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WO2020214012A1 - Composition pharmaceutique préventive ou thérapeutique contre l'hyperlipidémie comprenant un triple agoniste agissant sur tous les récepteurs du glucagon, du glp-1 et du gip, ou conjugué de ceux-ci, et procédé préventif ou thérapeutique - Google Patents

Composition pharmaceutique préventive ou thérapeutique contre l'hyperlipidémie comprenant un triple agoniste agissant sur tous les récepteurs du glucagon, du glp-1 et du gip, ou conjugué de ceux-ci, et procédé préventif ou thérapeutique Download PDF

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Publication number
WO2020214012A1
WO2020214012A1 PCT/KR2020/005233 KR2020005233W WO2020214012A1 WO 2020214012 A1 WO2020214012 A1 WO 2020214012A1 KR 2020005233 W KR2020005233 W KR 2020005233W WO 2020214012 A1 WO2020214012 A1 WO 2020214012A1
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Prior art keywords
cysteine
glutamine
lysine
alanine
glutamic acid
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PCT/KR2020/005233
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English (en)
Korean (ko)
Inventor
조효상
김정국
이아람
김상윤
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • the present invention relates to the therapeutic use of a triple activator or a conjugate thereof having activity on both glucagon, GLP-1 and GIP receptors for hyperlipidemia.
  • Lipids typically include cholesterol and triglycerides, and cholesterol is divided into low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • a condition in which cholesterol and triglyceride levels in the blood are out of the normal range (including both increase and decrease) and hypercholesterolemia a condition in which total cholesterol is high in the blood, hyperlipidemia is It is a disease that is a generic term for a case in which one or both of low-density lipoprotein cholesterol or triglycerides is high, and is a disease that is distinguished from dyslipidemia and hypercholesterolosis.
  • the pathogenesis and the patient's condition are different from each other, and different treatment and diet control methods are required.
  • it is a disease caused by abnormal regulation of lipid levels in the body, and abnormally low cholesterol levels can be a problem in dyslipidemia.
  • cholesterol levels essential for biological activities through dietary regimens such as dietary supplements It is important to increase.
  • cardiovascular disease and cerebrovascular disease are the three major causes of death in Korea along with cancer.
  • Hyperlipidemia is increasing as the obese population increases due to Western-style eating habits, and the number of hyperlipidemia patients is increasing by about 10% each year in Korea. It is known that obesity and alcohol are the causes of such hyperlipidemia. Obesity is the biggest etiology among them.
  • statin which acts as an HMGCR (HMG-CoA reductase) inhibitor and has an effect of inhibiting the synthesis of cholesterol
  • NPC1L1 Niemann-Pick C1-Like 1
  • Ezetimibe, and evolocumab which inhibits PCSK9 (Proprotein convertase subtilisin/kexin type 9), which interferes with LDL absorption, has been developed and is being used as a therapeutic agent.
  • Ezetimibe has a disadvantage in that its efficacy in improving blood lipids in clinical practice is significantly lower than that of conventional drugs.
  • Evolocumab has been reported to be ineffective in patients with genetic mutations in LDLR (LDL receptor).
  • LDLR LDL receptor
  • GLP-1 Glucagon-like peptide-1
  • GIP Glucose-dependent insuliontropic polypeptide
  • GLP-1 is a hormone secreted from the small intestine when stimulated by food intake. It promotes the secretion of insulin in the pancreas in a blood sugar concentration-dependent manner and helps to lower blood sugar levels. In addition, it acts as a satiety factor, slowing the digestion of the stomach and delaying the passage time of food digests, thereby reducing food intake. Moreover, when administered to rats, it was reported that there was an effect of inhibiting food intake and reducing weight, and these effects were found to be the same in both normal and obese states, showing the potential as a treatment for obesity.
  • GIP GIP
  • ApoB48 Apolipoprotein B
  • Glucagon is produced by the pancreas when blood sugar starts to drop due to drug treatment, disease, or hormone or enzyme deficiency. Glucagon signals the liver to break down glycogen to induce glucose to be released, and to raise blood sugar levels to normal levels. In addition, it has been reported that glucagon can suppress appetite, brown fat cells, and promote energy expenditure in animals and humans in addition to synergistic effects on blood sugar.
  • One object of the present invention is for the prevention or treatment of hyperlipidemia comprising a peptide or conjugate having activity against a glucagon receptor, a GLP-1 (Glucagon-like peptide-1) receptor, and a GIP (Glucose-dependent insuliontropic polypeptide) receptor. It is to provide a pharmaceutical composition.
  • Another object of the present invention is to provide a method for preventing or treating hyperlipidemia, comprising administering the peptide, conjugate, or composition containing the same to an individual in need thereof.
  • Another object of the present invention is to provide the use of the peptide, conjugate or a composition comprising the same in the manufacture of a medicament for the prevention or treatment of hyperlipidemia.
  • One aspect embodying the present invention is for the prevention or treatment of hyperlipidemia comprising a peptide having activity against a glucagon receptor, a GLP-1 (Glucagon-like peptide-1) receptor, and a GIP (Glucose-dependent insuliontropic polypeptide) receptor. It is a pharmaceutical composition.
  • the amino acid sequence added from the peptide is characterized in that it is derived from a native GLP-1, a native GIP, or a native exendin-4 amino acid sequence.
  • the peptide is characterized in that it is a peptide comprising an amino acid sequence represented by the following general formula 1:
  • Xaa1 is histidine (His, H), 4-imidazoacetyl (CA), or tyrosine (Tyr, Y)
  • Xaa2 is glycine (Gly, G), alpha-methyl-glutamic acid, or Aib (aminoisobutyric acid)
  • Xaa3 is glutamic acid (Glu, E) or glutamine (Gln, Q)
  • Xaa7 is threonine (Thr, T) or isoleucine (Ile, I)
  • Xaa10 is leucine (Leu, L), tyrosine (Tyr, Y), lysine (Lys, K), cysteine (Cys, C), or valine (Val, V)
  • Xaa12 is lysine (Lys, K), serine (Ser, S), or isoleucine (Ile, I)
  • Xaa13 is glutamine (Gln, Q),
  • R1 is cysteine (Cys, C), GKKNDWKHNIT (SEQ ID NO: 106), m-SSGAPPPS-n (SEQ ID NO: 107), or m-SSGQPPPS-n (SEQ ID NO: 108), or absent, wherein m is -Cys- , -Pro-, or -Gly-Pro-, and n is -Cys-, -Gly-, -Ser-, or -His-Gly-, or it is characterized in that it does not exist.
  • the peptide is characterized in that in the general formula 1, Xaa14 is leucine or methionine, and Xaa15 is cysteine, aspartic acid, or leucine.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 Is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, glutamine, or cysteine
  • Xaa14 is leucine, cysteine, or methionine
  • Xaa15 is cysteine, leucine, glutamic acid, or aspartic acid
  • Xaa17 is glutamine, arginine, isoleucine, cysteine.
  • Xaa18 is alanine, glutamine, arginine, or histidine
  • Xaa19 is alanine, glutamine, valine, or cysteine
  • Xaa20 is lysine, arginine, or glutamine
  • Xaa21 is glutamic acid, glutamine, leucine, cysteine , Or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, alanine, glutamine, asparagine, glutamic acid, or aspartic acid
  • Xaa27 is leucine or lysine.
  • the peptide is characterized in that it is a peptide comprising an amino acid sequence represented by the following general formula 2.
