WO2014017843A1 - Composition for treating hyperlipidemia comprising oxyntomodulin derivative - Google Patents

Composition for treating hyperlipidemia comprising oxyntomodulin derivative Download PDF

Info

Publication number
WO2014017843A1
WO2014017843A1 PCT/KR2013/006668 KR2013006668W WO2014017843A1 WO 2014017843 A1 WO2014017843 A1 WO 2014017843A1 KR 2013006668 W KR2013006668 W KR 2013006668W WO 2014017843 A1 WO2014017843 A1 WO 2014017843A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
fatty liver
liver disease
group
oxyntomodulin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2013/006668
Other languages
English (en)
French (fr)
Inventor
Sung Youb Jung
Jin-Sun Kim
Myung Hyun Jang
Sang Hyun Lee
In Young Choi
Se Chang Kwon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=49997578&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014017843(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to ES13823727T priority Critical patent/ES2942187T3/es
Priority to EP13823727.6A priority patent/EP2884994B1/en
Priority to MX2015001218A priority patent/MX360024B/es
Priority to BR122022025353-9A priority patent/BR122022025353B1/pt
Priority to RU2015104492A priority patent/RU2642267C2/ru
Priority to US14/415,200 priority patent/US20150182593A1/en
Priority to CN201380039596.XA priority patent/CN104507492B/zh
Priority to JP2015524182A priority patent/JP2015524427A/ja
Priority to AU2013293714A priority patent/AU2013293714B2/en
Priority to CA2888407A priority patent/CA2888407C/en
Priority to EP18169490.2A priority patent/EP3384925B1/en
Priority to BR112015001596-4A priority patent/BR112015001596B1/pt
Priority to UAA201501078A priority patent/UA118177C2/uk
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Priority to EP20188520.9A priority patent/EP3766520A1/en
Priority to HK15107083.6A priority patent/HK1206280B/xx
Priority to SG11201500519UA priority patent/SG11201500519UA/en
Priority to NZ705384A priority patent/NZ705384A/en
Publication of WO2014017843A1 publication Critical patent/WO2014017843A1/en
Priority to PH12015500158A priority patent/PH12015500158B1/en
Priority to IL236913A priority patent/IL236913B/en
Anticipated expiration legal-status Critical
Priority to ZA2015/01238A priority patent/ZA201501238B/en
Priority to US15/086,499 priority patent/US9901621B2/en
Priority to US15/846,395 priority patent/US10493132B2/en
Priority to AU2018203729A priority patent/AU2018203729B2/en
Priority to PH12019501131A priority patent/PH12019501131A1/en
Priority to IL274106A priority patent/IL274106B2/en
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • 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
    • A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • 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
    • A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • 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
    • A61K47/6435—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 the peptide or protein in the drug conjugate being a connective tissue peptide, e.g. collagen, fibronectin or gelatin
    • 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
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07K14/76—Albumins
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes

Definitions

  • the present invention relates to a composition for preventing or treating hyperlipidemia, fatty liver disease or arteriosclerosis, which comprises an oxyntomodulin derivative as an active ingredient, and to a method for treating hyperlipidemia, fatty liver disease or arteriosclerosis using the composition.
  • Hyperlipidemia refers to a condition associated with elevated levels of lipids, such as free cholesterol, cholesterol esters, phospholipids and triglycerides, in blood. Hyperlipidemia can appear in three forms: (1) hypercholesterolemia, (2) hypertriglyceridemia, and (3) combined hyperlipidemia (hypercholesterolemia and hypertriglyceridemia). Hyperlipidemia is generally classified into primary hyperlipidemia and secondary hyperlipidemia. Primary hyperlipidemia is generally caused by genetic defects, whereas secondary hyperlipidemia is caused by various disease conditions, drugs and dietary habits. In addition, hyperlipidemia is also caused by a combination of the primary and secondary causes of hyperlipidemia. As criteria for the diagnosis of hyperlipidemia, a total cholesterol level of 220 mg/dl or higher and a triglyceride level of 150 mg/dl or higher are generally used.
  • LDL Low-density
  • HDL high-density
  • fatty liver refers to a condition in which the ratio of fats in the weight of the liver is more than 5%. The fatty liver can be caused not only by excessive intake of fats, but also by intake of alcohol.
  • Drugs for reducing lipid levels include bile acid binding resin, cholesterol-lowering drugs such as HMG-CoA reductase inhibitors important in cholesterol biosynthesis, triglyceride-lowering drugs such as fibric acid derivatives and nicotinic acid, etc.
  • cholesterol-lowering drugs such as HMG-CoA reductase inhibitors important in cholesterol biosynthesis
  • triglyceride-lowering drugs such as fibric acid derivatives and nicotinic acid, etc.
  • these drugs were reported to have side effects such as hepatic toxicity, gastrointestinal disorder and carcinogenesis.
  • hyperlipidemia and related diseases e.g., atherosclerosis and fatty liver disease
  • Oxyntomodulin is produced from pre-glucagon and is a peptide that can bind to both glucagon-like peptide-1 (GLP-1) and glucagon receptor to perform dual function. Because of such characteristics, oxyntomodulin has been studied for various purposes, including the treatment of obesity, hyperlipidemia and fatty liver disease. However, oxyntomodulin has a problem in that it should be administered at a high dose, because it has a short half-life in vivo and the activity thereof is insufficient for use in the treatment of obesity, hyperlipidemia and fatty liver disease.
  • the present inventors have developed an oxyntomodulin derivative having increased activity compared to native oxyntomodulin and have found that the oxyntomodulin derivative reduced the content and ratio of lipids in blood in a hyperlipidemia-induced hamster model, indicating that the derivative can be effectively used for the treatment of hyperlipidemia diseases, thereby completing the present invention.
  • Another object of the present invention is to provide a method for treating hyperlipidemia, fatty liver disease or atherosclerosis, the method comprising a step of administering an oxyntomodulin derivative to a subject.
  • Still another object of the present invention is to provide the use of an oxyntomodulin derivative in the preparation of a medicament for preventing or treating hyperlipidemia, fatty liver disease or atherosclerosis.
  • the present invention provides a composition for preventing or treating hyperlipidemia, fatty liver disease or atherosclerosis, which contains an oxyntomodulin derivative as an active ingredient.
  • oxyntomodulin refers to a peptide produced from pre-glucagon that a precursor of glucagon.
