stereoisomers of D-amino acid residues.

[0028] "Equivalent amino acid residue" refers to an amino acid residue that can be substituted for another amino acid residue in a polypeptide without substantially altering the structure and / or function of the polypeptide. Thus, equivalent amino acids have similar properties such as side chain bulkiness, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic) and side chain organization of carbon molecules (aromatic / aliphatic). Thus, "equivalent amino acid residues" can be considered as "conservative amino acid substitutions", which are substitutions of amino acids that have similar biochemical properties in their side chains and therefore do not affect the function of the peptide.

[0029] Among the common amino acids, for example, "conservative amino acid substitutions" can also be represented by substitutions between amino acids from each of the following groups: (1) glycine, alanine, valine, leucine, and isoleucine; (2) phenylalanine, tyrosine, and tryptophan; (3) serine and threonine; (4) aspartic acid and glutamic acid; (5) glutamine and asparagine; and (6) lysine, arginine, and histidine.

[0030] In the sense of the term "equivalent amino acid substitution" as applied herein, one amino acid may in one embodiment be substituted for another amino acid within the group of amino acids presented herein below. i) Amino acids with polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gln, Ser, Thr, Tyr and Cys) ii) Amino acids with non-polar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Pro, and Met) iii) Amino acids with aliphatic side chains (Gly, Ala, Val, Leu, Ile) iv) Amino acids with cyclic side chains (Phe, Tyr, Trp, His, Pro) v) Amino acids with aromatic side chains (Phe, Tyr, Trp) vi) Amino acids with acidic side chains (Asp, Glu) vii) Amino acids with basic side chains (Lys, Arg, His) viii) Amino acids with amide side chains (Asn, Gln) ix) Amino acids with hydroxy side chains (Ser, Thr, Tyr) x) amino acids with sulfur-containing side chains (Cys, Met); xi) Neutral and slightly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr) xii) hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and xiii) Hydrophobic amino acids (Leu, Ile, Val)

[0031] In addition, serine residues of the peptides of the present disclosure may be substituted with an amino acid selected from the group consisting of Gln, Asn, and Thr (all having polar, uncharged side chains); independently, glycine residues (Gly) are substituted with an amino acid selected from the group consisting of Ala, Val, Leu, and Ile; independently, arginine residues (Arg) are substituted with an amino acid selected from the group consisting of Lys and His (all having positively charged side chains); and independently, lysine residues (Lys) are substituted with an amino acid selected from the group consisting of Arg and His. and independently, a methionine residue (Met) may be substituted with an amino acid selected from the group consisting of Leu, Pro, Ile, Val, Phe, Tyr and Trp (all having hydrophobic side chains); independently, a glutamine residue (Gln) may be substituted with an amino acid selected from the group consisting of Asp, Glu, and Asn; and independently, an alanine residue (Ala) may be substituted with an amino acid selected from the group consisting of Gly, Val, Leu, and Ile.

[0032] When the L or D configuration (optical isomer) is not specified, the amino acid is understood to have the naturally occurring L configuration (Pure & Appl. Chem. Vol. (56(5) pp595-624 (1984)) or D configuration, whereby the peptide formed may be composed of L, D, or a series of mixed L and D amino acids.

[0033] As used herein, a glutamic acid (Glu) mimetic is a moiety that has two carboxy functional groups separated by three carbon atoms. Examples are β-Glu, γ-Glu or glutaric acid. Glutaric acid is also known as pentanedioic acid.

[0034] A "functional variant" of a peptide is a peptide that can perform substantially the same function as the peptide of which it is a functional variant. In particular, a functional variant can essentially bind to the same molecule, such as a receptor, or perform the same receptor-mediated response as the peptide of which it is a functional variant. A functional variant of a "glucose-dependent insulinotropic peptide (GIP) antagonist GIP peptide" is a peptide that can bind to GIPR and inhibit GIPR downstream signaling, such as cAMP production.

[0035] A "bioactive agent" (i.e., biologically active substance / drug) is any agent, drug, compound, composition or mixture that produces some pharmacological, often beneficial, effect that can be demonstrated in vivo or in vitro. A bioactive agent refers to a GIPR antagonist GIP peptide as defined herein, and a compound or composition that contains them, such as a GIPR antagonist GIP peptide as defined herein and a GLP-1 receptor agonist as defined herein, a composition that contains only a GIPR antagonist GIP peptide as defined herein, or only a GLP-1 receptor agonist as defined herein. As used herein, this term further includes any physiologically or pharmacologically active substance that produces a local or systemic effect in an individual.

[0036] As used herein, the terms "drug" and "pharmaceutical agent" include biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body. The terms "treatment" and "treating" as used herein refer to the management and care of a patient for the purpose of addressing a condition, disease or disorder. The terms are intended to include the full range of treatments for a given condition from which a patient is suffering, and refer equally to curative, preventive or prophylactic, and ameliorative or palliative therapies, such as the administration of a bioactive agent with the purpose of alleviating or relieving symptoms or complications, slowing the progression of a condition, partially arresting clinical symptoms, disease or disorder, curing or eliminating a condition, disease or disorder, improving or alleviating a condition or symptoms, remission (partial or complete), detectable or undetectable, and / or preventing or reducing the risk of contracting a condition, disease or disorder, and "preventing" or "prevention" is understood to refer to the management and care of a patient with the purpose of preventing the onset of a condition, disease or disorder, and includes the administration of a bioactive agent to prevent or reduce the risk of developing a condition or complication. As used herein, the term "ameliorating effect" and variations thereof means that the severity and / or undesirable occurrence of a physiological condition or symptom is reduced and / or the progression is slowed or prolonged over time, as compared to the absence of administration of a bioactive agent of the invention.

[0037] The individual to be treated is preferably a mammal, in particular a human, however, treatment of animals such as mice, rats, dogs, cats, cows, horses, sheep and pigs is also within the scope of the invention.

[0038] "Individual in need thereof" refers to an individual who may benefit from the present disclosure. In one embodiment, the individual in need thereof is an obese or overweight individual.

[0039] Treatment according to the present invention may be prophylactic, ameliorative and / or curative.

[0040] A "pharmacologically effective amount," "pharmacologically effective amount," or "physiologically effective amount" of a bioactive agent is the amount of bioactive agent present in a pharmaceutical composition described herein necessary to provide a desired level of active agent in the bloodstream or at the site of action (e.g., lungs, gastric system, colorectal system, prostate, etc.) of the individual being treated, and to give an expected physiological response when such composition is administered. Bioactive agent in this context refers to the GIPR antagonist GIP peptides disclosed herein.

[0041] As used herein, "co-administration" or "co-administration" refers to the administration of a state-of-the-art pharmaceutical composition comprising a GIPR antagonist GIP peptide of the present disclosure and a GLP-1 receptor agonist. The at least two components can be administered separately, sequentially or simultaneously.

[0042] Detailed Description Combination therapy One aspect of the disclosure is the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO:1 in that the amino acid sequence of the variant contains one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Provided is a peptide for use in a method for the treatment of obesity, obesity-related disorders and / or dyslipidemia, the method comprising one or more steps of co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0043] Amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; In the formula, X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Also disclosed is a GIPR antagonist GIP peptide for use in a method of inhibiting or reducing one or more of: i) feeding, ii) body weight, iii) fasting blood glucose levels, iv) fasting blood insulin levels, v) insulin resistance, vi) fasting blood triglyceride levels, vii) fasting cholesterol levels, viii) fasting blood low-density lipoprotein (LDL) cholesterol levels, the method comprising one or more steps of co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0044] Amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Also disclosed are peptides for use in a method for the treatment of dyslipidemia, the method comprising one or more steps of co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0045] GLP-1R agonist and the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Also disclosed is the use in the manufacture of a medicament for the treatment of obesity, obesity-related disorders and / or dyslipidemia.

[0046] GLP-1R agonist and the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Also disclosed is the use in the manufacture of a medicament for inhibiting or decreasing one or more of: i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and viii) fasting blood low-density lipoprotein (LDL) cholesterol level.

[0047] GLP-1R agonist and the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Use in the manufacture of a medicament for treating dyslipidemia is also disclosed.

[0048] Also provided herein is a method for treating obesity, obesity-related disorders and / or dyslipidemia, comprising administering to an individual in need thereof an amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions; The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Disclosed are methods which include one or more steps of co-administering a GLP-1R agonist.

[0049] Also disclosed herein is a method of inhibiting or reducing one or more of: i) feeding, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting cholesterol level, viii) fasting blood low density lipoprotein (LDL) cholesterol level in an individual in need thereof, the method comprising administering to a subject a compound having the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions; The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; The methods include one or more steps of co-administering a GLP-1R agonist.

[0050] In one aspect, the disclosure provides a composition comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, either separately or together, or a kit of parts comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, The GIPR antagonist GIP peptide has the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions; The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof.

[0051] Also disclosed herein is a composition comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, either separately or together, or a kit of parts comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, The GIPR antagonist GIP peptide has the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions; The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; For use in a method for treating obesity, obesity-related disorders and / or dyslipidemia.

[0052] Also disclosed herein is a composition comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, either separately or together, or a kit of parts comprising a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, The GIPR antagonist GIP peptide has the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions; The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; The invention is for use in a method for inhibiting or reducing one or more of: i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and viii) fasting blood low-density lipoprotein (LDL) cholesterol level.

[0053] Also disclosed is i) a glucagon-like peptide-1 (GLP-1) receptor agonist, and ii) an amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO:1 in that the amino acid sequence of the variant contains one, two or three individual amino acid substitutions, Also disclosed is a drug combination, wherein the peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof.

[0054] Also disclosed is i) a glucagon-like peptide-1 (GLP-1) receptor agonist, and ii) an amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO:1 in that the amino acid sequence of the variant contains one, two or three individual amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Drug combinations for use in methods for treating obesity, obesity-related disorders, and / or dyslipidemia are also disclosed.