  • Xaa1 is 4-imidazoacetyl, histidine, or tyrosine
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa10 is tyrosine, or cysteine
  • Xaa13 is alanine, glutamine, tyrosine, Or cysteine
  • Xaa14 is leucine, methionine, or tyrosine
  • Xaa15 is aspartic acid, glutamic acid, or leucine
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine, arginine, isoleucine, glutamic acid, cysteine, or lysine.
  • Xaa18 is alanine, glutamine, arginine, or histidine
  • Xaa19 is alanine, glutamine, cysteine, or valine
  • Xaa20 is lysine, glutamine, or arginine
  • Xaa21 is cysteine, glutamic acid, glutamine, leucine, or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, alanine, glutamine, asparagine, or glutamic acid
  • Xaa28 is lysine, cysteine, asparagine, or aspartic acid
  • Xaa29 is glycine, glutamine, cysteine, or histidine
  • Xaa30 is cysteine, Glycine, lysine, or histidine
  • Xaa31 is proline or cysteine
  • Xaa40 is cysteine or absent.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 Is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa17 is glutamine
  • Xaa18 is alanine, arginine.
  • Xaa19 is alanine, glutamine, or cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid, cysteine, or aspartic acid
  • Xaa23 is valine
  • Xaa24 is alanine, glutamine, cysteine, asparagine, or aspartic acid. It is an acid
  • Xaa27 is characterized in that it is leucine or lysine.
  • Xaa13 is alanine, tyrosine, or cysteine
  • Xaa15 is aspartic acid or glutamic acid
  • Xaa17 is glutamine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa21 is cysteine, glutamic acid, glutamine, or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, glutamine, or asparagine
  • Xaa28 is cysteine, asparagine, or aspartic acid
  • Xaa29 is glutamine, cysteine, or histidine
  • Xaa30 is cysteine, lysine, or histidine.
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine or cysteine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is arginine
  • Xaa18 is alanine, arginine, or histidine.
  • Xaa19 is alanine, glutamine, or cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa23 is valine
  • Xaa24 is glutamine, asparagine, or aspartic acid
  • Xaa27 is leucine
  • Xaa28 is It is characterized in that it is cysteine, alanine, asparagine, or aspartic acid.
  • Xaa10 is tyrosine
  • Xaa12 is isoleucine
  • Xaa13 is alanine or cysteine
  • Xaa14 is methionine
  • Xaa15 is aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is isoleucine or lysine
  • Xaa18 is alanine or histidine
  • Xaa20 is lysine
  • Xaa21 is aspartic acid
  • Xaa23 is valine
  • Xaa24 is asparagine
  • Xaa27 is leucine
  • Xaa28 is alanine or asparagine
  • Xaa29 is glutamine or threonine
  • Xaa30 is cysteine or It is characterized by being lysine or absent.
  • the peptide is characterized in that it is a peptide comprising the amino acid sequence of the following general formula 3.
  • Xaa1 is histidine or tyrosine
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa13 is alanine, tyrosine or cysteine
  • Xaa17 is arginine, cysteine, or lysine
  • Xaa18 is alanine or arginine
  • Xaa19 is alanine or cysteine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa24 is glutamine or asparagine
  • Xaa28 is cysteine or aspartic acid
  • Xaa29 is cysteine, histidine, or glutamine
  • Xaa30 is cysteine or histidine
  • Xaa31 is proline Or cysteine
  • Xaa40 is cysteine or absent.
  • composition wherein the peptide is a cysteine, GKKNDWKHNIT (SEQ ID NO: 106), CSSGQPPPS (SEQ ID NO: 109), GPSSGAPPPS (SEQ ID NO: 110), GPSSGAPPPSC (SEQ ID NO: 111), PSSGAPPPS (SEQ ID NO: Number 112), PSSGAPPPSG (SEQ ID NO: 113), PSSGAPPPSHG (SEQ ID NO: 114), PSSGAPPPSS (SEQ ID NO: 115), PSSGQPPPS (SEQ ID NO: 116), or PSSGQPPPSC (SEQ ID NO: 117), or absent.
  • GKKNDWKHNIT SEQ ID NO: 106
  • CSSGQPPPS SEQ ID NO: 109
  • GPSSGAPPPS SEQ ID NO: 110
  • GPSSGAPPPSC SEQ ID NO: 111
  • PSSGAPPPS SEQ ID NO: Number 112
  • PSSGAPPPSG SEQ ID NO: 113
  • PSSGAPPPSHG SEQ
  • composition according to any one of the preceding embodiments, wherein the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 102.
  • composition according to any one of the preceding embodiments, wherein the peptide is amidated at its C-terminus.
  • composition according to any one of the preceding embodiments, wherein the pharmaceutical composition has any one or more of an effect of increasing LDL absorption, inhibiting 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) activity, and promoting fatty acid degradation. To do.
  • HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase
  • Another aspect embodying the present invention is a pharmaceutical composition for the prevention or treatment of hyperlipidemia comprising a conjugate comprising the peptide.
  • the conjugate may be characterized in that it is represented by the following Formula 1:
  • X is a peptide having activity against the glucagon receptor, GLP-1 receptor, and GIP receptor,
  • L is polyethylene glycol
  • a is 0 or a natural number, provided that when a is 2 or more, each L is independent of each other,
  • F is an immunoglobulin Fc region.
  • the peptide is characterized in that it is a peptide comprising an amino acid sequence represented by the following general formula 1:
  • Xaa1 is histidine (His, H), 4-imidazoacetyl (CA), or tyrosine (Tyr, Y),
  • Xaa2 is glycine (Gly, G), alpha-methyl-glutamic acid, or Aib (aminoisobutyric acid),
  • Xaa3 is glutamic acid (Glu, E) or glutamine (Gln, Q),
  • Xaa7 is threonine (Thr, T) or isoleucine (Ile, I),
  • Xaa10 is leucine (Leu, L), tyrosine (Tyr, Y), lysine (Lys, K), cysteine (Cys, C), or valine (Val, V),
  • Xaa12 is lysine (Lys, K), serine (Ser, S), or isoleucine (Ile, I),
  • Xaa13 is glutamine (Gln, Q), tyrosine (Tyr, Y), alanine (Ala, A), or cysteine (Cys, C),
  • Xaa14 is leucine (Leu, L), methionine (Met, M), or tyrosine (Tyr, Y),
  • Xaa15 is cysteine (Cys, C), aspartic acid (Asp, D), glutamic acid (Glu, E), or leucine (Leu, L),
  • Xaa16 is glycine (Gly, G), glutamic acid (Glu, E), or serine (Ser, S),
  • Xaa17 is glutamine (Gln, Q), arginine (Arg, R), isoleucine (Ile, I), glutamic acid (Glu, E), cysteine (Cys, C), or lysine (Lys, K),
  • Xaa18 is alanine (Ala, A), glutamine (Gln, Q), arginine (Arg, R), or histidine (His, H),
  • Xaa19 is alanine (Ala, A), glutamine (Gln, Q), cysteine (Cys, C), or valine (Val, V),
  • Xaa20 is lysine (Lys, K), glutamine (Gln, Q), or arginine (Arg, R),
  • Xaa21 is glutamic acid (Glu, E), glutamine (Gln, Q), leucine (Leu, L), cysteine (Cys, C), or aspartic acid (Asp, D),
  • Xaa23 is isoleucine (Ile, I) or valine (Val, V),
  • Xaa24 is alanine (Ala, A), glutamine (Gln, Q), cysteine (Cys, C), asparagine (Asn, N), aspartic acid (Asp, D), or glutamic acid (Glu, E),
  • Xaa27 is valine (Val, V), leucine (Leu, L), lysine (Lys, K), or methionine (Met, M),
  • Xaa28 is cysteine (Cys, C), lysine (Lys, K), alanine (Ala, A), asparagine (Asn, N), or aspartic acid (Asp, D),
  • Xaa29 is cysteine (Cys, C), glycine (Gly, G), glutamine (Gln, Q), threonine (Thr, T), glutamic acid (Glu, E), or histidine (His, H),
  • Xaa30 is cysteine (Cys, C), glycine (Gly, G), lysine (Lys, K), or histidine (His, H) or absent,
  • R1 is cysteine (Cys, C), GKKNDWKHNIT (SEQ ID NO: 106), m-SSGAPPPS-n (SEQ ID NO: 107), or m-SSGQPPPS-n (SEQ ID NO: 108), or absent,
  • m is -Cys-, -Pro-, or -Gly-Pro-,
  • n is -Cys-, -Gly-, -Ser-, or -His-Gly- or absent.