  • oxyntomodulin is meant include native oxyntomodulin and its precursor, analog (derivative), fragment and variant.
  • oxyntomodulin has an amino acid sequence of SEQ ID NO: 1 (HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA).
  • oxyntomodulin variant is a peptide that has one or more amino acid residues different from those of the amino acid sequence of native oxyntomodulin and possesses a function of activating GLP-1 and glucagon receptors.
  • the oxyntomodulin variant can be prepared by any one of substitution, addition, deletion, modification, or a combination thereof of some amino acids of native oxyntomodulin.
  • oxyntomodulin derivative refers to a peptide, peptide derivative or peptide mimic that is prepared by the addition, deletion or substitution of some amino acids of native oxyntomodulin and can activate both GLP-1 receptor and glucagon receptor at a high level compared to the level activated by native oxyntomodulin.
  • oxyntomodulin fragment refers to a fragment having an addition or deletion of one or more amino acids at the amino or carboxyl terminal end of native oxyntomodulin, in which the added amino acids may also be non-naturally occurring amino acids (e.g., D-type amino acid). Such amino acids have a function of regulating blood glucose levels in vivo .
  • the present invention includes a peptide that has one or more amino acids different from those of native peptide and deamination of the N-terminal amino acid residues and has a function of activating both GLP-1 receptor and glucagon receptor.
  • the oxyntomodulin derivative encompasses any peptide that is prepared by the substitution, addition, deletion or post-translational modification (e.g., methylation, acylation, ubiquitination, or intramolecular covalent bonding) of amino acids in the amino acid sequence of SEQ ID NO: 1 and can activate both the glucagon and GLP-1 receptors.
  • substitution or addition of amino acids not only 20 amino acids commonly found in human proteins, but also atypical or non-naturally occurring amino acids can be used.
  • Commercial sources of atypical amino acids include Sigma-Aldrich, ChemPep Inc., and Genzyme Pharmaceuticals.
  • the peptides including these amino acids and atypical peptide sequences may be synthesized and purchased from commercial suppliers, for example, American Peptide Company or Bachem (USA) or Anygen (Korea).
  • the oxyntomodulin derivative of the present invention is a novel peptide including the amino acid sequence of the following formula 1:
  • R1 is histidine, desamino-histidyl, dimethyl-histidyl (N-dimethyl-histidyl), beta-hydroxyimidazopropionyl, 4-imidazoacetyl, beta-carboxy imidazopropionyl or tyrosine;
  • X1 is Aib (aminosiobutyric acid), d-alanine, glycine, Sar(N-methylglycine), serine, or d-serine;
  • X2 is glutamic acid or glutamine
  • X3 is leucine or tyrosine
  • X4 is serine or alanine
  • X5 is lysine or arginine
  • X6 is glutamine or tyrosine
  • X7 is leucine or methionine
  • X8 is aspartic acid or glutamic acid
  • X9 is glutamic acid, serine, alpha-methyl-glutamic acid or is deleted
  • X10 is glutamine, glutamic acid, lysine, arginine or serine or is deleted;
  • X11 is alanine, arginine or valine or is deleted
  • X12 is alanine, arginine, serine or valine or is deleted
  • X13 is lysine, glutamine, arginine or alpha-methyl-glutamic acid or is deleted;
  • X14 is aspartic acid, glutamic acid or leucine or is deleted
  • X15 is phenylalanine or is deleted
  • X16 is isoleucine or valine or is deleted
  • X17 is alanine, cysteine, glutamic acid, lysine, glutamine or alpha-methyl-glutamic acid or is deleted;
  • X18 is tryptophan or is deleted
  • X19 is alanine, isoleucine, leucine, serine or valine or is deleted;
  • X20 is alanine, lysine, methionine, glutamine or arginine or is deleted;
  • X21 is asparagine or is deleted
  • X22 is alanine, glycine or threonine or is deleted
  • X23 is cysteine or lysine or is deleted
  • X24 is a peptide having 2 to 10 amino acids consisting of a combination of alanine, glycine and serine or is deleted;
  • R2 is KRNRNNIA (SEQ ID NO: 35), GPSSGAPPPS (SEQ ID NO: 36), GPSSGAPPPSK (SEQ ID NO: 37), HSQGTFTSDYSKYLD (SEQ ID NO: 38), HSQGTFTSDYSRYLDK (SEQ ID NO: 39), HGEGTFTSDLSKQMEEEAVK (SEQ ID NO: 40) or is deleted (excluded if the amino acid sequence of formula 1 is identical to that of SEQ ID NO: 1).
  • the oxyntomodulin derivative of the present invention may be substituted with 4-imidazoacetyl obtained by deletion of the alpha carbon of histidine at position 1 of the amino acid sequence of SEQ ID NO: 1, desamino-histidyl obtained by deletion of the N-terminal amino group, dimethyl-histidyl (N-dimethyl-histidyl) obtained by modification of the N-terminal amino group with two methyl groups, beta-hydroxy imidazopropionyl obtained by substitution of the N-terminal amino group with a hydroxyl group, or beta-carboxy imidazopropionyl obtained by substitution of the N-terminal amino group with a carboxyl group.
  • the GLP-1 receptor-binding region may be substituted with amino acids that enhance hydrophobic and ionic bonds or a combination thereof.
  • a portion of the oxyntomodulin sequence may be substituted with the amino acid sequence of GLP-1 or Exendin-4 to increase the activity of the GLP-1 receptor.
  • oxyntomodulin sequence may be substituted with a sequence that enhances alpha helix.
  • amino acids at positions 10, 14, 16, 20, 24 and 28 of the amino acid sequence of formula 1 may be substituted with amino acids or amino acid derivatives consisting of Tyr(4-Me), Phe, Phe(4-Me), Phe(4-Cl), Phe(4-CN), Phe(4-NO 2 ),Phe(4-NH 2 ), Phg, Pal, Nal, Ala(2-thienyl) and Ala (benzothienyl) that are known to stabilize alpha helix, and the type and number of alpha helix-stabilizing amino acid or amino acid derivatives to be inserted are not limited.
  • amino acids at positions 10 and 14, 12 and 16, 16 and 20, 20 and 24, and 24 and 28 of the amino acid sequence may be also substituted with glutamic acid or lysine so as to form rings, and the number of rings to be inserted is not limited.
  • the oxyntomodulin derivative may have an amino acid sequence selected from among the following formulas 1 to 6.