[0055] Also disclosed is i) a glucagon-like peptide-1 (GLP-1) receptor agonist, and ii) an amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO:1 in that the amino acid sequence of the variant contains one, two or three individual amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; Also disclosed are drug combinations for use in methods to inhibit or reduce one or more of: i) food intake, ii) body weight, iii) fasting blood glucose levels, iv) fasting blood insulin levels, v) insulin resistance, vi) fasting blood triglyceride levels, vii) fasting blood cholesterol levels, and viii) fasting blood low-density lipoprotein (LDL) cholesterol levels.

[0056] In one embodiment, the GIPR antagonist GIP peptide of the present disclosure and the GLP-1 receptor agonist are included together in the same composition or pharmaceutical formulation.

[0057] In one embodiment, the GIPR antagonist GIP peptide and the GLP-1 receptor agonist of the present disclosure are each contained in separate compositions or pharmaceutical formulations.

[0058] In some embodiments, the GIPR antagonist GIP peptide and the GLP-1 receptor agonist are administered simultaneously.

[0059] In some embodiments, the GIPR antagonist GIP peptide and the GLP-1 receptor agonist are administered separately.

[0060] In some embodiments, the GIPR antagonist GIP peptide and the GLP-1 receptor agonist are administered sequentially.

[0061] Monotherapy Thus, one aspect of the disclosure is the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; The present invention relates to a peptide for use in a method for inhibiting or reducing one or more of: i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and viii) fasting blood low-density lipoprotein (LDL) cholesterol level.

[0062] Another aspect of the disclosure is the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof; The present invention relates to a peptide for use in a method for treating obesity, obesity-related disorders and / or dyslipidemia.

[0063] In one embodiment, the peptide for use in a method for inhibiting or reducing any one of i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and vii) fasting blood low density lipoprotein (LDL) cholesterol level, and / or for use in a method for treating dyslipidemia comprises: i.EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], ii. XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and iii. XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 11; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0064] In one embodiment, the peptide for use in a method for inhibiting or reducing any one of i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and vii) fasting blood low density lipoprotein (LDL) cholesterol level, and / or for use in a method for treating dyslipidemia is EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0065] In one embodiment, the peptide for use in a method for inhibiting or reducing any one of i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and vii) fasting blood low density lipoprotein (LDL) cholesterol level, and / or for use in a method for treating dyslipidemia is XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39)[E3 glutarate (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0066] In one embodiment, the peptide for use in a method for inhibiting or reducing any one of i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin level, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and vii) fasting blood low density lipoprotein (LDL) cholesterol level, and / or for use in a method for treating obesity, obesity related disorders and / or dyslipidemia is XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 11; GIP(3-30)+Cex(31-39)[E3 glutarate (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0067] patient group Overweight and obesity are defined as abnormal or excessive fat accumulation that indicates a risk to health. A BMI (Body Mass Index) above 25 is considered overweight and above 30 is obese. Obesity is a complex disease that involves excess body fat mass. Obesity increases the risk of other diseases and health problems such as heart disease, diabetes, hypertension, and certain cancers.

[0068] Individuals are usually 30 kg / m 2 More than 35kg / m 2 More than 40kg / m 2 If an individual has a BMI (body mass index) of 25-30 or above, they are considered obese. If an individual has a BMI below 25-30, they are usually considered overweight.

[0069] In one embodiment of the present disclosure, the individual has a maximum body weight of 25 kg / m 2 More than 30kg / m 2 More than 35kg / m 2 More than 40kg / m 2 A person is considered obese if their BMI is above 100.

[0070] In some embodiments of the present disclosure, an individual is considered Class 1 obese if their BMI is less than 30-35. In some embodiments of the present disclosure, an individual is considered Class 2 obese if their BMI is less than 35-40. In some embodiments of the present disclosure, an individual is considered Class 3 obese if their BMI is greater than 40. Class 3 obesity is sometimes classified as "severe" obesity.

[0071] In one embodiment, an individual is considered obese if they have a BMI greater than 25 and have one or more obesity-related disorders (comorbidities).

[0072] In one embodiment, an individual is considered obese if their waist circumference is 80 cm or more for women or 94 cm or more for men.

[0073] In one embodiment, the obesity-related disorder of the present disclosure is overeating.

[0074] In one embodiment, the obesity-related disorder of the present disclosure is selected from the group consisting of heart disease, stroke, high blood pressure, high blood cholesterol, high blood low density lipoprotein (LDL) cholesterol, high blood triglycerides, dyslipidemia, gallbladder disease and gallstones, NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis), osteoarthritis, gout, breathing disorders such as sleep apnea and asthma, insulin resistance and diabetes.

[0075] In one embodiment, the obesity-related disorder of the present disclosure is type II diabetes.

[0076] In one embodiment, the obesity-related disorder of the present disclosure is dyslipidemia.

[0077] In one embodiment, the present disclosure provides for the treatment of obesity-related disorders in individuals with normal weight, overweight or obese individuals.An individual who is not obese or overweight may suffer from any of the obesity-related disorders mentioned herein for other reasons, such as heart disease, stroke, high blood cholesterol, high blood low-density lipoprotein (LDL) cholesterol, high blood triglycerides, dyslipidemia, gallbladder disease and gallstones, NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis), osteoarthritis, gout, respiratory disorders such as sleep apnea and asthma, insulin resistance and diabetes.

[0078] In one embodiment, the disclosure provides treatments such as optimized GIPR antagonist GIP peptides as defined herein, alone or in combination with a GLP-1R agonist, for use in the treatment of one or more of heart disease, stroke, hypertension, high blood cholesterol, high blood low density lipoprotein (LDL) cholesterol, high blood triglycerides, dyslipidemia, gallbladder disease and gallstones, NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis), osteohepatitis, gout, respiratory disorders such as sleep apnea and asthma, insulin resistance, and diabetes.

[0079] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of an obesity-related disorder in an overweight individual.

[0080] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of an obesity-related disorder in an obese individual.

[0081] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of an obesity-related disorder in an individual with a BMI of 18-25.

[0082] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of obesity-related disorders in individuals with a BMI greater than 25.

[0083] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of obesity related disorders in individuals with a BMI below 30-35.

[0084] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of obesity related disorders in individuals with a BMI below 35-40.

[0085] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of obesity-related disorders in individuals with a BMI of over 40.

[0086] In one embodiment, the peptide(s) or composition for use according to the present disclosure is for the treatment of an obesity-related disorder in an individual with a waist circumference of 80 cm or more in women or 94 cm or more in men.

[0087] GIPR antagonist GIP peptide In one embodiment, the present disclosure provides the amino acid sequence, SEQ ID NO:1: 3 -4-5-6 7 8 9 10 11 12 13 14 15 16 17 X1-GTFISEY- S- I- Aib-X2-E- K- I- 18 19 20 21 22 23 24 25 26 27 28 29 30 31 K- Q- Q- E- F- V- E- W- L- L- A- Q- K- P 32 33 34 35 36 37 38 39 S-S-G-A-P-P-P-S (SEQ ID NO: 1), In the formula, X1 is E, glutaric acid, adipic acid or succinic acid; wherein X2 is M, L or Nle; or a functional variant thereof, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1 in that the amino acid sequence of the variant comprises one, two or three distinct amino acid substitutions, The peptide comprises a fatty acid molecule attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof, and is used in combination as disclosed herein.

[0088] The GIPR antagonist GIP peptide of the present disclosure has a sequence based on natural human GIP3-30, and for the GIPR antagonist GIP peptide, the numbering of the amino acid residues of natural hGIP is maintained.Therefore, as provided herein, the residue at position 3 is actually the first residue (the residue at position 1 in the official sequence listing) of the GIPR antagonist GIP peptide of the present disclosure.Similarly, the lysine at position 18 used for the addition of fatty acid is actually the residue at position 16 in the official sequence listing.

[0089] The GIPR antagonist GIP peptides of the present disclosure are characterized by having greater solubility, greater physical stability, and / or improved antagonistic properties compared to native hGIP and compared to hGIP3-30.

[0090] In some embodiments, the GIP peptide according to the disclosure is such that X1 of SEQ ID NO:1 is E.

[0091] In some embodiments, a GIP peptide according to the present disclosure is such that X1 of SEQ ID NO:1 is glutaric acid.

[0092] In some embodiments, the GIP peptide or variant thereof according to the present disclosure is such that X2 of SEQ ID NO:1 is L.

[0093] In some embodiments, the GIP peptide or variant thereof according to the present disclosure is such that X2 of SEQ ID NO:1 is Nle.

[0094] In some embodiments, the GIP peptide or variant thereof according to the present disclosure is such that X1 of SEQ ID NO:1 is E and X2 of SEQ ID NO:1 is L.

[0095] In some embodiments, the GIP peptide or variant thereof according to the present disclosure is such that X1 of SEQ ID NO:1 is glutaric acid and X2 of SEQ ID NO:1 is L.

[0096] In some embodiments, the GIP peptide or variant thereof according to the present disclosure comprises a GIP peptide having a structure in which X1 of SEQ ID NO:1 is glutaric acid and X 2が It's like being Nle.

[0097] In some embodiments, the amino acid sequence of the functional variant of a GIP peptide according to the present disclosure differs from SEQ ID NO:1 in that the amino acid sequence of the variant comprises three distinct amino acid substitutions.

[0098] In some embodiments, the amino acid sequence of the functional variant of a GIP peptide according to the present disclosure differs from SEQ ID NO:1 in that the amino acid sequence of the variant comprises two separate amino acid substitutions.

[0099] In some embodiments, the amino acid sequence of the functional variant of a GIP peptide according to the present disclosure differs from SEQ ID NO:1 in that the amino acid sequence of the variant comprises one amino acid substitution.