  • the pharmaceutical composition is characterized in that it comprises a conjugate in which the peptide represented by the general formula 1 is bound to an immunoglobulin Fc region through polyethylene glycol.
  • composition according to any one of the preceding embodiments, wherein the pharmaceutical composition has any one or more of an effect of increasing LDL absorption, inhibiting 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) activity, and promoting fatty acid degradation. To do.
  • HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase
  • Another embodiment of the present invention is a method for preventing or treating hyperlipidemia, comprising administering the peptide, conjugate, or a composition containing the same to an individual in need thereof.
  • Another aspect embodying the present invention is the use of the peptide, conjugate, or a composition comprising the same in the manufacture of a medicament for the prevention or treatment of hyperlipidemia.
  • the triple activator long-acting conjugate according to the present invention has activity against the glucagon receptor, the GLP-1 (Glucagon-like peptide-1) receptor, and the GIP (Glucose-dependent insuliontropic polypeptide) receptor, and can be applied to the treatment of hyperlipidemia.
  • 1 is a diagram confirming in vivo the effect of treating hyperlipidemia of the triple activator long-acting conjugate of the present invention.
  • Figure 2 is a diagram confirming that LDL absorption is increased by the triple-active agent long-acting conjugate of the present invention.
  • HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase
  • Figure 4 is a diagram confirming the effect of promoting fatty acid decomposition of the triple active substance long-acting conjugate of the present invention.
  • One aspect for embodying the present invention is the prevention of hyperlipidemia, including a peptide having activity against glucagon receptor, GLP-1 (Glucagon-like peptide-1) receptor, and GIP (Glucose-dependent insuliontropic polypeptide) receptor Or a therapeutic pharmaceutical composition.
  • hyperlipidemia including a peptide having activity against glucagon receptor, GLP-1 (Glucagon-like peptide-1) receptor, and GIP (Glucose-dependent insuliontropic polypeptide) receptor Or a therapeutic pharmaceutical composition.
  • the triple activator of the present invention is characterized by having a therapeutic or preventive effect on hyperlipidemia.
  • hyperlipidemia unlike dyslipidemia, in which cholesterol and triglyceride levels in the blood are out of the normal range (including both increase and decrease) and hypercholesterolemia, in which total cholesterol in the blood is high, is low-density lipoprotein in the blood. It is a disease that is a generic term for a case in which one or both of cholesterol or triglycerides is high, and is a disease distinguished from dyslipidemia and hypercholesterolosis.
  • glucagon receptor GLP-1 receptor
  • peptide having activity against the GIP receptor may be used interchangeably as a triple activator in the present invention.
  • Such peptides include various substances, such as various peptides, with significant levels of activity against glucagon, GLP-1, and GIP receptors.
  • the triple activator having a significant level of activity against glucagon, GLP-1, and GIP receptors is one or more of glucagon, GLP-1, and GIP receptors, specifically two or more. More receptors, more specifically, in vitro activity against all three receptors is 0.1% or more, 1% or more, 2% compared to the natural ligands of the receptor (natural glucagon, natural GLP-1, and natural GIP).
  • a method of measuring the in vitro activity of such a triple activator may refer to Experimental Example 1 of the present specification, but is not particularly limited thereto.
  • the peptide is characterized by having one or more, two or more, specifically three activities, specifically significant activities of the following i) to iii):
  • activating the receptor means that the in vitro activity against the receptor is 0.1% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% or more An example is the case. However, it is not limited thereto.
  • the composition according to the present invention contains an isolated peptide having activity against a glucagon receptor, a GLP-1 (Glucagon-like peptide-1) receptor, and a GIP (Glucose-dependent insuliontropic polypeptide) receptor, thereby increasing LDL absorption and synthesizing cholesterol. It may exhibit an effect of any one or more of the inhibitory and fatty acid decomposition promoting effects, thereby exhibiting an excellent therapeutic effect for hyperlipidemia. For example, the activity of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) 24 to 48 hours after administration of the composition may be less than 50%.
  • HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase
  • the peptide may have an increased half-life in the body compared to any one of natural GLP-1, natural glucagon, and natural GIP, but is not particularly limited thereto.
  • such a peptide may be non-naturally occurring.
  • the isolated peptide may be an analog of natural glucagon, but is not particularly limited thereto.
  • the natural-type glucagon analog according to the present invention includes a peptide having one or more differences in amino acid sequence compared to the natural-type glucagon, a peptide modified through modification of the natural-type glucagon sequence, and a mimic of natural-type glucagon.
  • the native glucagon may have the following amino acid sequence:
  • the peptide is selected from the group consisting of substitution, addition, deletion, modification, and combinations thereof in at least one amino acid in the natural glucagon sequence. It may be an analog of glucagon, but is not particularly limited thereto.
  • substitution of the amino acid includes both substitution with amino acids and substitution with non-natural compounds.
  • addition may be made at the N-terminus and/or C-terminus of the peptide.
  • the length of the added amino acid is not particularly limited thereto, and 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 or more amino acids are added It may be, and broadly includes the addition of a polypeptide, but is not particularly limited thereto.
  • the glucagon analog is 1 times, 2 times, 3 times, 7 times, 10 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times in the natural glucagon amino acid sequence, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, selected from the group consisting of 19 times, 20 times, 21 times, 23 times, 24 times, 27 times, 28 times and 29 times, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 amino acids may be substituted with other amino acids,
  • 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 or more amino acids may be added to the C-terminus thereof. However, it is not particularly limited thereto.
  • the glucagon analog is 1, 2, 3, 10, 12, 13, 14, 15, 16, 17, 18, 19, in the natural glucagon amino acid sequence, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, selected from the group consisting of 20, 21, 23, 24, 27, 28 and 29, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, or 19 amino acids may be substituted with other amino acids, and independently or additionally 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 or more amino acids may be added to the C-terminus, but is particularly limited thereto It is not.
  • the glucagon analog is 1, 2, 3, 10, 13, 14, 15, 16, 17, 18, 19, 20, in the natural glucagon amino acid sequence, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, selected from the group consisting of 21 times, 23 times, 24 times, 28 times and 29 times, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, or 17 amino acids may be substituted with other amino acids, and also independently or additionally at the C-terminus of 1 or more, 2 or more, 3 or more , 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 or more amino acids may be added, but is not particularly limited thereto.
  • the glucagon analog is 1, 2, 13, 16, 17, 18, 19, 20, 21, 23, 24, 27, in the natural glucagon amino acid sequence, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, selected from the group consisting of 28 and 29, Or 14 amino acids may be substituted with other amino acids, and independently or additionally at the C-terminus of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more , 10 or more, or 11 or more amino acids may be added, but is not particularly limited thereto.