  • the oxyntomodulin derivative of the present invention is a novel peptide including the amino acid sequence of the following formula 2, obtained by substitution of the amino acid sequence of oxyntomodulin with that of exendin or GLP-1:
  • the oxyntomodulin derivative of the present invention is a novel peptide including the amino acid sequence of the following formula 3, which is prepared by linking a portion of the amino acid sequence of oxyntomodulin and a portion of the amino acid sequence of exendin or GLP-1 via a proper amino acid linker:
  • the oxyntomodulin derivative of the present invention is a novel peptide including the amino acid sequence of the following formula 4, wherein a portion of the amino acid sequence of oxyntomodulin is substituted with an amino acid capable of enhancing the binding affinity to GLP-1 receptor, for example, Leu at position 26 which binds with GLP-1 receptor by hydrophobic interaction is substituted with the hydrophobic residue Ile or Val.
  • the oxyntomodulin derivative of the present invention is a novel peptide including the amino acid sequence of the following formula 5, wherein a portion of the amino acid sequence of native oxyntomodulin is deleted, added, or substituted with other amino acids in order to increase the abilities of native oxyntomodulin to activate GLP-1 receptor and glucagon receptor:
  • R1 is as described in formula 1;
  • A is selected from the group consisting of SQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO: 41), SQGTFTSDYSKYLDEEAVRLFIEWLMNT (SEQ ID NO: 42), SQGTFTSDYSKYLDERRAQDFVAWLKNT (SEQ ID NO: 43), GQGTFTSDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO: 44), GQGTFTSDYSRQMEEEAVRLFIEWLKNG (SEQ ID NO: 45), GEGTFTSDLSRQMEEEAVRLFIEWAA (SEQ ID NO: 46), and SQGTFTSDYSRQMEEEAVRLFIEWLMNG (SEQ ID NO: 47);
  • SQGTFTSDYSKYLDSRRAQDFVQWLMNT SEQ ID NO: 41
  • SQGTFTSDYSKYLDEEAVRLFIEWLMNT SEQ ID NO: 42
  • SQGTFTSDYSKYLDERRAQDFVAWLKNT SEQ ID NO: 43
  • GQGTFTSDYSRYLEEEAVRLFIEWLKNG SEQ ID NO: 44
  • GQGTFTSDYSRQMEEEAVRLFIEWLKNG SEQ ID NO: 45
  • GEGTFTSDLSRQMEEEAVRLFIEWAA SEQ ID NO: 46
  • SQGTFTSDYSRQMEEEAVRLFIEWLMNG SEQ ID NO: 47
  • GEGTFTSDLSRQMEEEAVRLFIEW SEQ ID NO: 48
  • SQGTFTSDYSRYLD SEQ ID NO: 49
  • C is a peptide having 2 to 10 amino acids consisting of a combination of alanine, glycine and serine;
  • D1 is serine, glutamic acid or arginine
  • D2 is arginine, glutamic acid or serine
  • D3 is arginine, alanine or valine
  • D4 is arginine, valine or serine
  • D5 is glutamine, arginine or lysine
  • D6 is isoleucine, valine or serine
  • D7 is methionine, arginine or glutamine
  • D8 is threonine, glycine or alanine
  • E1 is serine, Aib, Sar, d-alanine or d-serine;
  • E2 is serine or glutamic acid
  • E3 is arginine or lysine
  • E4 is glutamine or lysine
  • E5 is aspartic acid or glutamic acid
  • E6 is glutamine, cysteine or lysine
  • E7 is cysteine or lysine or is deleted
  • R3 is KRNRNNIA (SEQ ID NO: 35), GPSSGAPPPS (SEQ ID NO: 36) or GPSSGAPPPSK (SEQ ID NO: 37);
  • R4 is HSQGTFTSDYSKYLD (SEQ ID NO: 38), HSQGTFTSDYSRYLDK (SEQ ID NO: 39) or HGEGTFTSDLSKQMEEEAVK (SEQ ID NO: 40); and
  • R5 is KRNRNNIA (SEQ ID NO: 35), GPSSGAPPPS (SEQ ID NO: 36) or GPSSGAPPPSK (SEQ ID NO: 37) or is deleted (excluded if the amino acid sequences of formulas 2 to 5 are identical to that of SEQ ID NO: 1).
  • the oxyntomodulin derivative of the present invention may be a novel peptide of the following formula 6:
  • R1 is histidine, desamino-histidyl, 4-imidazoacetyl or tyrosine;
  • X1 is Aib(aminosiobutyric acid), glycine, serine or d-serine;
  • X2 is glutamic acid or glutamine
  • X3 is leucine or tyrosine
  • X4 is serine or alanine
  • X5 is lysine or arginine
  • X6 is glutamine or tyrosine
  • X7 is leucine or methionine
  • X8 is aspartic acid or glutamic acid
  • X9 is glutamic acid or alpha-methyl-glutamic acid or is deleted
  • X10 is glutamine, glutamic acid, lysine or arginine or is deleted;
  • X11 is alanine or arginine or is deleted
  • X12 is alanine or valine or is deleted
  • X13 is lysine, glutamine, arginine or alpha-methyl-glutamic acid or is deleted;
  • X14 is aspartic acid, glutamic acid or leucine or is deleted
  • X15 is phenylalanine or is deleted
  • X16 is isoleucine or valine or is deleted
  • X17 is alanine, cysteine, glutamic acid, glutamine or alpha-methyl-glutamic acid or is deleted;
  • X18 is tryptophan or is deleted
  • X19 is alanine, isoleucine, leucine or valine or is deleted;
  • X20 is alanine, lysine, methionine or arginine or is deleted;
  • X21 is asparagine or is deleted
  • X22 is threonine or is deleted
  • X23 is cysteine, lysine or is deleted
  • X24 is a peptide having 2 to 10 amino acids consisting of glycine or is deleted.
  • R2 is KRNRNNIA (SEQ ID NO: 35), GPSSGAPPPS (SEQ ID NO: 36), GPSSGAPPPSK (SEQ ID NO: 37), HSQGTFTSDYSKYLD (SEQ ID NO: 38), HSQGTFTSDYSRYLDK (SEQ ID NO: 39) or HGEGTFTSDLSKQMEEEAVK (SEQ ID NO: 40) or is deleted (excluded if the amino acid sequence of formula 6 is identical to that of SEQ ID NO: 1).