[0100] In some embodiments, the amino acid sequence of the functional variant of a GIP peptide according to the present disclosure differs from SEQ ID NO:1 in that the amino acid sequence of the variant contains one, two, or three conservative amino acid substitutions.

[0101] In some embodiments, the amino acid sequence of the functional variant of a GIP peptide according to the present disclosure differs from SEQ ID NO:1 in that the amino acid sequence of the variant comprises one, two, or three individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, 25-39 of SEQ ID NO:1.

[0102] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure is selected from the group consisting of: EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 1; GIP(3-30) [D9E; I12Aib; M14Nle; D15E; H18K; N24E], EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO:2; GIP(3-30)[D9E;A13Aib;D15E;H18K;N24E], EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 3; GIP(3-30)[A13Aib; H18K; N24E], EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 4; GIP(3-30)[A13Aib; M14L; H18K; N24E], EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 5; GIP(3-30) [A13Aib; M14Nle; H18K; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 6; GIP(3-30) [D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 7; GIP(3-30) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 8; GIP(3-30) [D9E; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 9; GIP(3-30) [D9E; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 10; GIP(3-30) [D9E; A13Aib; M14L; D15E; H18K; N24E] XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 11; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 12; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], XGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 13; GIP(3-30) [E3 glutaric acid (X); D9E; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibMEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 14; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAibMEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 15; GIP(3-30) [D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAMEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 16; GIP(3-30) [D9E; D15E; H18K; D21E; N24E], EGTFISEYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 17; GIP(3-30) [D9E; A13Aib; M14L; H18K; N24E] XGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 18; GIP(3-30) [E3 glutaric acid (X); A13Aib; H18K; N24E], EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO:2; GIP(3-30) [D9E,A13Aib;D15E;H18K;N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO:20; GIP(3-30) [E3 succinic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO:21; GIP(3-30) [E3 adipic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions.

[0103] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 6; GIP(3-30) [D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 11; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 12; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions.

[0104] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure is carboxylated (-COOH) at the C-terminus.

[0105] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is a straight chain fatty acid.

[0106] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is a branched chain fatty acid.

[0107] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is a diacyl fatty acid molecule.

[0108] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule has the formula CH3(CH2) n It contains an acyl group of CO-, where n is an integer of 4 to 24.

[0109] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, the fatty acid molecule being CH3(CH2)6CO-, CH3(CH2)8CO-, CH3(CH2) 10 CO-, CH3(CH2) 12 CO-, CH3(CH2) 14 CO-, CH3(CH2) 16 CO-, CH3(CH2) 18 CO-, CH3(CH2) 20 CO- and CH3(CH2) 22 CO-.

[0110] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, the fatty acid molecule having a CH3 (CH2) 10 CO-(Lauryl, C12), CH3(CH2) 12 CO-(myristoyl, C14), CH3(CH2) 14 CO-(Palmitoyl, C16), CH3(CH2) 16 CO-(Stearyl, C18), CH3(CH2) 18 CO-(arachidyl, C20) and CH3(CH2) 20 Contains an acyl group selected from the group consisting of CO-(behenyl, C22).

[0111] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, the fatty acid molecule being HOOC-CH3(CH2) 10 CO-(dodecanoyl, C12), HOOC-CH3(CH2) 12 CO-(1-tetradecanoyl, C14), HOOC-CH3(CH2) 14 CO-(hexadecanoyl, C16), HOOC-CH3(CH2) 15 CO-(15-carboxy-pentadecanoyl, C17), HOOC-CH3(CH2) 16 CO-(octadecanoyl, C18), HOOC-CH3(CH2) 17 CO-(17-carboxy-heptadecanoyl, C19), HOOC-CH3(CH2) 18 CO-(eicosanoyl, C20), HOOC-CH3(CH2) 19 CO-(19-carboxy-nonadecanoyl, C21) and HOOC-CH3(CH2) 20 CO-(behenyl, C22).

[0112] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule has the formula COOH(CH2) n It contains an acyl group of CO-(dicarboxylic acid), where n is an integer of 4-24.

[0113] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, the fatty acid molecule being COOH(CH2) 14 CO-, COOH(CH2) 16 CO-, COOH(CH2) 18 CO- and COOH(CH2) 20 CO-.

[0114] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is COOH(CH2) 14 Contains or consists of CO-.

[0115] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is COOH(CH2) 16 Contains or consists of CO-.

[0116] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is COOH(CH2) 18 Contains or consists of CO-.

[0117] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is attached to the side chain amino group of the lysine residue at position 18 of SEQ ID NO:1 or a variant of SEQ ID NO:1.

[0118] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is attached to the side chain amino group of the ornithine residue at position 18 of SEQ ID NO:1 or a variant of SEQ ID NO:1.

[0119] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, the fatty acid molecule being linked via a linker to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a variant of SEQ ID NO:1.

[0120] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, the fatty acid molecule being linked to an amino acid residue of SEQ ID NO:1 or a variant thereof via a linker, wherein the carboxyl group of the fatty acid molecule forms an amide bond with the amino group of the linker.

[0121] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid molecule linked to an amino acid residue of SEQ ID NO:1 or a variant thereof via a linker, the linker comprising one or more moieties individually selected from the group consisting of: a. an α-amino acid, a γ-amino acid, or an ω-amino acid; b. one or more amino acids selected from the group consisting of succinic acid, Lys, Glu, and Asp c. one or more amino acids selected from the group consisting of Gly and Ser; d. one or more amino acids selected from the group consisting of Ala, Glu, Lys, and Leu; e. one or more of γ-aminobutanoyl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparagyl), β-Ala (β-alanyl), 2-aminoisobutyric acid (Aib) and Gly, and f.[8-Amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer of 1 to 50, for example, an integer of 1 to 4, 1 to 3, or 1 to 2.

[0122] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid molecule linked to an amino acid residue of SEQ ID NO:1 or a variant thereof via a linker, the linker comprising γ-Glu, one or more 8-amino-3,6-dioxaoctanoic acid (AEEAc), or a combination thereof, for example, wherein the linker is [8-amino-3,6-dioxaoctanoic acid] n (AEEAc) n In the formula, n is an integer of 1 to 50, for example, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 20, 20 to 25, 25 to 30, 30 to 35, 35 to 40, 40 to 45, 45 to 50, and preferably, n is 1, 2 or 3.

[0123] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid molecule linked to an amino acid residue of SEQ ID NO:1 or a variant thereof via a linker, the linker comprising or consisting of γ-Glu and two AEEAc.

[0124] In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid molecule linked to an amino acid residue of SEQ ID NO:1 or a variant thereof via a linker, the linker comprising or consisting of γ-Glu-AEEAc-AEEAc.

[0125] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is linked to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof via a linker, and the combination of the linker and the fatty acid molecule is selected from the group consisting of: i. Hexadecanoyl-γ-Glu- ii. Hexadecanoyl-γ-Glu-γ-Glu- iii. Hexadecanoyl-γ-Glu-AEEAc- iv. Hexadecanoyl-γ-Glu-AEEAc-AEEAc- v.Hexadecanoyl-γ-Glu-AEEAc-AEEAc-AEEAc- vi. [15-Carboxy-pentadecanoyl]-γ-Glu- vii. [15-Carboxy-pentadecanoyl]-γ-Glu-γ-Glu- viii. [15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc- ix. [15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc-AEEAc- x.[15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc-AEEAc-AEEAc- xi. Octadecanoyl-γ-Glu- xii. Octadecanoyl-γ-Glu-γ-Glu- xiii. Octadecanoyl-γ-Glu-AEEAc- xiv. Octadecanoyl-γ-Glu-AEEAc-AEEAc- xv. Octadecanoyl-γ-Glu-AEEAc-AEEAc-AEEAc- xvi. [17-Carboxy-heptadecanoyl]-γ-Glu- xvii. [17-Carboxy-heptadecanoyl]-γ-Glu-γ-Glu- xviii. [17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc- xix. [17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc- xx.[17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-AEEAc- xxi. Eicosanoyl-γ-Glu- xxii.Eicosanoyl-γ-Glu-γ-Glu- xxiii.Eicosanoyl-γ-Glu-AEEAc- xxiv. Eicosanoyl-γ-Glu-AEEAc-AEEAc- xxv.Eicosanoyl-γ-Glu-AEEAc-AEEAc-AEEAc- xxvi. [19-Carboxy-nonadecanoyl]-γ-Glu- xxvii. [19-Carboxy-nonadecanoyl]-γ-Glu-γ-Glu- xxviii. [19-Carboxy-nonadecanoyl]-γ-Glu-AEEAc- xxix. [19-Carboxy-nonadecanoyl]-γ-Glu-AEEAc-AEEAc-, and xxx.[19-Carboxy-nonadecanoyl]-γ-Glu-AEEAc-AEEAc-AEEAc-.

[0126] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is linked to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or its functional variant via a linker, and the combination of the linker and the fatty acid molecule is [17-carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-.

[0127] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure comprises a fatty acid, wherein the fatty acid molecule is attached directly, i.e., without a linker or spacer, to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:1 or a functional variant thereof, and the fatty acid is selected from the group consisting of: i. [15-carboxypentadecanoyl], and ii.[17-Carboxy-heptadecanoyl].