  • amino acids introduced from the natural glucagon are tyrosine, alpha-methyl-glutamic acid, Aib, methionine, glutamic acid, histidine, lysine, leucine, isoleucine, glutamine, valine, glycine, alanine, cysteine, serine, alanine, aspartic acid, and arginine. It may be selected from the group consisting of, but is not particularly limited thereto.
  • the added amino acid sequence may be one or more amino acid sequences derived from native GLP-1, native GIP, or native exendin-4 amino acid sequence.
  • glucagon analogs or triple activators may include intramolecular bridges (e.g., covalent bridges or non-covalent bridges), and specifically may be in a form including a ring, such as glucagon analogs or triples.
  • a ring may be formed between amino acids 16 and 20 of the active substance, but is not particularly limited thereto.
  • Non-limiting examples of the ring may include a lactam bridge (or a lactam ring).
  • the glucagon analogue or triple activator includes all those modified to include an amino acid capable of forming a ring at a desired position to include a ring.
  • the pair of amino acids 16 and 20 of the glucagon analog or triple activator may be substituted with glutamic acid or lysine capable of forming a ring, but is not limited thereto.
  • Such a ring may be formed between the side chains of amino acids in the glucagon analog or triple activator, for example, a lactam ring may be formed between the side chain of lysine and the side chain of glutamic acid, but is not particularly limited thereto.
  • an analogue of glucagon prepared by a combination of these methods, in which one or more amino acid sequences are different from natural glucagon, and the alpha-carbon of the N-terminal amino acid residue has been removed, glucagon receptor, GLP-1 receptor, and GIP receptor.
  • glucagon receptor GLP-1 receptor
  • GIP receptor GIP receptor
  • amino acids may be substituted with other amino acids or non-natural compounds in order to avoid the recognition of activator decomposing enzymes to increase half-life in the body.
  • it may be a peptide having an increased half-life in the body by avoiding the recognition of a degrading enzyme through substitution of the second amino acid sequence of the amino acid sequence of the triple active agent, but amino acid substitution or Changes are included without limitation.
  • modifications for the production of analogs of natural glucagon include modifications using L-type or D-type amino acids, and/or non-natural amino acids; And/or by modifying the native sequence, for example, modification of side chain functional groups, intramolecular covalent bonds, such as inter-side chain ring formation, methylation, acylation, ubiquitination, phosphorylation, aminohexanation, biotinylation, etc. It includes everything you do.
  • substituted or added amino acids not only the 20 amino acids commonly observed in human proteins, but also atypical or non-naturally occurring amino acids may be used.
  • Commercial sources of atypical amino acids include Sigma-Aldrich, ChemPep and Genzyme pharmaceuticals. Peptides containing such amino acids and typical peptide sequences can be synthesized and purchased through commercial peptide synthesis companies, such as American peptide company or Bachem in the US, or Anygen in Korea.
  • Amino acid derivatives can also be obtained in the same way, and to name only some examples, 4-imidazoacetic acid or the like can be used.
  • the peptide according to the present invention has its N-terminus and/or C-terminus chemically modified or protected with an organic terminal in order to protect from protein cleavage enzymes in vivo and increase stability, or amino acid is added to the peptide terminal. It may be added and modified.
  • the N-terminus is acetylated and/or the C-terminus is amidated to remove such charge. It can be, but is not particularly limited thereto.
  • the peptide according to the present invention includes the peptide itself, a salt thereof (eg, a pharmaceutically acceptable salt of the peptide), or a solvate thereof.
  • the peptide may be in any pharmaceutically acceptable form.
  • the kind of the salt is not particularly limited. However, it is preferable that it is a safe and effective form for individuals, such as mammals, but is not particularly limited thereto.
  • pharmaceutically acceptable refers to a substance that can be effectively used for a desired purpose without causing excessive toxicity, irritation, or allergic reaction within the scope of medical judgment.
  • the term "pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
  • suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid.
  • Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid may include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.
  • solvate refers to the formation of a complex with a solvent molecule of the peptide or salt thereof according to the present invention.
  • the peptide may include an amino acid sequence represented by the following general formula 1.
  • Xaa1 is histidine, 4-imidazoacetyl, or tyrosine
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa3 is glutamic acid or glutamine
  • Xaa7 is threonine or isoleucine
  • Xaa10 is Leucine, tyrosine, lysine, cysteine, or valine
  • Xaa12 is lysine, serine, or isoleucine
  • Xaa13 is glutamine, tyrosine, alanine, or cysteine
  • Xaa14 is leucine, methionine, or tyrosine
  • Xaa15 is cysteine, aspartic acid.
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine, arginine, isoleucine, glutamic acid, cysteine, or lysine
  • Xaa18 is alanine, glutamine, arginine, or histidine
  • Xaa19 is alanine, glutamine , Cysteine, or valine
  • Xaa20 is lysine, glutamine, or arginine
  • Xaa21 is glutamic acid, glutamine, leucine, cysteine, or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is alanine, glutamine, cysteine, asparagine, aspartic acid.
  • Xaa27 is valine, leucine, lysine, or methionine
  • Xaa28 is cysteine, lysine, alanine, asparagine, or aspartic acid
  • Xaa29 is cysteine, glycine, glutamine, threonine, glutamic acid, or histidine
  • Xaa30 Is cysteine, glycine, lysine, or histidine, or is absent
  • R1 is cysteine, GKKNDWKHNIT (SEQ ID NO: 106), m-SSGAPPPS-n (SEQ ID NO: 107), or m-SSGQPPPS-n (SEQ ID NO: 108), or absent,
  • n is -Cys-, -Gly-, -Ser-, or -His-Gly-, or may be absent.
  • triple activator examples include those comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 102, and those consisting of (essentially) an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 102, but are limited thereto. It does not become.
  • Xaa14 may be leucine or methionine
  • Xaa15 may be cysteine, aspartic acid, or leucine.
  • a peptide examples include, but are not limited to, a peptide comprising or (essentially) an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 12, 14 to 17, and 21 to 102.
  • These peptides may significantly activate one or more of the glucagon receptor, the GLP-1 receptor, and the GIP receptor, but are not particularly limited thereto. Specifically, it may significantly activate GLP-1, or significantly activate the glucagon receptor and/or the GIP receptor, but is not particularly limited thereto.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine.
  • Xaa14 is leucine, cysteine, or methionine
  • Xaa15 is cysteine, leucine, glutamic acid, or aspartic acid
  • Xaa17 is glutamine, arginine, isoleucine, cysteine, glutamic acid, or lysine
  • Xaa18 is Alanine, glutamine, arginine, or histidine
  • Xaa19 is alanine, glutamine, valine, or cysteine
  • Xaa20 is lysine, arginine, or glutamine
  • Xaa21 is glutamic acid, glutamine, leucine, cysteine, or aspartic acid
  • Xaa23 is isoleucine.
  • Xaa24 is cysteine, alanine, glutamine, asparagine, glutamic acid, or aspartic acid
  • Xaa27 may be leucine or lysine, or a peptide, but is not particularly limited thereto.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine.
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa17 is glutamine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid, cysteine, or aspartic acid
  • Xaa23 is valine
  • Xaa24 is alanine, glutamine, cysteine, asparagine, or aspartic acid
  • Xaa27 is leucine or lysine.