  • the oxyntomodulin derivative of the present invention may be selected from the group consisting of the peptides of SEQ ID NOs: 2 to 34. Even more preferably, the oxyntomodulin derivative of the present invention may be an oxyntomodulin derivative described in Table 1 of Example 2-1.
  • oxyntomodulin derivatives having the amino acid sequences of SEQ ID NOs: 2 to 34, respectively, were prepared, and it was found that the oxyntomodulin derivatives showed excellent GLP-1 receptor and glucagon receptor activities compared to native oxyntomodulin (Example 2). In other words, it could be seen from the above results that the oxyntomodulin derivative of the present invention exhibited excellent therapeutic effects against hyperlipidemia, fatty liver disease or atherosclerosis by activating the GLP-1 receptor and the glucagon receptor.
  • the oxyntomodulin derivatives of the present invention are present in the form of conjugates comprising various polymer in order to improve the therapeutic effect and in vivo half-life of the derivatives.
  • the conjugate of the present invention shows an increase in the duration of effects compared to native oxyntomodulin
  • the long-acting conjugates include an oxyntomodulin prepared by the modification, substitution, addition or deletion of the amino acids of native oxyntomodulin, an oxyntomodulin conjugated to a biodegradable polymer such as polyethylene glycol (PEG), an oxyntomodulin conjugated to a polysaccharide such as albumin, antibody, elastin, fibronectin or chitin or to a long-acting protein such as an immunoglobulin fragment, an oxyntomodulin conjugated to fatty acid having the ability of binding to albumin in vivo , or an oxyntomodulin encapsulated in biodegradable nanoparticles, and the type of long-acting conjugate that is used in the present invention is not limited.
  • the conjugate is a conjugate wherein an oxyntomodulin derivative having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 to 34 is linked to an immunoglobulin Fc region via a non-peptidyl polymer.
  • the immunoglobulin Fc region is a biodegradable polypeptide that is metabolized in vivo ,and thus is safe for use as a carrier for a drug.
  • the immunoglobulin Fc region has a low molecular weight compared to the entire immunoglobulin molecule, and thus is advantageous in terms of the preparation, purification and yield of conjugates.
  • a Fab portion showing high non-homogeneity and thus the homogeneity of the material can be greatly increased and the possibility of inducing blood antigenicity can also be reduced.
  • immunoglobulin Fc region refers to a protein that contains the heavy-chain constant region 2 (CH2) and heavy-chain constant region 3 (CH3) of an immunoglobulin, excluding the heavy-chain and light-chain variable regions, the heavy-chain constant region 1 (CH1) and the light-chain constant region 1 (CL1) of the immunoglobulin. It may further include a hinge region at the heavy-chain constant region.
  • the immunoglobulin Fc region of the present invention may be an expanded Fc region including part or all of the heavy-chain constant region 1 (CH1) and/or the light-chain constant region 1 (CL1), except for the heavy-chain and light-chain variable regions, as long as it has an effect that is substantially equal to or better than the native protein.
  • the immunoglobulin Fc region may be a region having a deletion of a portion of a relatively long amino acid sequence corresponding to CH2 and/or CH3.
  • the immunoglobulin Fc region of the present invention may comprise 1) a CH1 domain, a CH2 domain, a CH3 domain and a CH4 domain, 2) a CH1 domain and a CH2 domain, 3) a CH1 domain and a CH3 domain, 4) a CH2 domain and a CH3 domain, 5) a combination of one or more domains and an immunoglobulin hinge region (or a portion of the hinge region), or 6) a dimer of each domain of the heavy-chain constant regions and the light-chain constant region.
  • the immunoglobulin Fc region of the present invention includes a native amino acid sequence, and a sequence derivative (mutant) thereof.
  • amino acid sequence derivative refers to a sequence that is different from the native amino acid sequence due to the deletion, insertion, non-conservative or conservative substitution or a combination thereof of one or more amino acid residues of the native amino acid sequence.
  • amino acid residues at positions 214 to 238, 297 to 299, 318 to 322, or 327 to 331, which are known to be important in binding may be used as suitable sites for modification.
  • a deletion may occur in a complement-binding site, such as a C1q-binding site and an ADCC (antibody dependent cell mediated cytotoxicity) site.
  • a complement-binding site such as a C1q-binding site and an ADCC (antibody dependent cell mediated cytotoxicity) site.
  • Amino acid exchanges in proteins and peptides which do not generally alter the activity of the proteins or peptides, are known in the art (H. Neurath, R. L. Hill, The Proteins, Academic Press, New York, 1979).
  • the most commonly occurring exchanges are Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu and Asp/Gly, in both directions.
  • the Fc region may, if necessary, be modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, acetylation, amidation, and the like.
  • Fc derivatives show biological activity identical to that of the Fc region of the present invention or have increased structural stability against heat, pH, or the like.
  • this Fc region may be obtained from native forms isolated from humans and other animals including cows, goats, pigs, mice, rabbits, hamsters, rats and guinea pigs, or may be recombinants or derivatives thereof, obtained from transformed animal cells or microorganisms.
  • the Fc region may be obtained from a native immunoglobulin by isolating a whole immunoglobulin from a living human or animal body and treating it with proteinase. When the whole immunoglobulin is treated with papain, it is digested into Fab and Fc regions, and when the whole immunoglobulin is treated with pepsin, it is digested into pF'c and F(ab) 2 fragments.
  • Fc or pF'c can be isolated using size exclusion chromatography or the like.
  • a human-derived Fc region is a recombinant immunoglobulin Fc region obtained from a microorganism.
  • the immunoglobulin Fc region of the present invention may be in the form of having native sugar chains or increased or decreased sugar chains compared to a native form, or may be in a deglycosylated form.
  • the increase, decrease or removal of the immunoglobulin Fc sugar chains may be achieved by conventional methods such as a chemical method, an enzymatic method and a genetic engineering method using a microorganism.
  • the Fc region obtained by removal of sugar chains from Fc shows a significant decrease in binding affinity to the C1q part of the first complement component C1 and a decrease or loss in antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity, and thus does not induce unnecessary immune responses in vivo .
  • an immunoglobulin Fc region in a deglycosylated or aglycosylated form may be more suitable to the object of the present invention as a drug carrier.
  • deglycosylation refers to enzymatically removing sugar moieties from an Fc region
  • amino acid sequence refers to an unglycosylated Fc region produced in a prokaryote, preferably E.coli .
