BR-122025019469-A2 - Isolated peptide, isolated conjugate, pharmaceutical composition and method for preventing and treating congenital hyperinsulinism, pharmaceutical composition and method for preventing and treating hypoglycemia, pharmaceutical composition and method for preventing and treating metabolic syndrome.

BR122025019469A2BR 122025019469 A2BR122025019469 A2BR 122025019469A2BR-122025019469-A2

Abstract

The present invention relates to a glucagon derivative, a conjugate thereof, and a composition comprising the same, and a therapeutic use thereof, in particular for metabolic syndrome, hypoglycemia, and congenital hyperinsulinism.

Inventors

JUNG KUK KIM
YOUNG JIN PARK
IN YOUNG CHOI
SUNG YOUB JUNG

Assignees

HANMI PHARM. CO., LTD.

Dates

Publication Date: 20260317
Application Date: 20170629
Priority Date: 20160629

Claims (20)

1. Pharmaceutical composition for preventing and treating congenital hyperinsulinism characterized by comprising an isolated conjugate comprising a peptide chemical portion and a biocompatible chemical portion that is linked to the peptide chemical portion, wherein the peptide comprises the amino acid sequence of the following General Formula 2: Y-Aib-QGTF-X7-SD-X10-S-X12-Y-L-X15-X16-X17-R-A-X20-X21-F-V-X24-W-L-M-N-T-X30 (General Formula 2, SEQ ID NO: 46) wherein, in General Formula 2, X7 is threonine (T), valine (V) or cysteine (C); X10 is tyrosine (Y) or cysteine (C); X12 is lysine (K) or cysteine (C); X15 is aspartic acid (D) or cysteine (C); X16 is glutamic acid (E) or serine (S); X17 is lysine (K) or arginine (R); X20 is glutamine (Q) or lysine (K); X21 is aspartic acid (D) or glutamic acid (E); X24 is valine (V) or glutamine (Q); and X30 is cysteine (C) or is absent, provided that the amino acid sequence of General Formula 2 identical to SEQ ID NO: 2 is excluded.
2. Pharmaceutical composition for preventing or treating congenital hyperinsulinism characterized by comprising an isolated conjugate comprising a peptide chemical portion and a biocompatible chemical portion that is the same as the peptide chemical portion, wherein the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 11, 13 to 15 and 18 to 44.
3. Pharmaceutical composition, according to claim 1, characterized by the peptide comprising an amino acid sequence selected from the group consisting of sequence IDs NOS: 13, 15 and 36 to 44.
4. Pharmaceutical composition, according to claim 1, characterized in that the chemical portion of biocompatible material is selected from the group consisting of a polymer, fatty acid, cholesterol, albumin and a fragment thereof, an albumin binding material, a polymer of repeating units of a particular amino acid sequence, an antibody, an antibody fragment, an FcRn binding material, in vivo connective tissue or a derivative thereof, a nucleotide, fibronectin, transferrin, a saccharide, heparin and elastin.
5. Pharmaceutical composition, according to claim 4, characterized by the FcRn binding material being a polypeptide comprising an Fc immunoglobulin region.
6. Pharmaceutical composition, according to claim 1, characterized by the chemical proportion of peptide and the chemical portion of biocompatible material being linked to each other through a ligand.
7. Pharmaceutical composition, according to claim 6, characterized in that the ligand is selected from the group consisting of a peptide, a fatty acid, a saccharide, a polymer, a low molecular weight compound, a nucleotide and a combination thereof.
8. Pharmaceutical composition, according to claim 7, characterized by the polymer being selected from the group consisting of a polyethylene glycol, polypropylene glycol, an ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, a polysaccharide, dextran, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, chitin, hyaluronic acid, an oligonucleotide and a combination thereof.
9. Pharmaceutical composition according to claim 5, characterized in that the immunoglobulin Fc region is an IgG4 Fc region.
10. Pharmaceutical composition, according to claim 9, characterized in that the Fc immunoglobulin region is an aglycosylated Fc region derived from human IgG4.
11. Pharmaceutical composition, according to claim 6, characterized by the ligand being linked to a residue of the peptide chemical moiety.
12. Pharmaceutical composition, according to claim 6, characterized by the ligand being respectively linked to the peptide chemical portion and to the biocompatible material chemical portion through covalent bonds, which are respectively formed by reacting one end of the ligand with an amine group or thiol group of the biocompatible material chemical portion and reacting the other end of the ligand with an amine group or thiol group of the peptide chemical portion.
13. Pharmaceutical composition, according to claim 2, characterized by the peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 13, 15 and 36 to 44.
14. Pharmaceutical composition, according to claim 2, characterized by the biocompatible material being selected from the group consisting of polyethylene glycol, fatty acid, cholesterol, albumin and a fragment thereof, an albumin binding material, a polymer of repeating units of a specific amino acid sequence, an antibody, an antibody fragment, an FcRn binding material, in vivo connective tissue or a derivative thereof, a nucleotide, fibronectin, transferrin, a saccharide and a polymer.
15. Pharmaceutical composition, according to claim 14, characterized by the FcRn binding material being a polypeptide comprising an Fc immunoglobulin region.
16. Pharmaceutical composition, according to claim 2, characterized in that the peptide chemical portion and the biocompatible material portion are covalently linked to each other through a ligand.
17. Pharmaceutical composition, according to claim 16, characterized in that the ligand is selected from the group consisting of a peptide, a fatty acid, a saccharide, a polymer, a low molecular weight compound, a nucleotide and a combination thereof.
18. Pharmaceutical composition, according to claim 17, characterized by the polymer being selected from the group consisting of polyethylene glycol, polypropylene glycol, an ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, chitins, hyaluronic acid, an oligonucleotide and a combination thereof.
19. Pharmaceutical composition according to claim 17, characterized in that the immunoglobulin Fc region is an IgG4 Fc region.
20. Pharmaceutical composition, according to claim 19, characterized in that the Fc immunoglobulin region is an aglycosylated Fc region derived from human IgG4.