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa7 is threonine
  • Xaa10 is tyrosine or cysteine
  • Xaa12 is lysine or isoleucine
  • Xaa13 is tyrosine, alanine, or cysteine.
  • Xaa14 is leucine or methionine
  • Xaa15 is cysteine or aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is arginine, isoleucine, cysteine, or lysine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine, glutamine, or Cysteine
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa23 is valine
  • Xaa24 is glutamine, asparagine, or aspartic acid
  • Xaa27 is leucine
  • Xaa28 is cysteine, alanine, asparagine, or aspartic acid.
  • I can.
  • Xaa1 is histidine or 4-imidazoacetyl
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa3 is glutamine
  • Xaa7 is threonine
  • Xaa10 is tyrosine
  • Xaa12 is isoleucine.
  • Xaa13 is alanine or cysteine
  • Xaa14 is methionine
  • Xaa15 is aspartic acid
  • Xaa16 is glutamic acid
  • Xaa17 is isoleucine or lysine
  • Xaa18 is alanine or histidine
  • Xaa19 is glutamine or cysteine
  • Xaa20 is lysine
  • Xaa21 is aspartic acid
  • Xaa23 is valine
  • Xaa24 is asparagine
  • Xaa27 is leucine
  • Xaa28 is alanine or asparagine
  • Xaa29 is glutamine or threonine
  • Xaa30 is cysteine or lysine, or may be absent.
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa3 is glutamine
  • Xaa7 is threonine
  • Xaa10 is tyrosine, cysteine, or valine
  • Xaa12 is lysine
  • Xaa13 Is tyrosine
  • Xaa14 is leucine
  • Xaa15 is aspartic acid
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine
  • Xaa18 is alanine, arginine, or histidine
  • Xaa19 is alanine.
  • Xaa20 is lysine or glutamine
  • Xaa21 is glutamic acid, cysteine, or aspartic acid
  • Xaa23 is valine
  • Xaa24 is alanine, glutamine, or cysteine
  • Xaa27 is leucine or lysine
  • Xaa29 is glycine, glutamine, It may be threonine or histidine, but is not particularly limited thereto.
  • These peptides have a significant degree of activation of the GLP-1 receptor and the glucagon receptor, and are higher than that of the GIP receptor;
  • the degree of activation of the GLP-1 receptor, the glucagon receptor, and the GIP receptor are all significant;
  • the degree of activation of the GLP-1 receptor and the GIP receptor is significant, and may correspond to a case that is higher than that of the glucagon receptor, but is not particularly limited thereto.
  • Examples of such peptides SEQ ID NO: 8, 9, 21 to 37, 39, 42, 43, 49 to 61, 64 to 83, 85, 86, 88, 89, 91 to 93, selected from the group consisting of 95 to 102 Peptides including or (essentially) composed of an amino acid sequence may be mentioned, but are not particularly limited thereto.
  • the peptide may include an amino acid sequence represented by the following general formula 2.
  • Xaa1 is 4-imidazoacetyl, histidine, or tyrosine
  • Xaa2 is glycine, alpha-methyl-glutamic acid, or Aib
  • Xaa10 is tyrosine or cysteine
  • Xaa13 is alanine, glutamine, tyrosine, or cysteine
  • Xaa14 is leucine, methionine, or tyrosine
  • Xaa15 is aspartic acid, glutamic acid, or leucine
  • Xaa16 is glycine, glutamic acid, or serine
  • Xaa17 is glutamine, arginine, isoleucine, glutamic acid, cysteine, or lysine
  • Xaa18 is alanine, glutamine, arginine, or histidine
  • Xaa19 is alanine, glutamine, cysteine, or valine
  • Xaa20 is
  • Xaa13 is alanine, tyrosine, or cysteine
  • Xaa15 is aspartic acid or glutamic acid
  • Xaa17 is glutamine, arginine, cysteine, or lysine
  • Xaa18 is alanine, Arginine, or histidine
  • Xaa21 is cysteine, glutamic acid, glutamine, or aspartic acid
  • Xaa23 is isoleucine or valine
  • Xaa24 is cysteine, glutamine, or asparagine
  • Xaa28 is cysteine, asparagine, or aspartic acid
  • Xaa29 is glutamine, cysteine, or histidine
  • Xaa30 can be cysteine, lysine, or histidine.
  • the peptide may include the amino acid sequence of the following general formula 3.
  • Xaa1 is histidine or tyrosine
  • Xaa2 is alpha-methyl-glutamic acid or Aib
  • Xaa13 is alanine, tyrosine or cysteine
  • Xaa17 is arginine, cysteine, or lysine
  • Xaa18 is alanine or arginine
  • Xaa19 is alanine or cysteine
  • Xaa21 is glutamic acid or aspartic acid
  • Xaa24 is glutamine or asparagine
  • Xaa28 is cysteine or aspartic acid
  • Xaa29 is cysteine, histidine, or glutamine
  • Xaa30 is cysteine or histidine
  • Xaa31 is proline or cysteine
  • Xaa40 may be cysteine or absent.
  • Such peptides include, or (essentially) a peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 22, 42, 43, 50, 64 to 71, 75 to 77, and 96 to 102. However, it is not particularly limited thereto.
  • R1 is cysteine, GKKNDWKHNIT (SEQ ID NO: 106), CSSGQPPPS (SEQ ID NO: 109), GPSSGAPPPS (SEQ ID NO: 110), GPSSGAPPPSC (SEQ ID NO: 111), PSSGAPPPS (SEQ ID NO: 112), PSSGAPPPSG (SEQ ID NO: 113), PSSGAPPPSHG (SEQ ID NO: 114), PSSGAPPPSS (SEQ ID NO: 115), PSSGQPPPS (SEQ ID NO: 116), or PSSGQPPPSC (SEQ ID NO: 117), or may be absent, but is not particularly limited thereto.
  • the peptide of the present invention can be synthesized by a method well known in the art, for example, an automatic peptide synthesizer, depending on its length, or can be produced by genetic engineering techniques.
  • the peptides of the present invention can be prepared by standard synthetic methods, recombinant expression systems, or any other art method.
  • the peptides according to the invention can be synthesized by a number of methods, including, for example, methods including:
  • the glucagon receptor, the GLP-1 receptor, and the peptide having an activity against the GIP receptor in vivo for increasing its half-life in vivo. It may be in the form of a combination, in which a suitable substance is combined.
  • the biocompatible material may be mixed with a carrier.
  • the conjugate of the peptide may exhibit increased persistence of potency compared to the peptide to which no carrier is bound, and in the present invention, the conjugate is referred to as a "persistent conjugate".
  • such a conjugate may be non-naturally occurring.
  • Another aspect for implementing the present invention comprises a conjugate comprising a peptide having activity against a glucagon receptor, a GLP-1 (Glucagon-like peptide-1) receptor, and a GIP (Glucose-dependent insuliontropic polypeptide) receptor.
  • a conjugate comprising a peptide having activity against a glucagon receptor, a GLP-1 (Glucagon-like peptide-1) receptor, and a GIP (Glucose-dependent insuliontropic polypeptide) receptor.
  • GLP-1 Glucagon-like peptide-1 receptor
  • GIP Glucose-dependent insuliontropic polypeptide
  • the conjugate is a conjugate represented by the following formula (1):
  • X is a peptide having activity against the glucagon receptor, GLP-1 receptor, and GIP receptor;
  • L is polyethylene glycol;
  • a is 0 or a natural number, provided that when a is 2 or more, each L is independent of each other;
  • F is an immunoglobulin Fc region.