  • the immunoglobulin Fc region may be derived from humans or other animals including cows, goats, pigs, mice, rabbits, hamsters, rats and guinea pigs, and preferably from humans.
  • the immunoglobulin Fc region may be derived from IgG, IgA, IgD, IgE, IgM, or a combination or hybrid thereof.
  • it is derived from IgG or IgM, which are among the most abundant proteins in human blood, and most preferably from IgG, which is known to enhance the half-lives of ligand-binding proteins.
  • a dimer or multimer may be formed from two or more fragments selected from the group consisting of IgG Fc, IgA Fc, IgM Fc, IgD Fc, and IgE Fc fragments.
  • hybrid means that sequences corresponding to two or more immunoglobulin Fc fragments of different origins are present in a single-chain immunoglobulin Fc region.
  • various forms of hybrid are possible.
  • a hybrid composed of 1 to 4 domains selected from the group consisting of the CH1, CH2, CH3 and CH4 of IgG Fc, IgM Fc, IgA Fc, IgE Fc and IgD Fc is possible, and it may include a hinge.
  • IgG can also be sub-classified into IgG1, IgG2, IgG3 and IgG4, and in the present invention, a combination or hybrid of these subclasses is also possible.
  • IgG is the IgG2 ad IgG4 subclass, and most preferably, it is the Fc region of IgG4 that substantially lacks effector functions such as complement-dependent cytotoxicity (CDC).
  • CDC complement-dependent cytotoxicity
  • the most preferred immunoglobulin Fc region that is used as a drug carrier in the present invention is an Fc region derived from human IgG4.
  • a human-derived Fc region is more preferable than a non-human-derived Fc region, which may act as an antigen in the human body and cause undesirable immune responses such as the production of a new antibody against the antigen.
  • non-peptidyl polymer refers to a biocompatible polymer including two or more repeating units linked to each other by any covalent bond in place of a peptide bond.
  • the non-peptidyl polymer may be interchangeably used with the non-peptidyl linker.
  • the non-peptidyl polymer that can be used in the present invention may be selected from the group consisting of polyethylene glycol, polypropylene glycol, an ethylene glycol/propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, biodegradable polymers such as PLA (poly(lactic acid)) and PLGA (polylactic-glycolic acid), lipid polymers, chitins, hyaluronic acid, and combinations thereof.
  • the non-peptidyl polymer is polyethylene glycol.
  • derivatives thereof known in the art and derivatives that may be easily prepared by a method known in the art are included in the scope of the present invention.
  • the peptide linker that is used in a fusion protein obtained by a conventional inframe fusion method has drawbacks in that it is easily cleaved by proteinase in vivo ,and thus a sufficient effect of increasing the serum half-life of the active drug by a carrier cannot be obtained as expected.
  • the polymer having resistance to proteinase can be used to maintain the serum half-life of the peptide, similar to the carrier. Therefore, any non-peptidyl polymer can be used without limitation in the present invention, as long as it is a polymer having the aforementioned function, that is, a polymer having resistance to proteinase in vivo .
  • the non-peptidyl polymer has a molecular weight in the range of 1 to 100 kDa, and preferably 1 to 20 kDa.
  • the non-peptidyl polymer of the present invention, which is linked to the immunoglobulin Fc region, may be one kind of polymer or a combination of different polymers.
  • the non-peptidyl polymer that is used in the present invention may have a reactive group capable of binding to the immunoglobulin Fc region and the protein drug.
  • the reactive group at both ends of the non-peptidyl polymer is preferably selected from the group consisting of a reactive aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group and a succinimide derivative.
  • the succinimide derivative may be succinimidyl propionate, hydroxy succinimidyl, succinimidyl carboxymethyl, or succinimidyl carbonate.
  • non-peptidyl polymer has a reactive aldehyde group at both ends thereof, non-specific reactions can be minimized, and a physiologically active polypeptide and an immunoglobulin can be effectively bound to one and the other end of the non-peptidyl polymer, respectively.
  • a final product generated by reductive alkylation with an aldehyde bond is much more stable than that linked by an amide bond.
  • the aldehyde reactive group selectively binds to an N-terminus at a low pH and can form a covalent bond with a lysine residue at a high pH such as pH 9.0.
  • the reactive groups at both ends of the non-peptidyl polymer may be the same or different.
  • the non-peptidyl polymer may possess a maleimide group at one end, and an aldehyde group, a propionaldehyde group or a butyraldehyde group at the other end.
  • the hydroxy group may be activated to various reactive groups by known chemical reactions, or a polyethylene glycol having a commercially available modified reactive group may be used so as to prepare the long acting conjugate of the present invention.
  • the conjugate of the present invention may be one in which one end of the non-peptidyl polymer and the other are linked to an amine group or a thiol group of the immunoglobulin Fc region and the oxyntomodulin derivative, respectively.
  • the non-peptidyl polymer of the present invention has a functional group at both ends which can be linked to either an immunoglobulin Fc region or a protein drug.
  • the functional groups can be an aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group and a succinimide derivative (i.e., succinimidyl propionate, hydroxy succinimidyl, succinimidyl carboxymethyl, or succinimidyl carbonate), but are not limited thereto.
  • the reactive groups at both ends of the linker that is the non-peptidyl polymer may be the same or different.
  • the non-peptidyl polymer may have a maleimide group at one end and an aldehyde group, a propionaldehyde group or a butyraldehyde group at the other end.
  • the non-peptidyl polymer has a reactive aldehyde group at one end and a reactive maleimide group at the other end, non-specific reactions can be minimized, and a physiologically active polypeptide and an immunoglobulin can be effectively bound to both ends of the non-peptidyl polymer.
  • a conjugate was synthesized by linking oxyntomodulin or its derivative to the immunoglobulin Fc region via a covalent bond using the non-peptidyl polymer PEG including a propionaldehyde group alone or both a maleimide group and an aldehyde group.
  • the pharmaceutical composition of the present invention can be used for the prevention or treatment of hyperlipidemia, fatty liver disease or atherosclerosis.
  • prevention refers to all actions that inhibit or delay the development of a target disease.
  • prevention means administering the oxyntomodulin derivative of the present invention to inhibit or delay the development of hyperlipidemia, fatty liver disease or atherosclerosis, which shows an increase in blood total cholesterol and low-density cholesterol levels and a decrease in high-density cholesterol levels.