[0128] In some embodiments, the GIPR antagonist GIP peptide according to the present disclosure is selected from the group consisting of: EGTFISEYSIAMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 38; GIP(3-30)+Cex(31-39)[D9E; D15E; H18K; N24E], EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 1; GIP(3-30)+Cex(31-39)[D9E; I12Aib; M14Nle; D15E; H18K; N24E], EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:2; GIP(3-30)+Cex(31-39)[D9E; A13Aib; D15E; H18K; N24E], EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:3; GIP(3-30)+Cex(31-39)[A13Aib; H18K; N24E], EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 4; GIP(3-30)+Cex(31-39)[A13Aib; M14L; H18K; N24E], EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 4; GIP(3-30)+Cex(31-39)[A13Aib; M14L; H18K; N24E], EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:5; GIP(3-30)+Cex(31-39)[A13Aib;M14Nle;H18K;N24E], EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:5; GIP(3-30)+Cex(31-39)[A13Aib;M14Nle;H18K;N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 7; GIP(3-30)+Cex(31-39) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 7; GIP(3-30)+Cex(31-39) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:8; GIP(3-30)+Cex(31-39)[D9E;M14L;D15E;H18K;D21E;N24E], EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 9; GIP(3-30)+Cex(31-39) [D9E; M14Nle; D15E; H18K; D21EN24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], XGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS-OH-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 13; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibMEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 14; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAibMEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 15; GIP(3-30)+Cex(31-39)[D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAMEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 16; GIP(3-30)+Cex(31-39)[D9E; D15E; H18K; D21E; N24E], EGTFISEYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 17; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; H18K; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 18; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); A13Aib; H18K; N24E], EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:2; GIP(3-30)+Cex(31-39)[D9E; A13Aib; D15E; H18K; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 11; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 8; GIP(3-30)+Cex(31-39)[D9E; M14L; D15E; H18K; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-(GGGS-C16-diacid / 18K); SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-(ALEA-C16-diacid / 18K); SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 10; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-(Aib-C16-diacid / 18K); SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-(KAAAEKAAAEKAAAE-C16-diacid / 18K); SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:20; GIP(3-30)+Cex(31-39)[E3 succinic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO:21; GIP(3-30)+Cex(31-39)[E3 adipic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or or a functional variant thereof containing one, two or three individual amino acid substitutions.

[0129] In certain embodiments, the GIPR antagonist GIP peptide according to the present disclosure is selected from the group consisting of: i.EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], ii. XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and iii. XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: 11; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions.

[0130] In certain embodiments, a GIPR antagonist GIP peptide according to the present disclosure is EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0131] In certain embodiments, a GIPR antagonist GIP peptide according to the present disclosure is XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutarate (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0132] In certain embodiments, a GIPR antagonist GIP peptide according to the present disclosure is XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions.

[0133] GLP-1 receptor agonists In some embodiments, a GIPR antagonist GIP peptide according to the present disclosure is co-administered with a GLP-1 receptor (GLP-1R) agonist.

[0134] In some embodiments of the present disclosure, the GLP-1 receptor agonist is a non-peptide GLP-1 receptor agonist.

[0135] In some embodiments of the present disclosure, the GLP-1 receptor agonist is a small molecule GLP-1R agonist.

[0136] These include cyclobutane derivative-based non-peptide agonists for the GLP-1R, including Boc5 and its newly discovered analogue WB4-24.

[0137] In some embodiments of the disclosure, the small molecule GLP-1 receptor agonist is selected from the group consisting of Boc5, WB4-24, OWL833, TT-OAD2, LY3502970, and PF06882961.

[0138] In some embodiments of the present disclosure, the GLP-1 receptor agonist is a GLP-1 receptor activating antibody.

[0139] In some embodiments, the GLP-1R agonist is an agonist of the GLP-1 receptor. In some embodiments, the GLP-1R agonist is an agonist of the GLP-1 receptor only. In some embodiments, the GLP-1R agonist is an agonist of the GLP-1 receptor primarily. In some embodiments, the GLP-1R agonist is an agonist of the GLP-1 receptor and one or more additional receptors.

[0140] In some embodiments of the present disclosure, the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist. In some embodiments of the present disclosure, the GLP-1 receptor agonist is a dual agonist of the GLP-1 receptor and another receptor. These can be peptide-based or non-peptide-based.

[0141] In some embodiments of the present disclosure, the GLP-1 receptor agonist is a triple acting GLP-1 receptor agonist. In some embodiments of the present disclosure, the GLP-1 receptor agonist is a triple agonist of the GLP-1 receptor and two other receptors.

[0142] In some embodiments of the disclosure, the GLP-1 receptor agonist is a GLP-1R / Glucagon dual agonist.

[0143] In some embodiments of the disclosure, the GLP-1 receptor agonist is a peptide GLP-1 receptor agonist.

[0144] In some embodiments of the present disclosure, the GLP-1 receptor agonist is a GLP-1 peptide.

[0145] In some embodiments of the disclosure, the GLP-1 peptide is a protease-resistant analog of hGLP-1 (human GLP-1; SEQ ID NO:32).

[0146] In some embodiments of the disclosure, the GLP-1 peptide is exenatide (SEQ ID NO:22), lixisenatide (SEQ ID NO:23), albiglutide (SEQ ID NO:24), liraglutide (SEQ ID NO:25), taspoglutide (SEQ ID NO:26), dulaglutide (SEQ ID NO:27), semaglutide (SEQ ID NO:19), efpeglenatide, exendin-4 (Ex4, SEQ ID NO:22), Ex4(1-30) (SEQ ID NO:29), Ex4(9-39) (SEQ ID NO:3 0), Ex(9-30) (SEQ ID NO:28), hGLP-1(1-37) (SEQ ID NO:32), hGLP-1(7-36) (SEQ ID NO:33), hGLP-1(7-37) (SEQ ID NO:34), hGLP-1(1-36) (SEQ ID NO:35), hGLP-1(9-36) (SEQ ID NO:36), A7-hGLP-1(7-36) (SEQ ID NO:37) and A10-hGLP-1(7-36) (SEQ ID NO:28), or a functional variant thereof.

[0147] In some embodiments of the disclosure, the GLP-1 peptide is hGLP-1(7-37) or a variant thereof, such as a variant having one or two distinct amino acid substitutions, such as a variant having two distinct amino acid substitutions, optionally including a fatty acid molecule. In one embodiment, the variant has one or two distinct amino acid substitutions at positions 8 and 34.

[0148] In some embodiments of the disclosure, the GLP-1 peptide is (Arg34)hGLP-1(7-37): JPEG2024521398000001.jpg37159 or a variant thereof, such as a variant having one individual amino acid substitution and optionally comprising a fatty acid molecule, or a variant comprising a fatty acid molecule.

[0149] In some embodiments of the disclosure, the GLP-1 peptide is hGLP-1(7-37) comprising a fatty acid molecule attached to a lysine at position 26 (Arg34), or a variant thereof, such as a variant having one amino acid substitution. In one embodiment, the variant has an amino acid substitution at position 8.

[0150] In one embodiment of the disclosure, the GLP-1 peptide is hGLP-1(7-37) which comprises a fatty acid molecule attached to a lysine at position 26 (Arg34).

[0151] In some embodiments of the present disclosure, the GLP-1 peptide is liraglutide.

[0152] Liraglutide is a GLP-1 receptor agonist and its chemical structure is N26-(hexadecanoyl-γ-glutamyl)-(Arg34)GLP-1-(7-37)-peptide.

[0153] In one embodiment of the disclosure, the GLP-1 peptide is (Aib8)(Arg34)hGLP-1(7-37), which comprises a fatty acid molecule attached to a lysine at position 26.

[0154] In certain embodiments of the disclosure, the GLP-1 peptide is semaglutide.

[0155] In some embodiments of the disclosure, the GLP-1 peptide is a liquid formulation of semaglutide.

[0156] In some embodiments of the disclosure, the GLP-1 peptide is a solid oral dosage form composition of semaglutide.

[0157] Semaglutide is a GLP-1 receptor agonist and its chemical structure is N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37), as disclosed, for example, in US 8,129,343.

[0158] The amino acid sequence of semaglutide differs from human GLP-1 as it is a truncated analogue, with two amino acid substitutions at positions 8 and 34, and the lysine at position 26 is acylated with stearic diacid (C-18 fatty diacid chain) via a spacer corresponding to the modified residue N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

[0159] combination In one embodiment, the GIPR antagonist GIP peptide according to the present disclosure is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is (Arg34)hGLP-1(7-37) (SEQ ID NO:25), or a variant thereof, such as a variant having one individual amino acid substitution and optionally including a fatty acid molecule, or a variant including a fatty acid molecule.

[0160] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is (Arg34)hGLP-1(7-37) (SEQ ID NO:25), which comprises a fatty acid molecule attached to the lysine at position 26 of (SEQ ID NO:25), or a variant thereof, such as a variant having one individual amino acid substitution. In one embodiment, the variant has an amino acid substitution at position 8.

[0161] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is liraglutide or semaglutide.

[0162] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is semaglutide.

[0163] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is (Arg34)hGLP-1(7-37) (SEQ ID NO:25), or a variant thereof, such as a variant having one individual amino acid substitution and optionally including a fatty acid molecule, or a variant including a fatty acid molecule.

[0164] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is (Arg34)hGLP-1(7-37) (SEQ ID NO:25), which comprises a fatty acid molecule attached to the lysine at position 26 of (SEQ ID NO:25), or a variant thereof, such as a variant having one individual amino acid substitution. In one embodiment, the variant has an amino acid substitution at position 8.

[0165] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is liraglutide or semaglutide.

[0166] In certain embodiments, the GIPR antagonist GIP peptide is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], and XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof containing one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is semaglutide.

[0167] In certain embodiments, the GIPR antagonist GIP peptide is EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E] or a functional variant thereof comprising one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is semaglutide.

[0168] In certain embodiments, the GIPR antagonist GIP peptide is XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: 12; GIP(3-30)+Cex(31-39) [E3 glutarate (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E] or a functional variant thereof comprising one, two or three individual amino acid substitutions, The GLP-1 receptor agonist is semaglutide.

[0169] In certain embodiments, the GIPR antagonist GIP peptide is XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:11; GIP(3-30)+Cex(31-39)[E3 glutarate(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or a functional variant thereof comprising one, two or three individual amino acid substitutions; The GLP-1 receptor agonist is semaglutide.

[0170] Pharmaceutical Compositions and Formulations While it is possible for the bioactive agents of the present disclosure to be administered as raw chemicals (e.g., peptides), it is sometimes preferable to present them in the form of a pharmaceutical formulation, which may be referred to as a pharmaceutical composition, a pharma- ceutically acceptable composition, or a pharma- ceutically safe composition.