  • Peptides having activity against X in the conjugate that is, glucagon receptor, GLP-1 receptor, and GIP receptor are as described above.
  • F is a substance capable of increasing the half-life of the peptide, having activity against X, that is, the glucagon receptor, the GLP-1 receptor, and the GIP receptor, and is a component of the moiety constituting the conjugate of the present invention. It corresponds.
  • the F may be bonded to each other by a covalent chemical bond or a non-covalent chemical bond with X, and F and X may be bonded to each other through L through a covalent chemical bond, a non-covalent chemical bond, or a combination thereof.
  • the immunoglobulin Fc region may specifically be an IgG Fc region, but is not particularly limited thereto.
  • One or more amino acid side chains in the peptides of the invention may be conjugated to such biocompatible materials to increase solubility and/or half-life and/or increase bioavailability in vivo. Such modifications can also reduce the clearance of therapeutic proteins and peptides.
  • the biocompatible material described above may be water-soluble (amphiphilic or hydrophilic) and/or non-toxic and/or pharmaceutically acceptable.
  • the F may be directly linked to X (ie, a is 0 in Formula 1), or linked through a linker (L).
  • L may be a non-peptidyl linker polyethylene glycol.
  • a may be 1 or more, and when a is 2 or more, each L may be independent.
  • the conjugate is shared with each other through a non-peptidyl linker including F at both ends, specifically an immunoglobulin Fc region and X, specifically a reactive group capable of binding to a peptide drug. It may be connected in combination.
  • the molecular weight of polyethylene glycol which is a non-peptidyl linker that can be used in the present invention, is in the range of 1 to 100 kDa, specifically 1 to 20 kDa, but is not limited thereto.
  • the non-peptidyl linker of the present invention bonded to the polypeptide corresponding to F may be a combination of different types of polymers as well as one type of polymer.
  • both ends of the non-peptidyl linker may be bonded to F, such as an amine group or thiol group of an immunoglobulin Fc region, and an amine group or thiol group of X.
  • the non-peptidyl polymer is a reactive group capable of binding to F (eg, immunoglobulin Fc region) and X at both ends, specifically X, or the N-terminus of F (eg, immunoglobulin Fc region) Or it may include a reactive group that can be bonded to the amine group located in the lysine or the thiol group of cysteine, but is not limited thereto.
  • the reactive group of the non-peptide polymer which may be bound to F, such as an immunoglobulin Fc region and X, may be selected from the group consisting of an aldehyde group, a maleimide group, and a succinimide derivative, but is not limited thereto.
  • the aldehyde group may be a propion aldehyde group or a butyl aldehyde group, but is not limited thereto.
  • the succinimide derivatives include succinimidyl valereate, succinimidyl methylbutanoate, succinimidyl methylpropionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccini Mid, hydroxy succinimidyl, succinimidyl carboxymethyl or succinimidyl carbonate may be used, but is not limited thereto.
  • the non-peptidyl linker may be connected to X and F through such a reactive group, but is not particularly limited thereto.
  • the final product produced by reductive amination by aldehyde bonds is much more stable than those linked by amide bonds.
  • the aldehyde reactor reacts selectively to the N-terminus at a low pH, and can form a covalent bond with a lysine moiety at a high pH, for example, pH 9.0.
  • the reactive groups at both ends of the non-peptidyl linker may be the same or different from each other, for example, a maleimide group at one end and an aldehyde group, a propion aldehyde group, or a butyl aldehyde group at the other end.
  • F, specifically immunoglobulin Fc region and X can be bonded to each end of the non-peptide linker, it is not particularly limited thereto.
  • one end of the non-peptide linker may include a maleimide group as a reactive group, and the other end may include an aldehyde group, a propion aldehyde group, or a butyl aldehyde group.
  • the hydroxy group may be activated with the various reactive groups by a known chemical reaction, or a polyethylene glycol having a commercially available modified reactive group may be used.
  • the long-acting protein conjugate of the invention can be prepared.
  • the non-peptide polymer may be linked to a cysteine residue of X, more specifically to a -SH group of cysteine, but is not limited thereto.
  • cysteine residue 10 cysteine 13
  • cysteine 15 cysteine 17, cysteine 19
  • cysteine 21 cysteine 24, cysteine 28, 29
  • the non-peptidyl polymer may be linked to a cysteine residue, a cysteine residue 30, a cysteine 31, a cysteine 40, or a cysteine 41, but is not particularly limited thereto.
  • a reactive group of a non-peptidyl polymer may be connected to the -SH group of the cysteine residue, and all of the above descriptions apply to the reactive group.
  • maleimide-PEG-aldehyde is used, the maleimide group is linked by a -SH group of X and a thioether bond, and the aldehyde group is F, specifically, a reductive amination reaction with the -NH 2 group of immunoglobulin Fc. It can be connected through, but is not limited thereto, and this corresponds to one example.
  • the reactive group of the non-peptide polymer may be linked to -NH 2 located at the N-terminus of the immunoglobulin Fc region, but this corresponds to one example.
  • the "immunoglobulin Fc region” refers to a region including a heavy chain constant region 2 (CH2) and/or a heavy chain constant region 3 (CH3) portion, excluding the heavy and light chain variable regions of an immunoglobulin.
  • the immunoglobulin Fc region may be a component constituting the moiety of the conjugate of the present invention.
  • Such an immunoglobulin Fc region may include a hinge portion in the heavy chain constant region, but is not limited thereto.
  • the immunoglobulin Fc region of the present invention has substantially the same or improved effect with the native type, part or all of the heavy chain constant region 1 (CH1) and/or light chain constant region except for the heavy and light chain variable regions of the immunoglobulin It may be an expanded Fc region comprising 1 (CL1). In addition, it may be a region from which some considerably long amino acid sequences corresponding to CH2 and/or CH3 have been removed.
  • the immunoglobulin Fc region of the present invention is 1) CH1 domain, CH2 domain, CH3 domain and CH4 domain, 2) CH1 domain and CH2 domain, 3) CH1 domain and CH3 domain, 4) CH2 domain and CH3 domain, 5) Combination of one or two or more domains of the CH1 domain, CH2 domain, CH3 domain, and CH4 domain with an immunoglobulin hinge region (or part of the hinge region), 6) heavy chain constant region It may be a dimer of each domain and light chain constant region. . However, it is not limited thereto.
  • the immunoglobulin Fc region may be in a dimeric form, and one X molecule may be covalently linked to one Fc region in a dimer form, and at this time, the immunoglobulin Fc and X can be linked to each other by a non-peptidyl polymer.
  • two X molecules it is also possible for two X molecules to symmetrically bind to one Fc region in the form of a dimer. At this time, the immunoglobulin Fc and X may be linked to each other by a non-peptide linker.
  • a non-peptide linker it is not limited to the examples described above.
  • the immunoglobulin Fc region of the present invention includes a native amino acid sequence as well as a sequence derivative thereof.
  • An amino acid sequence derivative means that one or more amino acid residues in a natural amino acid sequence have a different sequence by deletion, insertion, non-conservative or conservative substitution, or a combination thereof.
  • amino acid residues 214 to 238, 297 to 299, 318 to 322, or 327 to 331, which are known to be important for binding may be used as a suitable site for modification.
  • various kinds of derivatives are possible, such as a site capable of forming a disulfide bond is removed, several amino acids at the N-terminus in a native Fc are removed, or a methionine residue may be added to the N-terminus of a native Fc.