  • treatment refers to all actions that alleviate, ameliorate or relieve the symptoms of the disease developed.
  • treatment means administering the oxyntomodulin derivative of the present invention to alleviate, ameliorate or relieve hyperlipidemia, fatty liver disease or atherosclerosis, which shows an increase in blood total cholesterol and low-density cholesterol levels and a decrease in high-density cholesterol levels.
  • hyperlipidemia refers to a condition associated with abnormally elevated levels of lipids, such as free cholesterol, cholesterol esters, phospholipids and triglycerides, in blood.
  • lipids such as free cholesterol, cholesterol esters, phospholipids and triglycerides
  • hyperlipidemia does not show specific symptoms by itself, excessive lipids in blood adhere to the blood vessel walls to reduce the blood vessel size and cause atherosclerosis by inflammatory reactions. For this reason, coronary heart disease, cerebrovascular disease, obstruction of peripheral blood vessels, etc., can occur.
  • the pharmaceutical composition of the present invention can be used for the treatment of not only hyperlipidemia, fatty liver disease or atherosclerosis, but also coronary heart disease, cerebrovascular disease, or obstruction of peripheral blood vessels.
  • fatty liver disease refers to a condition in which the ratio of fats in the weight of the liver is more than 5%.
  • fatty liver diseases include non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, nutritional fatty liver disease, starvation fatty liver disease, obesity fatty liver disease, diabetic fatty liver disease or steatohepatitis.
  • NAFLD non-alcoholic fatty liver disease
  • the non-alcoholic fatty liver disease is meant to include primary and secondary non-alcoholic fatty liver disease, but may preferably be a non-alcoholic fatty liver disease resulting from primary hyperlipidemia, diabetes or obesity.
  • non-alcoholic fatty liver disease is meant to include simple steatosis, non-alcoholic steatohepatitis, and liver fibrosis and liver cirrhosis which result from the progression of such diseases.
  • Atherosclerosis refers to a vascular disease in which atheroma is formed as a result of deposition of cholesterol in the endothelium of blood vessels and proliferation of endothelial cells.
  • a long-acting oxyntomodulin derivative conjugate was prepared by linking the oxyntomodulin derivative to the immunoglobulin Fc region by a covalent bond using polyethylene glycol, and the prepared conjugate was administered to hamster animal models having hyperlipidemia induced by intake of high-fat diet.
  • the group administered with the long-acting oxyntomodulin derivative conjugate according to the present invention showed a significant decrease in blood triglyceride levels (FIG. 1), a significant decrease in blood total cholesterol levels (FIG. 2), and a significant decrease in blood low-density (LDL) cholesterol levels, compared to the hyperlipidemia-induced animal models.
  • the group administered with the long-acting oxyntomodulin derivative conjugate according to the present invention showed a significant increase in blood high-density (HDL) cholesterol levels (FIG. 4) and a significant increase in the blood HDL-cholesterol/LDL-cholesterol ratio (FIG. 5), compared to the hyperlipidemia-induced animal models.
  • HDL blood high-density
  • the long-acting oxyntomodulin derivative conjugate according to the present invention showed a decrease in blood total cholesterol levels (FIG. 6) and a decrease in blood LDL-cholesterol and triglyceride levels (FIG. 7), compared to VICTOZA ® that is a commercial long-acting GLP-1 analog.
  • administration of the long-acting oxyntomodulin derivative conjugate of the present invention showed increases in blood HDL-cholesterol level and the HDL/LDL-cholesterol ratio compared to administration of VICTOZA ® (FIGS.8 and 9).
  • a long-acting conjugate of the peptide of SEQ ID NO: 25 with Fc showed significant increases in blood HDL levels and HDL/LDL-cholesterol ratio compared to VICTOZA ® .
  • the oxyntomodulin derivative according to the present invention reduce blood lipid levels, and thus can be used as an agent for treating hyperlipidemia, fatty liver disease or arteriosclerosis.
  • the conjugate of the present invention has an excellent ability to activate GLP-1 receptor and glucagon receptor compared to native oxyntomodulin and shows an increased blood half-life in vivo, and thus the activity thereof can be maintained in vivo for an extended period of time.
  • the oxyntomodulin derivative of the present invention can increase the activity of a factor (Protein kinase C- ⁇ or PKC- ⁇ ) regulating the activity of enzymes that are involved in the lipolysis of fats, and increase the expression of a factor (Glut2) that is involved in the lipolysis of fats, thereby treating hyperlipidemia, fatty liver disease or arteriosclerosis, but the scope of the present invention is not limited to the above mechanism of action.
  • a factor Protein kinase C- ⁇ or PKC- ⁇
  • Glut2 a factor that is involved in the lipolysis of fats
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutical agent exhibiting preventive or therapeutic effects against hyperlipidemia, fatty liver disease or arteriosclerosis.
  • the composition of the present invention may further comprise a pharmaceutical agent known as an agent for treating hyperlipidemia, fatty liver disease or arteriosclerosis in order to administer the pharmaceutical agent in combination with the derivative of the present invention.
  • composition of the present invention may be administered alone or in combination with other drugs in order to prevent or treat hyperlipidemia, fatty liver disease or arteriosclerosis.
  • the term "administration" means introducing a given material into a patient by any appropriate method.
  • the derivative of the present invention may be administered by any general route, as long as it can reach a target tissue.
  • the derivative of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, locally, intranasally, intrapulmonarily or intrarectally, but is not limited thereto.
  • the oral composition is preferably formulated so that the active ingredient is coated or protected from degradation in the stomach.
  • the composition of the present invention may be administered in an injectable form.
  • the pharmaceutical composition of the present invention may be administered using any system capable of delivering the active ingredient to target cells.
  • composition comprising the oxyntomodulin derivative of the present invention may further comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a colorant, and a flavorant.
  • pharmaceutically acceptable carriers include a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, and a stabilizer.
  • pharmaceutically acceptable carriers include a base, an excipient, a lubricant, and a preservative.
  • the pharmaceutical composition of the present invention may be formulated in various dosage forms using the aforementioned pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated into tablets, troches, capsules, elixirs, suspensions, syrups, wafers or the like.
  • the pharmaceutical composition may be provided in the form of a unit dosage ampoule or a multiple dosage container.
  • the pharmaceutical composition may also be formulated into solutions, suspensions, tablets, pills, capsules and sustained-release preparations.
  • examples of the carrier, excipient and diluent suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils.