Description

FIELD OF TECHNIQUE [001] The present invention relates to a glucagon derivative, a conjugate thereof, and a composition containing the same, and a use thereof, in particular, a therapeutic use thereof for metabolic syndrome, hypoglycemia and congenital hyperinsulinism. BACKGROUND OF THE INVENTION [002] Due to recent economic growth and changes in dietary habits, etc., the incidence of diseases associated with metabolic syndrome, which includes several diseases such as obesity, hyperlipidemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, and liver diseases, is rapidly increasing. These diseases can occur independently, but in general, they mostly occur in close relation to each other, being accompanied by various symptoms. [003] Overweight and obesity are responsible for increasing blood pressure and cholesterol levels and causing or worsening various diseases, such as heart disease, diabetes, arthritis, etc. In addition, the problem of obesity is also becoming a major cause of the increased incidence of arteriosclerosis, hypertension, hyperlipidemia, or heart disease in children or adolescents as well as in adults. [004] However, obesity is not easy to treat, due to the fact that it is a complex disease associated with the mechanisms of appetite control and energy metabolism. Consequently, the treatment of obesity requires not only the efforts of obese patients but also a method capable of treating abnormal mechanisms associated with appetite control and energy metabolism. Thus, efforts have been made to develop drugs to treat these abnormal mechanisms. [005] As a result of these efforts, drugs such as Rimonabant® (Sanofi-Aventis), Sibutramine® (Abbott), Contrave® (Takeda) and Orlistat® (Roche) have been developed, however, they have the disadvantages of serious adverse effects or very weak anti-obesity effects. For example, according to reports, Rimonabant® shows a side effect of central nervous system disorder, Sibutramine® and Contrave® show cardiovascular side effects and Orlistat® shows only about 4 kg of weight loss when used for 1 year. [006] Meanwhile, glucagon is produced by the pancreas when blood glucose levels fall as a result of other medications or diseases or hormonal or enzyme deficiencies. Glucagon sends a signal for glycogen breakdown in the liver and a subsequent release of glucose and plays a role in raising blood glucose levels to a normal range. Additionally, glucagon has been shown to be effective in treating hypoglycemia. The hypoglycemic therapeutic effect of glucagon results from stimulating the breakdown of glycogen into glucose (glycogen breakdown) or increasing glucose production (glucose biosynthesis) derived from amino acid precursors, resulting in increased glucose outflow from the liver. [007] In addition to increasing blood glucose levels, glucagon inhibits appetite and activates hormone-sensitive lipase in adipocytes to facilitate lipolysis, thus showing an anti-obesity effect. However, the use of glucagon as a therapeutic agent has been limited due to its low solubility and its property of being precipitated at a neutral pH. [008] Consequently, glucagon with enhanced properties alone can be used effectively for the treatment of severe hypoglycemia, non-alcoholic steatohepatitis (NASH), dyslipidemia, etc. due to its fat breakdown and e-oxidation activities in the liver. [009] One of the glucagon derivatives, glucagon-like peptide 1 (GLP-1), is under development as a therapeutic agent to treat hyperglycemia in patients with diabetes. GLP-1 has the functions of stimulating insulin synthesis and secretion, inhibiting glucagon secretion, slowing gastric emptying, increasing glucose utilization, and inhibiting food intake. [010] Exendin-4, prepared from lizard venom and having approximately 50% amino acid homology with GLP-1, has been reported to also activate the GLP-1 receptor, thereby improving hyperglycemia in diabetic patients (J Biol Chem. April 15, 1992; 267(11): 7402-7405). However, anti-obesity drugs containing GLP-1 have been reported to show side effects such as vomiting and nausea. [011] Therefore, as an alternative to GLP-1, much attention has been given to oxyntomodulin, which can bind to both receptors of the two peptides, GLP-1 and glucagon. Oxyntomodulin is a peptide prepared from a glucagon precursor, pre-glucagon, and has the functions of inhibiting food intake and intensifying satiety of GLP-1 and has lipolytic activity like glucagon, thus increasing its potency in anti-obesity therapy. [012] However, oxyntomodulin or its derivatives have a serious disadvantage in that an excessive amount of the drug must be administered daily due to their low efficacy and short in vivo half-life. Additionally, when both GLP-1 and glucagon activities are present in a single peptide, their activity ratio becomes fixed, making it difficult to use a dual agonist with multiple ratios. Consequently, combination therapy capable of using multiple activity ratios by a