  • the complement binding site eg, the C1q binding site
  • the ADCC antibody dependent cell mediated cytotoxicity
  • the Fc derivative described above exhibits a biological activity equivalent to that of the Fc region of the present invention, and may have increased structural stability against heat and pH of the Fc region.
  • these Fc regions may be obtained from natural types isolated in vivo from animals such as humans, cows, goats, pigs, mice, rabbits, hamsters, rats or guinea pigs, or obtained from transformed animal cells or microorganisms. It may be recombinant or a derivative thereof.
  • the method of obtaining from the natural form may be a method of obtaining the whole immunoglobulin by separating it from a human or animal body and then treating a protease. When papain is treated, it is cleaved into Fab and Fc, and when treated with pepsin, it is cleaved into pF'c and F(ab) 2 . This can be separated from Fc or pF'c using size-exclusion chromatography or the like.
  • the human-derived Fc region is a recombinant immunoglobulin Fc region obtained from a microorganism.
  • the immunoglobulin Fc region may be a natural type sugar chain, an increased sugar chain compared to the natural type, a reduced sugar chain compared to the natural type, or a form in which sugar chains are removed.
  • Conventional methods such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms may be used for the increase or decrease of such immunoglobulin Fc sugar chains.
  • the immunoglobulin Fc region from which the sugar chain has been removed from the Fc significantly decreases the binding ability with complement (c1q), and the antibody-dependent cytotoxicity or complement-dependent cytotoxicity is reduced or eliminated, so it does not induce unnecessary immune responses in vivo. Does not.
  • a form more suitable for the original purpose as a drug carrier would be referred to as an immunoglobulin Fc region in which sugar chains are removed or non-glycosylated.
  • deglycosylation refers to an Fc region from which sugar is removed by an enzyme
  • aglycosylation refers to an Fc region that is not glycosylated by producing in a prokaryotic animal, or in a more specific embodiment, E. coli. .
  • the immunoglobulin Fc region may be of human origin or animal origin, such as cattle, goats, pigs, mice, rabbits, hamsters, rats, and guinea pigs, and in more specific embodiments, human origin.
  • the immunoglobulin Fc region may be an Fc region derived from IgG, IgA, IgD, IgE, or IgM, or a combination thereof or a hybrid thereof. In a more specific embodiment, it is derived from IgG or IgM, which is most abundant in human blood, and in a more specific embodiment, it is derived from IgG known to improve the half-life of a ligand binding protein. In a more specific embodiment, the immunoglobulin Fc region is an IgG4 Fc region, and in the most specific embodiment, the immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4, but is not limited thereto.
  • “combination” means that when forming a dimer or multimer, a polypeptide encoding a single-chain immunoglobulin Fc region of the same origin forms a bond with a single-chain polypeptide of a different origin. That is, it is possible to prepare a dimer or a multimer from two or more fragments selected from the group consisting of IgG Fc, IgA Fc, IgM Fc, IgD Fc and IgE Fc fragment.
  • conjugate may be that the persistence of the potency is increased compared to the native GLP-1, GIP, or glucagon, or F is not modified compared to X, and such conjugates are not only in the above-described form, but also biodegradable nano Includes all shapes enclosed in particles, etc.
  • a composition comprising the peptide may be used for the prevention or treatment of hyperlipidemia.
  • prevention refers to any action that suppresses or delays the onset of hyperlipidemia by administration of the peptide or a composition comprising the same
  • treatment refers to the symptoms of hyperlipidemia by administration of the peptide or a composition comprising the same. It refers to any action that improves or benefits.
  • the term "administration" means introducing a predetermined substance to the patient by any suitable method, and the route of administration of the composition is not particularly limited thereto, but any general route by which the composition can reach the target in vivo Can be administered through, for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, or rectal administration. I can.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient, or diluent.
  • a pharmaceutically acceptable carrier, excipient, or diluent may be non-naturally occurring.
  • the term "pharmaceutically acceptable” means a sufficient amount to exhibit a therapeutic effect and does not cause side effects, and the type of disease, the patient's age, weight, health, sex, and the patient's sensitivity to drugs ,
  • the route of administration, the method of administration, the number of times of administration, the duration of the treatment, and drugs used in combination or concurrently can be easily determined by those skilled in the art according to factors well known in the medical field.
  • the pharmaceutical composition including the peptide or conjugate of the present invention may further include a pharmaceutically acceptable carrier.
  • the carrier is not particularly limited thereto, but when administered orally, a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizing agent, a suspending agent, a coloring agent, a flavoring agent, etc. may be used.
  • a buffer agent Preservatives, painless agents, solubilizers, isotonic agents, stabilizers, and the like can be mixed and used.
  • base agents, excipients, lubricants, preservatives, etc. can be used.
  • the formulation of the composition of the present invention can be variously prepared by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier as described above.
  • it when administered orally, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dosage ampoules or multiple dosage forms.
  • Others, solutions, suspensions, tablets, pills, capsules can be formulated as sustained-release preparations.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like may be used.
  • fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, preservatives, and the like may additionally be included.
  • the pharmaceutical composition of the present invention is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, freeze-dried preparations, and suppositories. It can have a formulation of.
  • composition is formulated in a unit dosage form suitable for intra-body administration of a patient according to a conventional method in the pharmaceutical field, specifically, in a form useful for administration of protein medicines, and administration commonly used in the art.
  • the peptide or conjugate may be used in combination with various carriers permitted as drugs such as physiological saline or an organic solvent, and carbohydrates such as glucose, sucrose or dextran, ascorbic acid, in order to increase stability or absorption.
  • drugs such as physiological saline or an organic solvent
  • carbohydrates such as glucose, sucrose or dextran, ascorbic acid, in order to increase stability or absorption.
  • Antioxidants such as (ascorbic acid) or glutathione, chelating agents, low-molecular proteins, or other stabilizers may be used as drugs.
  • the dosage and frequency of the pharmaceutical composition of the present invention are determined according to the type of drug as the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient, and the severity of the disease.
  • the total effective amount of the composition of the present invention may be administered to a patient in a single dose, and may be administered by a fractionated treatment protocol that is administered for a long period of time in multiple doses.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient according to the severity of the disease.
  • the preferred total dose of the conjugate of the present invention may be about 0.0001 mg to 500 mg per 1 kg of patient body weight per day.
  • the dose of the conjugate is determined by considering various factors such as the patient's age, weight, health status, sex, disease severity, diet and excretion rate, as well as the administration route and number of treatments of the pharmaceutical composition.
  • composition according to the present invention is not particularly limited in its formulation, route of administration, and method of administration as long as it shows the effect of the present invention.
  • the pharmaceutical composition of the present invention has excellent in vivo persistence and potency, and can significantly reduce the number and frequency of administration of the pharmaceutical formulation of the present invention.
  • Another aspect embodying the present invention provides a method for preventing or treating hyperlipidemia, comprising administering the peptide, conjugate, or composition comprising the same to an individual in need thereof.
  • the peptide, conjugate, or composition comprising the same, hyperlipidemia, prevention and treatment are as described above.
  • the subject is an individual suspected of hyperlipidemia
  • the suspected hyperlipidemia refers to mammals including mice, livestock, etc., including humans who have or may develop the disease, but the conjugate of the present invention or include the same Subjects treatable with the composition described above are included without limitation.
  • the method of the present invention may include administering a pharmaceutical composition containing the peptide or conjugate in a pharmaceutically effective amount.
  • the appropriate total daily use amount may be determined by the treating physician within the range of correct medical judgment, and may be administered once or in several divided doses.