[0171] Thus, there is further provided a pharmaceutical formulation comprising one or more bioactive agents of the present disclosure, or a pharma- ceutically acceptable salt or ester thereof, and a pharma- ceutically acceptable carrier, excipient and / or diluent.The pharmaceutical formulation can be prepared by conventional techniques, for example as described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

[0172] Pharmaceutically acceptable salts of the peptide compounds of the present application, where they can be prepared, are also intended to be encompassed by the present disclosure. These salts will be acceptable for application in pharmaceutical applications. It is thereby intended that the salts retain the biological activity of the parent compound and that the salts do not adversely or detrimentally affect its application and use in the treatment of disease.

[0173] Pharmaceutically acceptable salts are prepared by standard methods. If the parent compound is a base, it can be treated, for example, with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it can be treated, for example, with an inorganic or organic base in a suitable solvent.

[0174] A pharmaceutical formulation or composition according to the present disclosure comprises a GIPR antagonist GIP peptide, a GLP-1 receptor agonist, or both a GIPR antagonist GIP peptide and a GLP-1 receptor agonist according to the present disclosure.

[0175] The present disclosure relates to combination therapy of GIPR antagonist GIP peptides and GLP-1 receptor agonists.

[0176] In some embodiments of the present disclosure, the GIPR antagonist GIP peptide and the GLP-1 receptor agonist are present in the same pharmaceutical formulation.

[0177] In some embodiments of the present disclosure, the GIPR antagonist GIP peptide and the GLP-1 receptor agonist are present in two different pharmaceutical formulations that can be administered simultaneously, sequentially or separately to an individual in need thereof.

[0178] Administration and Dosage According to the present disclosure, the GIP peptide, GLP-1 receptor agonist, or composition comprising the GIP peptide and / or GLP-1 receptor agonist as defined herein is administered in a pharmacologic or therapeutically effective amount to an individual in need of treatment. The dosing requirements vary according to the particular drug composition used, the route of administration, and the particular subject being treated, which depend on the severity and type of disorder, as well as the subject's weight and general condition. Those skilled in the art will also recognize that the optimal amount and interval of individual doses of the peptide compound will be determined by the nature and extent of the condition being treated, the form, route, and site of administration, and the particular patient being treated, and that such optimal conditions can be determined by conventional techniques. Those skilled in the art will also recognize that the optimal course of treatment, i.e., the number of doses of the compound given per day for a defined number of days, can be ascertained using conventional therapeutic strategy determination tests.

[0179] In one embodiment, each of the bioactive agents is administered at least once per day, for example, once per day.

[0180] In one embodiment, each bioactive agent is administered at intermittent or spaced intervals, such that a dose is not administered on every day.

[0181] In one embodiment, one or more doses are administered once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every month, once every 5 weeks, once every 6 weeks, or at intervals within these ranges (e.g., once every 2-4 weeks or once every 4-6 weeks).

[0182] In one embodiment, the dose is administered once weekly, for example once a week, for example one dose per week.

[0183] In one embodiment, the dose of the GIPR antagonist GIP peptide of the disclosure is administered at least once a day, such as once a day, for example once every 2 days, for example once every 3 days, such as once every 4 days, for example once every 5 days, for example once every 6 days, for example once a week, for example once every 2 weeks (biweekly), for example once a month.

[0184] In one embodiment, a dose of a GIPR antagonist GIP peptide of the disclosure is administered once per day.

[0185] In one embodiment, a dose of a GIPR antagonist GIP peptide of the disclosure is administered once a week.

[0186] In one embodiment, a dose of a GIPR antagonist GIP peptide of the present disclosure is administered once every two weeks.

[0187] In one embodiment, a dose of a GIPR antagonist GIP peptide of the disclosure is administered once a month.

[0188] In one embodiment, the dose of the GLP-1 receptor agonist of the present disclosure is administered continuously, for example at least once a day, for example once a day, for example once every 2 days, for example once every 3 days, for example once every 4 days, for example once every 5 days, for example once every 6 days, for example once a week, for example once every 2 weeks, for example once a month.

[0189] In one embodiment, a dose of the GLP-1 receptor agonist of the present disclosure is administered once a day.

[0190] In one embodiment, a dose of the GLP-1 receptor agonist of the present disclosure is administered once a week.

[0191] In one embodiment, a dose of the GLP-1 receptor agonist of the present disclosure is administered once every two weeks (biweekly administration).

[0192] In one embodiment, the GIPR antagonist GIP peptide according to the present disclosure is administered at a concentration of about 15 nmol / kg, such as about 20 nmol / kg, for example about 25 nmol / kg, such as about 30 nmol / kg, for example about 35 nmol / kg, such as about 40 nmol / kg, for example about 45 nmol / kg, such as about 50 nmol / kg, for example about 55 nmol / kg, such as about 60 nmol / kg, for example about 65 nmol / kg, such as about 70 nmol / kg, for example about 7 5 nmol / kg, such as about 80 nmol / kg, for example about 85 nmol / kg, such as about 90 nmol / kg, for example about 95 nmol / kg, such as about 100 nmol / kg, for example about 110 nmol / kg, such as about 120 nmol / kg, for example about 125 nmol / kg, such as about 150 nmol / kg, for example about 175 nmol / kg, such as about 200 nmol / kg, for example about 250 nmol / kg, such as about 300 nmol / kg, for example about 350nmol / kg, such as about 400nmol / kg, for example about 450nmol / kg, such as about 500nmol / kg, for example about 550nmol / kg, such as about 600nmol / kg, for example about 650nmol / kg, such as about 700nmol / kg, for example about 750nmol / kg, such as about 800nmol / kg, for example about 850nmol / kg, such as about 900nmol / kg, for example about 950nmol / kg, such as about 1000nmol / kg In one embodiment, the dose of GIPR antagonist GIP peptide according to the present disclosure is administered in a daily dose, a weekly dose, a biweekly dose or a monthly dose.

[0193] In one embodiment, the GIPR antagonist GIP peptide according to the disclosure is administered at a concentration of about 15 nmol / kg, such as about 20 nmol / kg, for example about 25 nmol / kg, such as about 30 nmol / kg, for example about 35 nmol / kg, such as about 40 nmol / kg, for example about 45 nmol / kg, such as about 50 nmol / kg, for example about 55 nmol / kg, such as about 60 nmol / kg, for example about 65 nmol / kg, such as about 70 nmol / kg, for example about 75 nmol / kg. nmol / kg, such as about 80 nmol / kg, for example about 85 nmol / kg, such as about 90 nmol / kg, for example about 95 nmol / kg, such as about 100 nmol / kg, for example about 110 nmol / kg, such as about 120 nmol / kg, for example about 125 nmol / kg, such as about 150 nmol / kg, for example about 175 nmol / kg, such as about 200 nmol / kg, for example about 250 nmol / kg, such as about 300 nmol / kg, for example about 35 0 nmol / kg, such as about 400 nmol / kg, for example about 450 nmol / kg, for example about 500 nmol / kg, such as about 550 nmol / kg, for example about 600 nmol / kg, such as about 650 nmol / kg, for example about 700 nmol / kg, such as about 750 nmol / kg, for example about 800 nmol / kg, such as about 850 nmol / kg, for example about 900 nmol / kg, such as about 950 nmol / kg, for example about 1000 nmol / kg, For example, a weekly dose of about 1050 nmol / kg, such as about 1100 nmol / kg, for example about 1150 nmol / kg, such as about 1200 nmol / kg, for example about 1250 nmol / kg, such as about 1300 nmol / kg, for example about 1350 nmol / kg, such as about 1400 nmol / kg, for example about 1450 nmol / kg, such as about 1500 nmol / kg, for example about 2000 nmol / kg, such as about 2500 nmol / kg.

[0194] In one embodiment, the GIPR antagonist GIP peptide according to the present disclosure is administered at a concentration of 15-20 nmol / kg, such as 20-25 nmol / kg, for example 25-30 nmol / kg, for example 30-35 nmol / kg, for example 35-40 nmol / kg, for example 40-45 nmol / kg, for example 45-50 nmol / kg, for example 50-60 nmol / kg, for example 60-70 nmol / kg, for example 70-80 nmol / kg, for example 80-90 nmol / kg. kg, for example 90-100nmol / kg, for example 100-125nmol / kg, for example 125-150nmol / kg, for example 150-175nmol / kg, for example 175-200nmol / kg, for example 200-250nmol / kg, for example 250-300nmol / kg, for example 300-350nmol / kg, for example 350-400nmol / kg, for example 400-450nmol / kg, for example 450-500nmol / kg, for example 00-550nmol / kg, for example 550-600nmol / kg, for example 600-650nmol / kg, for example 650-700nmol / kg, for example 700-750nmol / kg, for example 750-800nmol / kg, for example 800-850nmol / kg, for example 850-900nmol / kg, for example 900-1000nmol / kg, for example 1000-1050nmol / kg, for example 1050-1100nmol / kg, for example 11 In one embodiment, the dose of the GIPR antagonist GIP peptide according to the present disclosure is administered in a daily dose, weekly dose, biweekly dose or monthly dose.

[0195] In one embodiment, the GLP-1 receptor agonist of the present disclosure is administered at a dose of about 5 μg / kg, such as about 10 μg / kg, for example about 15 μg / kg, such as about 20 μg / kg, for example about 25 μg / kg, for example about 30 μg / kg, such as about 40 μg / kg, for example about 50 μg / kg, such as about 75 μg / kg, for example about 100 μg / kg, such as about 200 μg / kg, for example about 300 μg / kg, such as about 400 μg / kg, for example about 500 μg / kg, such as about 600 μg / kg, for example about 700 μg / kg, such as about 800 μg / kg, for example about 900 μg / kg, such as about 1 mg / kg, for example about 5 mg / kg, such as about 10 mg / kg, for example about 25 mg / kg, for example about 50 mg / kg, for example about 100 mg / kg. In one embodiment, the dose of GLP-1 receptor agonist according to the present disclosure is administered in a daily dose, a weekly dose, a biweekly dose or a monthly dose.