  • the pharmaceutical composition of the present invention may further include fillers, anti-coagulating agents, lubricants, wetting agents, flavors, preservative and the like.
  • the dose of the pharmaceutical composition of the present invention is determined according to the kind of active ingredient, together with various factors such as the disease to be treated, the route of administration, the patient's age, sex and weight, and the severity of the disease.
  • the pharmaceutical composition of the present invention has a long in vivo half-life and excellent-potency, and thus the number and frequency of administration of the pharmaceutical composition can be significantly reduced.
  • the present invention provides a method for treating hyperlipidemia, fatty liver disease or arteriosclerosis, the method comprising a step of administering the oxyntomodulin derivative of the present invention to a subject.
  • the above oxyntomodulin, hyperlipidemia, fatty liver disease and arteriosclerosis are as described above.
  • the term "subject” refers to a subject suspected of having hyperlipidemia, fatty liver disease or arteriosclerosis. Specifically, the term means mammals, including humans, rats and domestic animals, which have or are at the risk of developing the above disease. In addition, the subject may be any subject that can be treated by the oxyntomodulin derivative of the present invention.
  • the therapeutic method of the present invention may comprise administering a pharmaceutically effective amount of the pharmaceutical composition comprising the conjugate.
  • the total daily dose of the composition can be determined through appropriate medical judgment by a physician, and the composition may be administered once or several times.
  • the specific therapeutically effective dose of the composition for any particular patient may vary depending on various factors well known in the medical field, including the kind and degree of response to be achieved, concrete compositions according to whether other agents are used therewith or not, the patient'age, body weight, health condition, sex and diet, the time and route of administration, the secretion rate of the composition, the duration of treatment, other drugs used in combination or coincident with the composition of the present invention, and other factors known in the medical field.
  • the present invention provides a method for preparing an oxyntomodulin derivative conjugate.
  • the preparation method may comprise the steps of: (1) covalently linking a non-peptidyl polymer having a reactive aldehyde, maleimide or succinimide group to the amine or thiol group of an oxyntomodulin derivative peptide; (2) separating the oxyntomodulin derivative peptide, having the non-peptidyl polymer covalently bonded thereto at positions other than the amino terminal end, from the reaction mixture of step (1); and (3) covalently an immunoglobulin Fc region to the other end of the linked non-peptidyl polymer, thereby producing a peptide conjugate comprising the immunoglobulin Fc region and the oxyntomodulin derivative peptide, linked to one and the other end of the non-peptidyl polymer, respectively.
  • the preparation method may comprise the steps of: 1) covalently linking a non-peptidyl polymer, having a reactive aldehyde group and a reactive maleimide group at one and the other end thereof, respectively, to the cysteine residue of an oxyntomodulin derivative; (2) separating the oxyntomodulin derivative, having the non-peptidyl polymer covalently linked to the cysteine residue, from the reaction mixture of step (1); and (3) covalently an immunoglobulin Fc region to the other end of the linked non-peptidyl polymer, thereby producing a peptide conjugate comprising the immunoglobulin Fc region and the oxyntomodulin derivative peptide, linked to one and the other end of the non-peptidyl polymer, respectively.
  • the present invention provides the use of the oxyntomodulin derivative in the preparation of a medicament for preventing or treating hyperlipidemia, fatty liver disease or arteriosclerosis.
  • the oxyntomodulin derivative of the present invention has a high ability to activate GLP-1 receptor and glucagon receptor compared to native oxyntomodulin and exhibits the effects of reducing the blood total cholesterol, low-density cholesterol and triglyceride levels that were increased by high-fat diet, and increasing high-density cholesterol levels and the high-density cholesterol/low-density cholesterol ratio.
  • the oxyntomodulin derivative of the present invention can be effectively used for the treatment of hyperlipidemia and related diseases.
  • FIG. 1 is a graph showing the change in blood triglyceride levels caused by administration of a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (#: indicates a significant increase compared to a general diet group within a confidence of 99.9% ( p ⁇ 0.001);*:indicates a significant decrease compared to a high-fat diet group within a confidence of 99.9% ( p ⁇ 0.001).
  • FIG. 2 is a graph showing the change in blood total cholesterol levels caused by administration of a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (#: indicates a significant increase compared to a general diet group within a confidence of 99.9% ( p ⁇ 0.001);*:indicates a significant decrease compared to a high-fat diet group within a confidence of 99.9% ( p ⁇ 0.001).
  • FIG. 3 is a graph showing the change in blood LDL-cholesterol levels caused by administration of a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (#: indicates a significant increase compared to a general diet group within a confidence of 99.9% ( p ⁇ 0.001);*:indicates a significant decrease compared to a high-fat diet group within a confidence of 99.9% ( p ⁇ 0.001).
  • FIG. 4 is a graph showing the change in blood HDL-cholesterol levels caused by administration of a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (*: indicates a significant decrease compared to a high-fat diet group within a confidence of 99% ( p ⁇ 0.01).
  • FIG. 5 is a graph showing the change in blood HDL/LDL-cholesterol levels caused by administration of a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (*: shows a significant decrease compared to a high-fat diet group within a confidence of 95% ( p ⁇ 0.05).
  • FIG. 6 is a graph showing the change in blood total cholesterol levels caused by administration of VICTOZA ® or a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (***: indicates a significant decrease compared to a high-fat diet group within a confidence of 99.9% ( p ⁇ 0.001).
  • FIG. 7 is a graph showing the change in blood LDL-cholesterol levels caused by administration of VICTOZA ® or a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (***: indicates a significant decrease compared to a high-fat diet group within a confidence of 99.9% ( p ⁇ 0.001).
  • FIG. 8 is a graph showing the change in blood HDL-cholesterol levels caused by administration of VICTOZA ® or a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (*: indicates a significant decrease compared to a high-fat diet group within a confidence of 95% ( p ⁇ 0.05).
  • FIG. 9 is a graph showing the change in blood HDL/LDL-cholesterol levels caused by administration of VICTOZA ® or a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (**: indicates a significant decrease compared to a high-fat diet group within a confidence of 99% ( p ⁇ 0.01).
  • FIG. 10 is a graph showing the change in blood triglyceride levels caused by administration of VICTOZA ® or a long-acting oxyntomodulin derivative to high-fat diet-induced hyperlipidemia hamsters (***: indicates a significant decrease compared to a high-fat diet group within a confidence of 99.9% ( p ⁇ 0.001).