  • a specific therapeutically effective amount for a specific patient is a specific composition, including the type and degree of reaction to be achieved, whether other agents are used in some cases, the patient's age, weight, general health status, It is preferable to apply differently according to various factors including sex and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used with or concurrently with the specific composition, and similar factors well known in the medical field.
  • Another aspect embodying the present invention is the use of the peptide, conjugate, or a composition comprising the same in the manufacture of a medicament for the prevention or treatment of hyperlipidemia.
  • the peptide, conjugate, or composition comprising the same, hyperlipidemia, prevention and treatment are as described above.
  • the amino acid indicated by X is non-natural amino acid Aib (aminoisobutyric acid), and the underlined amino acid means that the underlined amino acids form a ring with each other.
  • Aib amino acid Aib
  • CA 4-imidazoacetyl
  • Y represents tyrosine.
  • maleimide-PEG-aldehyde 10 kDa PEG having a maleimide group and an aldehyde group at both ends
  • maleimide-PEG-aldehyde 10 kDa, NOF, Japan
  • the triple active agent of Example 1 SEQ ID NOs: 21, 22, 42, 43, 50, 77, and 96
  • the molar ratio of the triactivator to the maleimide-PEG-aldehyde is 1:1 to 3
  • the protein concentration is 1 to 5 mg/ml, and 0.5 to 3 at low temperature. Reacted for hours.
  • the reaction was carried out in an environment in which 20 to 60% isopropanol was added to 50 mM Tris buffer (pH 7.5). After the reaction was completed, the reaction solution was applied to SP Sepharose HP (GE healthcare, USA) to purify a triactivator mono-pegylated to cysteine.
  • SP Sepharose HP GE healthcare, USA
  • the purified mono-pegylated triactivator and immunoglobulin Fc were reacted at a molar ratio of 1: 1 to 5, and a protein concentration of 10 to 50 mg/ml for 12 to 18 hours at 4 to 8°C. Made it.
  • the reaction was carried out in an environment in which 10 to 50 mM sodium cyanoborohydride and 10 to 30% isopropanol as a reducing agent were added to 100 mM potassium phosphate buffer (pH 6.0).
  • the reaction solution is applied to a butyl Sepharose FF purification column (GE healthcare, USA) and a Source ISO purification column (GE healthcare, USA) to purify a conjugate including a triple activator and an immunoglobulin Fc. I did.
  • the conjugate in which the triple active agent and immunoglobulin Fc prepared in this example are linked through PEG is referred to as a conjugate or long-acting conjugate including a triple conjugate and an immunoglobulin Fc.
  • conjugate in which the triple activator of SEQ ID NO: 42 and immunoglobulin Fc are linked through PEG was named as'conjugate comprising SEQ ID NO: 42 and immunoglobulin Fc' or'long-acting conjugate of SEQ ID NO: 42', These may be used interchangeably herein.
  • Each of the cell lines is transformed to express human GLP-1 receptor, human GCG receptor and human GIP receptor genes in CHO (chinese hamster ovary), and is suitable for measuring the activities of GLP-1, GCG and GIP. Therefore, the activity for each part was measured using each transformed cell line.
  • human GLP-1 was serially diluted from 50 nM to 0.000048 nM by 4 times, and prepared in Examples 1 and 2
  • the triple activator and its long-acting conjugate were serially diluted from 400nM to 0.00038nM by 4 times.
  • Remove the culture medium from the cultured human GLP-1 receptor-expressing CHO cells add 5 ⁇ l of each of the serially diluted substances to the cells, and then add 5 ⁇ l each of a buffer containing cAMP antibody for 15 minutes. During incubation at room temperature.
  • Table 3 is a table confirming the relative titer ratio of the triple active long-acting conjugate, and the novel triple-active long-acting conjugate prepared above has triple activity capable of activating all of the GLP-1 receptor, GIP receptor, and glucagon receptor. It was confirmed that it has a sieve function.
  • a hyperlipidemia model was induced by feeding Fructose for 2 weeks in a Golden syrian hamster (hereinafter referred to as hyperlipidemia hamster).
  • SEQ ID NO: 42 was selected, and the long-acting conjugate of SEQ ID NO: 42 (1.6, 3.1 nmol/kg, Q2D) was repeatedly administered subcutaneously for 3 weeks to hamsters inducing hyperlipidemia.
  • evolocumab 219.2 nmol/kg, QW
  • QW a commercially available treatment for hyperlipidemia
  • the triple active long-acting conjugate of Example 2 has excellent hyperlipidemia treatment efficacy.
  • the mode of action was confirmed in vitro .
  • HepG2 cells were treated with the control, the long-acting conjugate of SEQ ID NO: 42 (0.01, 0.1, 1, 10 ⁇ M) and evolocumab (10 ⁇ g/mL) for 48 hours, and then the amount of BODIPY-labeled LDL uptake was confirmed.
  • the results are shown in FIG. 2.
  • HMGCR 3-Hydroxy-3-methylglutaryl-CoA reductase
  • the ketone body a by-product of fatty acid decomposition, was measured.
  • the amount of the produced ketone body was measured using a commercially available ketone body measurement kit (Sigma #MAK041).
  • the triple activator and the long-acting conjugate thereof according to the present invention increases LDL absorption, inhibits cholesterol synthesis through inhibition of HMGCR activity, and reduces total cholesterol and LDL in blood through promotion of fatty acid degradation, thereby treating hyperlipidemia. It was confirmed that the effect can be exhibited.

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Abstract

La présente invention concerne l'utilisation thérapeutique d'un triple agoniste ou d'un conjugué de longue durée de celui-ci contre l'hyperlipidémie, le triple agoniste agissant sur tous les récepteurs du glucagon, du GLP-1 et du GIP.
PCT/KR2020/005233 2019-04-19 2020-04-20 Composition pharmaceutique préventive ou thérapeutique contre l'hyperlipidémie comprenant un triple agoniste agissant sur tous les récepteurs du glucagon, du glp-1 et du gip, ou conjugué de ceux-ci, et procédé préventif ou thérapeutique Ceased WO2020214012A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093823A2 (fr) * 2003-03-19 2004-11-04 Eli Lilly And Company Composes glp-1 a liaison polyethylene glycol
US20120329715A1 (en) * 2001-07-31 2012-12-27 The Gov. of the US, as represented by the Secretary, Dept. of Health & Human Services Glp-1, exendin-4, peptide analogs and uses thereof
US20130203659A1 (en) * 2006-04-20 2013-08-08 Leslie P. Miranda Glp-1 compounds
KR20150096433A (ko) * 2012-12-21 2015-08-24 사노피 이중 glp1/gip 또는 삼중 glp1/gip/글루카곤 효능제
KR20170080522A (ko) * 2015-12-31 2017-07-10 한미약품 주식회사 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체의 지속형 결합체

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120329715A1 (en) * 2001-07-31 2012-12-27 The Gov. of the US, as represented by the Secretary, Dept. of Health & Human Services Glp-1, exendin-4, peptide analogs and uses thereof
WO2004093823A2 (fr) * 2003-03-19 2004-11-04 Eli Lilly And Company Composes glp-1 a liaison polyethylene glycol
US20130203659A1 (en) * 2006-04-20 2013-08-08 Leslie P. Miranda Glp-1 compounds
KR20150096433A (ko) * 2012-12-21 2015-08-24 사노피 이중 glp1/gip 또는 삼중 glp1/gip/글루카곤 효능제
KR20170080522A (ko) * 2015-12-31 2017-07-10 한미약품 주식회사 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체의 지속형 결합체

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