[0196] In one embodiment, the GLP-1 receptor agonist of the present disclosure is administered at a dose of 5 to 10 μg / kg, such as 10 to 15 μg / kg, for example, 15 to 20 μg / kg, for example, 20 to 25 μg / kg, for example, 25 to 30 μg / kg, for example, 30 to 40 μg / kg, for example, 40 to 50 μg / kg, for example, 50 to 75 μg / kg, for example, 75 to 100 μg / kg, for example, 100 to 200 μg / kg, for example, 200 to 300 μg / kg, for example For example, it is administered at a dose of 300 to 400 μg / kg, for example, 400 to 500 μg / kg, for example, 500 to 600 μg / kg, for example, 600 to 700 μg / kg, for example, 700 to 800 μg / kg, for example, 800 to 900 μg / kg, for example, 900 to 1 mg / kg, for example, 1 to 5 mg / kg, for example, 5 to 10 mg / kg, for example, 10 to 25 mg / kg, for example, 25 to 50 mg / kg, for example, 50 to 100 mg / kg.

[0197] In one embodiment, the dose of GLP-1 receptor agonist according to the present disclosure is administered in a daily dose, a weekly dose, a biweekly dose or a monthly dose.

[0198] In one embodiment, the dose of the GLP-1 receptor agonist is administered in a daily dose of about 300 μg / kg, for example about 400 μg / kg.

[0199] In one embodiment, the dose of GLP-1 receptor agonist is administered separately from the dose of GIP peptide.For example, the dose of GLP-1 receptor agonist can be administered on the same day as the administration of GIP peptide, but at different time points.For example, the dose of GLP-1 receptor agonist can be administered on a different day than the administration of GIP peptide.

[0200] In one embodiment, the dose of the GLP-1 receptor agonist is administered separately from the dose of the GIP peptide, and the GLP-1 receptor agonist and the GIP peptide are contained in separate compositions.

[0201] In one embodiment, the dose of the GLP-1 receptor agonist is administered simultaneously with the dose of the GIP peptide. Simultaneous includes essentially simultaneous and exactly simultaneous. Simultaneous administration includes the two components being contained in the same composition.

[0202] In one embodiment, the doses of the GLP-1 receptor agonist and the GIP peptide are administered sequentially, such as administering the GLP-1R agonist before or after administration of the dose of the GIP peptide.

[0203] Route of administration It will be understood that the preferred route of administration will depend on the general condition and age of the subject being treated, the nature of the condition being treated, the location of the tissue being treated within the body, and the active ingredient selected, but may be, for example, subcutaneous.

[0204] Whole-body treatment For systemic treatment according to the present disclosure, the route of administration is one that can introduce the bioactive agent into the bloodstream for ultimate targeting to the desired site of action.

[0205] Such routes of administration may be any suitable route, such as enteral routes (including oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intravesical and intraperitoneal administration), and / or parenteral routes (including subcutaneous, intramuscular, intrathecal, intracerebral, intravenous and intradermal administration).

[0206] Parenteral Administration Parenteral administration is any administration route that is not oral / enteral, whereby the drug avoids first-pass degradation in the liver.Thus, parenteral administration includes any injection and infusion, for example, bolus injection or continuous infusion, such as intravenous, intramuscular, or subcutaneous administration.Furthermore, parenteral administration includes inhalation and topical administration.

[0207] Thus, the bioactive agent is administered topically across any mucous membrane of the animal to which the biologically active substance is administered, such as the nose, vagina, eye, mouth, reproductive tract, lungs, gastrointestinal tract, or rectum, preferably the nasal or oral mucosa, and thus parenteral administration can also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration, as well as pulmonary and bronchial administration by inhalation or introduction. The agent may also be administered topically across the skin.

[0208] According to an advantageous embodiment of the invention, the GIP peptide and / or the GLP-1 receptor agonist are administered subcutaneously.

[0209] In some embodiments of the present disclosure, the GIP peptide and / or the GLP-1 receptor agonist are administered systemically.

[0210] In some embodiments of the present disclosure, the GIP peptide and / or the GLP-1 receptor agonist are administered by injection.

[0211] In some embodiments of the present disclosure, the GIP peptide and / or the GLP-1 receptor agonist are administered by injection.

[0212] In some embodiments of the present disclosure, the GIP peptide and / or GLP-1 receptor agonist are administered parenterally, including subcutaneously, intramuscularly, intrathecally, intracerebrally, intravenously, and intradermally.

[0213] Local treatment The bioactive agent according to the present invention may in one embodiment be used as a local treatment, i.e., directly introduced to the site(s) of action. Thus, the bioactive agent may be applied directly to the skin or mucous membrane, or the bioactive agent may be injected into the site of action, for example, into the diseased tissue or into a terminal artery that leads directly to the diseased tissue. These administration forms preferably avoid the blood-brain barrier. EXAMPLES

[0214] Example 1. In vivo testing Peptides tested GIPR antagonist GIP peptides: Compound 1: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K (GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E]), corresponding to SEQ ID NO: 6, with the C16 diacid attached to the side chain of lysine in position 16 (18K if the numbering of native human GIP is taken into account).

[0215] Compound 2: XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K (GIP(3-30)+Cex(31-39)[E3 glutaric acid (X);D9E;A13Aib;M14Nle;D15E;H18K;D21E;N24E], corresponding to SEQ ID NO: 12, with the C18 diacid attached to the side chain of lysine at position 16 via the linker 2xAEEAc+yGlu (18K if the numbering of native human GIP is taken into account).

[0216] GLP-1 agonist: liraglutide.

[0217] Materials and Methods Efficacy studies in cynomolgus monkeys were conducted by Kunming Biomed International (KBI), China. The study was approved by the Institutional Animal Care and Use Committee of KBI. High-fat diet (HFD)-induced obese cynomolgus monkeys (Macaca fascicularis, male, >7.5 kg, fasting glucose <90 mg / dL, fasting insulin <60 μU / mL, >8 years old) were obtained from a stock colony at KBI. Lighting in the animal holding room was maintained on a 12:12-h light-dark cycle, and ambient temperature and humidity ranges were set at 18–29°C and 30–90%, respectively. The monkeys were housed individually in cages arranged to allow visual and auditory contact with other monkeys. The monkeys were provided with toys in their cages for environmental enrichment to ensure proper welfare and psychological well-being.

[0218] Eight days prior to the treatment phase, KBI's proprietary HFD was provided ad libitum, as opposed to the prescribed amount of 100 g that the monkeys were normally fed. During the entire treatment phase (42 days) and washout period (14 days), the monkeys received three meals per day consisting of 50 g of KBI's proprietary standard monkey formula chow in the morning from 9:00 to 10:00, one uniform apple (150 g) in the afternoon from 14:00 to 15:00, and ad libitum feeding of KBI's proprietary HFD in the evening from 16:00 to 17:00. Water was provided ad libitum. The monkeys fasted throughout the night, as all food was withdrawn at 17:00.

[0219] Prior to the start of treatment, cynomolgus monkeys were acclimated / trained according to the experimental procedures for 3 weeks, followed by 1 week of continuous training and induction of HFD ad libitum. Monkeys were randomly divided into 6 separate dose groups of 10 monkeys each based on the acclimation dataset.

[0220] During the treatment period, all monkeys received daily SC injections of each test substance after breakfast for a total of 42 days. Liraglutide was administered at escalating doses over 7 days to avoid nausea and vomiting issues associated with GLP-1R agonists. The final dose of liraglutide was 0.03 mg / kg. Compound 1 was administered at 540 nmol / kg, and due to its long half-life, compound 2 was administered at 1440 nmol / kg for the first 3 days of the study and 540 nmol / kg for the remaining 39 days to reach steady-state plasma concentrations at the same time as compound 1. The same concentrations were used for the combination treatment groups with compound 1 + liraglutide and compound 2 + liraglutide, respectively. All treatment and vehicle groups were administered injection doses based on individual body weight. After 42 days of treatment, body weight, food intake, and blood / serum biochemistry were monitored over an additional 14-day washout period. Blood sampling and dosing were performed throughout the study in conscious monkeys.

[0221] Daily food intake measurements were recorded throughout the study, from the acclimation period through the end of the washout period. Intake was determined by removing all remaining food after each feeding period and weighing the remaining food.

[0222] Body weights were measured every 3-4 days during the study period. Monkeys were not sedated and were transferred to small transfer cages and then to a weighing machine. The tare weight of the transfer cage was measured before weighing the monkeys in the transfer cage. Monkeys were weighed twice in the transfer cage and recorded to the nearest 0.1 kg.

[0223] Whole blood samples were collected from a peripheral vein at the indicated time points after an overnight fast and transferred directly into serum separator tubes (SSTs). Serum was separated by centrifugation at 2500xg for 10 min at 4°C. Insulin, CTX, and PTH levels were analyzed using a Cobas e411 immunoanalyzer. Other parameters were analyzed using a Roche C311 or C501 biochemistry analyzer.

[0224] result All treatment groups have lower cumulative energy intake compared to placebo.Compound 1 + liraglutide and compound 2 + liraglutide show the most significant reduction in energy intake of all groups (see Fig. 1A).From this, it can be concluded that the combination of our GIP antagonist and GLP-1 receptor agonist liraglutide has at least an additive effect on total energy intake.

[0225] The results on cumulative energy intake are consistent with those on weight loss. Placebo group had a total mean weight gain of 9% on the last treatment day (day 42), while monotherapy with compound 1 or compound 2 maintained weight throughout the study period, showing clear efficacy for both monotherapy. Treatment with liraglutide resulted in a total mean weight loss of 4%, while treatment with compound 1 + liraglutide and compound 2 + liraglutide resulted in a mean total weight loss of 8% and 9% (17% and 18% vs. placebo), respectively. These results clearly show that the combination of our GIP antagonist with the GLP-1 receptor agonist liraglutide is more effective for weight loss than treatment with liraglutide alone.

[0226] Weight loss is well known to cause improvements in insulin sensitivity and lipid profile, and therefore it is often difficult to assess whether a drug directly affects these parameters when weight loss is present. In this study, obese NHPs treated with compound 1 or compound 2 monotherapy were protected against the weight gain observed in placebo-treated animals, and importantly, no changes in weight occurred over the entire study period. This is important for the interpretation of the following data.

[0227] Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated and showed improved insulin sensitivity in the treatment groups, with the highest insulin sensitivity observed in the combination group (mean HOMA-IR on day 43 was 25.1, 11.2, 13.0, 6.2, 12.7 and 5.8 for placebo, liraglutide, compound 1, compound 1 + liraglutide, compound 2, and compound 2 + liraglutide, respectively). See Figure 1C. Importantly, the effect on insulin sensitivity was independent of weight loss, as both compound 1 and compound 2 maintained stable weight throughout the study period.

[0228] Animals treated with Compound 1 alone or in combination with liraglutide had reduced fasting triglycerides (see FIG. 1D). Both combination groups reached significant reductions after 22 days of treatment, indicating that there is at least an additive effect between GIPR antagonism and GLP-1 receptor agonism in lowering fasting triglycerides. Importantly, both Compound 1 treatment groups showed a trend toward lowering LDL-c, which was not seen in any of the other treatment groups (FIGS. 1E and 1F). Calculation of the individual % change in LDL-c from pre-dose shows that the placebo and GLP-1 groups increased LDL levels during the study period, while Compound 1 and Compound 1 + liraglutide groups reached a 26% and 43% reduction in LDL-c, respectively. Interestingly, these improvements are not dependent on weight loss, as the effects of Compound 1 on triglycerides and LDL-c are also observed in the monotherapy groups.

[0229] A wide range of safety biomarkers were evaluated during the study, including markers of bone metabolism, liver function and hematology, and no changes outside the normal range were detected.

[0230] Overview of Arrays EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 1; GIP(3-30) [D9E; I12Aib; M14Nle; D15E; H18K; N24E], EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO:2; GIP(3-30)[D9E;A13Aib;D15E;H18K;N24E], EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 3; GIP(3-30)[A13Aib; H18K; N24E], EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 4; GIP(3-30)[A13Aib; M14L; H18K; N24E], EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 5; GIP(3-30) [A13Aib; M14Nle; H18K; N24E], EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 6; GIP(3-30) [D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 7; GIP(3-30) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 8; GIP(3-30) [D9E; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 9; GIP(3-30) [D9E; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 10; GIP(3-30) [D9E; A13Aib; M14L; D15E; H18K; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 11; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 12; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], XGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 13; GIP(3-30) [E3 glutaric acid (X); D9E; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibMEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 14; GIP(3-30) [E3 glutaric acid (X); D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAibMEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 15; GIP(3-30) [D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAMEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 16; GIP(3-30) [D9E; D15E; H18K; D21E; N24E], EGTFISEYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 17; GIP(3-30)[D9E; A13Aib; M14L; H18K; N24E], XGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 18; GIP(3-30) [E3 glutaric acid (X); A13Aib; H18K; N24E], HAibEGTFTSDVSSYLEGQAAKEFIAWLVRGRG; SEQ ID NO: 19; Semaglutide, XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO: 20; GIP(3-30) [E3 succinic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS; SEQ ID NO:21; GIP(3-30) [E3 adipic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: 22; Exenatide, HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK; SEQ ID NO: 23; Lixisenatide, HGEGX1FX2SDVSSYLEGQAAKEFX3DAWLVKGR; SEQ ID NO: 24; albiglutide [X1 is allothreonine; X2 is allothreonine; X3 is alle (alloisoleucine)], HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG; SEQ ID NO: 25; Liraglutide; HX1EGTFTSDVSSYLEGQAAKEFIAWLVKX2R; SEQ ID NO: 26; Taspoglutide [X1 is Aib; X2 is Aib], HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG; SEQ ID NO: 27; Dulaglutide, HAEATFTSDVSSYLEGQAAKEFIAWLVKGR; SEQ ID NO: 28; A10-hGLP-1(7-36), HGEGTFTSDLSKQMEEEAVRLFIEWLKNGG; SEQ ID NO:29; Ex4(1-30), DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO:30; Ex4(9-39), DLSKQMEEEAVRLFIEWLKNGG; SEQ ID NO:31; Ex4(9-30), HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG; SEQ ID NO: 32; hGLP-1 (same as hGLP-1(1-37)), HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR; SEQ ID NO: 33; hGLP-1(7-36), HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG; SEQ ID NO: 34; hGLP-1(7-37), HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGR; SEQ ID NO: 35; hGLP-1(1-36), EGTFTSDVSSYLEGQAAKEFIAWLVKGR; SEQ ID NO: 36; hGLP-1(9-36), AAEGTFTSDVSSYLEGQAAKEFIAWLVKGR; SEQ ID NO: 37; A7-hGLP-1(7-36), EGTFISEYSIAMEKIKQQDFVEWLLAQKPSSGAPPPS; SEQ ID NO: 38; GIP(3-30)+Cex(31-39)[D9E; D15E; H18K; N24E].

Claims

1. A glucose-dependent insulinotropic peptide receptor (GIPR) antagonist GIP peptide consisting of the amino acid sequence GIP(3-30)+Cex(31-39) SEQ ID NO: 39, or a pharmaceutical composition comprising an effective amount of a functional GIP(3-30)+Cex(31-39) variant thereof, wherein said variant comprises 1, 2 or 3 individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of GIP(3-30)+Cex(31-39) SEQ ID NO: 39, (wherein X １ is E, glutaric acid, adipic acid or succinic acid, and X ２ is M, L or Nle) The GIPR antagonist GIP peptide comprises a fatty acid molecule directly or via a linker bonded to the side chain amino group of the K amino acid residue (18K) at position 18 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 39 or the functional variant thereof, The pharmaceutical composition is for use in the treatment of obesity, obesity-related disorders and / or dyslipidemia, characterized in that it is used in combination with an effective amount of a glucagon-like peptide-1 (GLP-1) receptor agonist.

2. A glucose-dependent insulinotropic peptide receptor (GIPR) antagonist GIP peptide consisting of the amino acid sequence GIP(3-30)+Cex(31-39) SEQ ID NO: 39, or a pharmaceutical composition comprising an effective amount of a functional GIP(3-30)+Cex(31-39) variant thereof, wherein said variant comprises 1, 2 or 3 individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 39, The GIPR antagonist GIP peptide comprises a fatty acid molecule directly or via a linker bonded to the side chain amino group of the K amino acid residue (18K) at position 18 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 39 or the functional variant thereof, (wherein X １ is E, glutaric acid, adipic acid or succinic acid, and X ２ is M, L or Nle) ​ ​ The pharmaceutical composition is characterized by being used in combination with an effective amount of a glucagon-like peptide-1 (GLP-1) receptor agonist for inhibiting or reducing one or more of: i) food intake, ii) body weight, iii) fasting blood glucose level, iv) fasting blood insulin concentration, v) insulin resistance, vi) fasting blood triglyceride level, vii) fasting blood cholesterol level, and viii) fasting blood low-density lipoprotein (LDL) cholesterol level.

3. The GLP-1 receptor agonist is a GLP-1 peptide or a protease-resistant analog of hGLP-1, or The GLP-1 receptor agonist is selected from exenatide (SEQ ID NO: 22), lixisenatide (SEQ ID NO: 23), albiglutide (SEQ ID NO: 24), liraglutide (SEQ ID NO: 25), taspoglutide (SEQ ID NO: 26), dulaglutide (SEQ ID NO: 27), semaglutide (SEQ ID NO: 19), efpeglenatide, exendin-4 (Ex4, SEQ ID NO: 22), Ex4(1-30) (SEQ ID NO: 29), Ex4(9-39) (SEQ ID NO: 30), Ex(9-30) (SEQ ID NO: 28), hGLP-1(1-37) (SEQ ID NO: 32), hGLP-1(7-36) (SEQ ID NO: 33), hGLP-1(7-37) (SEQ ID NO: 34), hGLP-1(1-36) (SEQ ID NO: 35), hGLP-1(9-36) (SEQ ID NO: 36), A7-hGLP-1(7-36) (SEQ ID NO: 37), and A10-hGLP-1(7-36) (SEQ ID NO: 28), or functional variants thereof. The pharmaceutical composition according to claim 1 or 2.

4. The GLP-1 receptor agonist is i) hGLP-1(7-37) or a variant thereof having, for example, one or two individual amino acid substitutions and optionally containing a fatty acid molecule. ii) (Arg34)hGLP-1(7-37) (SEQ ID NO: 25) or a variant thereof having, for example, one amino acid substitution and optionally containing a fatty acid molecule. iii) (Arg34)hGLP-1(7-37) (SEQ ID NO: 25) containing a fatty acid molecule bound to the lysine at position 26 of (SEQ ID NO: 25), or a variant thereof having, for example, one amino acid substitution. iv) (Arg34)hGLP-1(7-37) (SEQ ID NO: 25) or (Aib8)(Arg34)hGLP-1(7-37) (SEQ ID NO: 19) containing a fatty acid molecule bound to a 26-position lysine, v) liraglutide, or vi) semaglutide, the pharmaceutical composition according to claim 1 or 2.

5. The pharmaceutical composition according to claim 1 or 2, wherein the GLP-1 receptor agonist is semaglutide, a liquid formulation of semaglutide, or a solid oral dosage form composition of semaglutide.

6. The pharmaceutical composition according to claim 1 or 2, wherein the GLP-1 receptor agonist is a non-peptide GLP-1 receptor agonist, a small molecule GLP-1 receptor agonist, a GLP-1 receptor activating antibody, a dual-acting or triple-acting GLP-1 receptor agonist, or a GLP-1 / glucagon dual agonist.

7. i) X of SEQ ID NO: 39 １ wherein E or glutamic acid ii) X of SEQ ID NO: 39 ２ is L or Nle, iii) X of SEQ ID NO: 39 １ is E, and X of SEQ ID NO: 39 ２ is L iv) X of SEQ ID NO: 39 １ is glutaric acid, and X of SEQ ID NO: 39 ２ is L, or v) X of SEQ ID NO: 39 １ is glutaric acid, and X of SEQ ID NO: 39 ２ is Nle, the pharmaceutical composition according to claim 1 or 2.

8. The GIPR antagonist GIP peptide is EGTFISEYSIAibLEKIKQQEFVEWLLAQQKPSSGAPPPS; SEQ ID NO: 6; GIP(3-30)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIKQQEFVEWLLAQQKPSSGAPPPS; SEQ ID NO: 7; GIP(3-30)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIALEKIKQQEFVEWLLAQQKPSSGAPPPS; SEQ ID NO: 8; GIP(3-30)[D9E; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIANleEKIKQQEFVEWLLAQQKPSSGAPPPS; SEQ ID NO: 9; GIP(3-30)[D9E; M14Nle; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIKQQEFVEWLLAQQKPSSGAPPPS; SEQ ID NO: 11; GIP(3-30)[E3 glutamic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIKQQEFVEWLLAQQKPSSGAPPPS; SEQ ID NO: 12; GIP(3-30)[E3 glutamic acid (X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], XGTFISEYSIALEKIKQQEFVEVWLLAQQPSGAPPP; SEQ ID NO: 13; GIP(3-30) [E3 glutamic acid (X); D9E; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIabMEKIKQQEFVEVWLLAQQPSGAPPP; SEQ ID NO: 14; GIP(3-30) [E3 glutamic acid (X); D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIabMEKIKQQEFVEVWLLAQQPSGAPPP; SEQ ID NO: 15; GIP(3-30) [D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIMEKIKQQEFVEVWLLAQQPSGAPPP; SEQ ID NO: 16; GIP(3-30) [D9E; D15E; H18K; D21E; N24E], XGTFISEYSIabLEKIKQQEFVEVWLLAQQPSGAPPP; SEQ ID NO: 20; GIP(3-30) [E3 succinic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], and XGTFISEYSIabLEKIKQQEFVEVWLLAQQPSGAPPP; SEQ ID NO: 21; GIP(3-30) [E3 adipic acid (X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or 1, 2 or 3 individual amino acid substitutions in any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) GIPR antagonist GIP peptide, their functional variants selected from, a GIP(3-30)+Cex(31-39) amino acid sequence, the pharmaceutical composition according to claim 1 or 2.

9. The GIPR antagonist GIP peptide is C-terminally carboxylated (-COOH), the pharmaceutical composition according to claim 1 or 2.

10. The fatty acid molecule is a straight-chain fatty acid or a branched-chain fatty acid, and / or The fatty acid molecule is a diacyl fatty acid molecule, The fatty acid molecule has an acyl group of the formula CH ３ (CH ２ ) ｎ CO—, where n is an integer from 4 to 24, and / or The fatty acid molecule has an acyl group of the formula COOH(CH ２ ), ｎ CO-(dicarboxylic acid), where n is an integer from 4 to 24, and / or The fatty acid molecule is CH ３ (CH ２ ) ６ CO—, CH ３ (CH ２ ) ８ CO—, CH ３ (CH ２ ) １０ CO—, CH ３ (CH ２ ) １２ CO—, COOH(CH ２ ) １４ CO—, COOH(CH ２ ) １６ CO—, COOH(CH ２ ) １８ CO—, COOH(CH ２ ) ２０ CO—, and CH ３ (CH ２ ) ２２ The pharmaceutical composition according to claim 1 or 2, comprising an acyl group selected from CO—.

11. The pharmaceutical composition according to claim 1 or 2, wherein the fatty acid molecule is directly bonded to the side-chain amino group of the K amino acid residue (18K) at the 18th position of the GIP(3-30)+Cex(31-39) SEQ ID NO: 39 or the variant of the GIP(3-30)+Cex(31-39) SEQ ID NO:

39.

12. The fatty acid molecule is bonded via a linker, and the linker is a. α-amino acid, γ-amino acid, and ω-amino acid, b. one or more amino acids selected from succinic acid, Lys, Glu, and Asp, c. one or more amino acids selected from Gly and Ser, d. one or more amino acids selected from Ala, Glu, Lys, and Leu, e. one or more of γ-aminobutanoyl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparagyl), β-Ala (β-alanyl), 2-aminoisobutyric acid (Aib), and Gly, and f. [8-amino-3,6-dioxaoctanoic acid] ｎ (AEEAc ｎ ) wherein n is an integer from 1 to 50, for example an integer from 1 to 4, from 1 to 3 or from 1 to 2. The pharmaceutical composition according to claim 1 or 2, comprising one or more parts individually selected from the above.

13. The GIPR antagonist GIP peptide is EGTFISEYSIAibLEKIK(C16-diacid / 18K)QQEFVEVWLLAQQKPSSGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIK(2xAEEAc + yGlu-C18-diacid / 18K)QQEFVEVWLLAQQKPSSGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIK(C16-diacid / 18K)QQEFVEVWLLAQQKPSSGAPPPPS; SEQ ID NO: 7; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIK(2xAEEAc + yGlu-C18-diacid / 18K)QQEFVEVWLLAQQKPSSGAPPPPS; SEQ ID NO: 7; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIALEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS; SEQ ID NO: 8; GIP(3-30)+Cex(31-39)[D9E; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIANleEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS; SEQ ID NO: 9; GIP(3-30)+Cex(31-39)[D9E; M14Nle; D15E; H18K; D21E N24E], XGTFISEYSIAibLEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS; SEQ ID NO: 11; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS; SEQ ID NO: 12; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], XGTFISEYSIALEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS-OH; SEQ ID NO: 13; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibMEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS; SEQ ID NO: 14; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAibMEKIK(2xAEAc + yGlu-C18-diacid / 18K)QQEFVEWLLAQQKPSGGAPPPPS; SEQ ID NO: 15; GIP(3-30)+Cex(31-39)[D9E; A13Aib; D15E; H18K; D21E; N24E], EGTFISEYSIAMEKIK(2xAEEAc + yGlu-C18-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 16; GIP(3-30)+Cex(31-39)[D9E; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIK(2xAEEAc + yGlu-C18-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 11; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIK(2xAEEAc + yGlu-C18-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIK(C16-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 11; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIK(GGGS-C16-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIK(ALEAC16-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibNleEKIK(C16-diacid / 18K)QQEFVEVWLLAQQKPSGGAPPPPS); SEQ ID NO: 12; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIK (Aib-C16-diacid / 18K) QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibLEKIK (KAAAAEKAAAAEKAAAAE-C16-diacid / 18K) QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], XGTFISEYSIAibLEKIK (2xAEAc + yGlu-C18-diacid / 18K) QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 20; GIP(3-30)+Cex(31-39)[E3 succinic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E] and XGTFISEYSIAibLEKIK (2xAEAc + yGlu-C18-diacid / 18K) QQEFVEVWLLAQQKPSGGAPPPPS; SEQ ID NO: 21; GIP(3-30)+Cex(31-39)[E3 adipic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], A GIP(3-30)+Cex(31-39) selected from the above, or a functional variant thereof containing one, two or three individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) GIPR antagonist GIP peptide, the pharmaceutical composition according to claim 1 or 2.

14. A pharmaceutical composition containing a GIPR antagonist GIP peptide and a GLP-1 receptor agonist, separately or together, wherein the GIPR antagonist GIP peptide has the amino acid sequence GIP(3-30)+Cex(31-39) SEQ ID NO: 39: (wherein X １ is E, glutaric acid, adipic acid or succinic acid, and X ２ is M, L or Nle) Consisting of, or a functional GIP(3-30)+Cex(31-39) variant thereof, wherein the variant contains one, two or three individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 39, The GIPR antagonist GIP peptide is a pharmaceutical composition comprising a fatty acid molecule directly or via a linker bonded to the side-chain amino group of the 18th K amino acid residue (18K) of the GIP(3-30)+Cex(31-39) SEQ ID NO: 39 or its functional variant thereof.

15. The GIPR antagonist GIP peptide is EGTFISEYSIAbLEKIK(C16-dioic acid / 18K)QQEFVEVWLLAQQKPSSSGAPPPPS; SEQ ID NO: 6; GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or their functional variants containing 1, 2 or 3 individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 6, XGTFISEYSIAbLEKIK(C16-dioic acid / 18K)QQEFVEVWLLAQQKPSSSGAPPPPS; SEQ ID NO: 11; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], or their functional variants containing 1, 2 or 3 individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 11, and XGTFISEYSIAbNleEKIK(2xAEEA + yGlu-C18-dioic acid / 18K)QQEFVEVWLLAQQKPSSSGAPPPPS; SEQ ID NO: 12; GIP(3-30)+Cex(31-39)[E3 glutamic acid(X); D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], or their functional variants containing 1, 2 or 3 individual amino acid substitutions at any one of positions 4-8, 10-13, 16, 17, 19, 20, 22, 23, and 25-39 of the GIP(3-30)+Cex(31-39) SEQ ID NO: 12, selected from GIP(3-30)+Cex(31-39), The GLP-1 receptor agonist is liraglutide or semaglutide, the pharmaceutical composition according to claim 1 or 2 or the pharmaceutical composition according to claim 14.

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