  • Example 1-1 Production of cell line showing cAMP response to GLP-1
  • PCR was performed using reverse and forward primers including a HindIII cleavage site and an EcoRI cleavage site, respectively, thereby obtaining a PCR product.
  • Reverse primer 5'-GAACGGTCCGGAGGACGTCGACTCTTAAGATAG-3' (SEQ ID NO: 51)
  • the PCR product was cloned into the known animal cell expression vector x0GC/dhfr, thereby constructing the recombinant vector x0GC/GLP-1R.
  • the recombinant vector x0GC/GLP-1R was introduced into a CHO DG44 cell line, cultured in DMEM/F12 (10% FBS) medium, using lipofectamine (Invitrogene, USA), to obtain a transformant.
  • the transformant was incubated in a selective medium containing 1 mg/mL G418 and 10 nM methotraxate, and monoclonal cell lines were selected therefrom. Then, a cell line showing a good concentration-dependent cAMP response to GLP-1 was finally selected from the monoclonal cell lines.
  • Example 1-2 Production of cell line showing cAMP response to glucagon
  • PCR was performed using reverse and forward primers including an EcoRI cleavage site and a XhoI cleavage site, respectively, thereby obtaining a PCR product.
  • the PCR product was cloned into the known animal cell expression vector x0GC/dhfr, thereby constructing the recombinant vector x0GC/GCGR.
  • the recombinant vector x0GC/GCGR was introduced into a CHO DG44 cell line, cultured in DMEM/F12 (10% FBS) medium, using lipofectamine (Invitrogene, USA), to obtain a transformant.
  • the transformant was incubated in a selective medium containing 1 mg/mL G418 and 10 nM methotraxate, and monoclonal cell lines were selected therefrom. Then, a cell line showing a good concentration-dependent cAMP response to glucagon was finally selected from the monoclonal cell lines.
  • oxyntomodulin derivatives having the amino acid sequences shown in Table 1 below.
  • amino acids indicated by the bold letters mean ring formation
  • amino acids indicated by X mean alpha-methyl-glutamic acid that is a non-native amino acid.
  • CA indicates 4-imidazoacetyl
  • DA indicates desamino-histidyl
  • Aib indicates aminosiobutyric acid
  • (d)S indicates d-serine.
  • Example 2-2 Measurement of in vitro activities of oxyntomodulin derivatives
  • Each of the transformants was transformed so as to express each of human GLP-1 receptor and glucagon receptor genes in CHO (Chinese hamster ovary) and was suitable for measuring the activities of GLP-1 and glucagon.
  • the activity of each of the oxyntomodulin derivatives was measured using each of the transformants.
  • each of the transformants was subcultured twice or three times a week, and the cells were dispensed into each well of a 96-well plate at a density of 1 X 10 5 cells/well and cultured for 24 hours.
  • the cultured cells were washed with KRB buffer, suspended in 40 ml of 1 mM IBMX-containing KRB buffer, and then allowed to stand at room temperature for 5 minutes.
  • Each of oxyntomodulin and the oxyntomodulin derivatives (SEQ ID NOs: 2-6, 8, 10-13, 17, 18, 23-25, 27, 28 and 32-34) was serially diluted by five-fold from 1000 nM to 0.02 nM, and 40 ml of each of the dilutions was added to the cells, which were then incubated in a CO 2 incubatorat37°C for 1 hour.
  • the oxyntomodulin derivatives showed excellent in vitro GLP-1 and glucagon activities compared to the oxyntomodulin of SEQ ID NO:1.
  • Oxyntomodulin is known to have the effect of treating hyperlipidemia, fatty liver disease or arteriosclerosis by activating GLP-1 receptor and glucagon receptor.
  • the oxyntomodulin derivatives according to the present invention have an excellent activity to activate GLP-1 receptor and glucagon receptor compared to native oxyntomodulin, and thus can be used to treat hyperlipidemia and the fatty liver disease and arteriosclerosis related to hyperlipidemia, in place of native oxyntomodulin.
  • Example 3 Preparation of a conjugate comprising an oxyntomodulin derivative ( SEQ ID NO : 23) with immunoglobulin Fc ( immunoglobulin Fc -conjugated oxyntomodulin derivative 23)
  • the oxyntomodulin derivative (SEQ ID NO: 23) and MAL-10K-ALD PEG were allowed to react with each other at molar ratio of 1:3 at a protein concentration of 3mg/ml at room temperature for 3 hours.
  • the reaction was performed in 50mM Tris buffer (pH 8.0) containing 1M guanidine.
  • reaction solution was purified using SOURCE S under the following conditions, thereby obtaining an oxyntomodulin mono-pegylated into the cysteine: column: SOURCE S, flow rate: 2.0 ml/min, gradient: A 0 ⁇ 100% 50 min B (A: 20 mM Na-citrate, pH 3.0 + 45% ethanol, B: A + 1M KCl)).
  • the purified mono-pegylated oxyntomodulin derivative (SEQ ID NO: 23) and immunoglobulin Fc were allowed to react with each other at a molar ratio of 1:5 at a protein concentration of 20 mg/ml at 4 °C for 16 hours.
  • the reaction was performed in 100 mM potassium phosphate buffer (pH 6.0) containing 20mM SCB as a reducing agent.
  • the reaction solution was purified under the following conditions, thereby obtaining a conjugate comprising the oxyntomodulin derivative (SEQ ID NO: 23) and immunoglobulin: column: SOURCE 15Q, flow rate: 2.0 ml/min, gradient: A 0 ⁇ 4% 1 min, B ⁇ 20% 80 min B (A: 20mM Tris-HCl, pH 7.5, B: A + 1M NaCl)); source ISO column: SOURCE ISO, flow rate: 2.0 ml/min, gradient: B 0 ⁇ 100% 100 min A, (A: 20mM Tris-HCl, pH 7.5, B: A + 1.1M AS).
  • Example 4 Preparation of a conjugate comprising an oxyntomodulin derivative ( SEQ ID NO : 25) with immunoglobulin Fc ( immunoglobulin Fc -conjugated oxyntomodulin derivative 25)
  • the oxyntomodulin derivative (SEQ ID NO: 25) and MAL-10K-ALD PEG were allowed to react with each other at molar ratio of 1:3 at a protein concentration of 3 mg/ml at room temperature for 3 hours.
  • the reaction was performed in 50mM Tris buffer (pH 8.0) containing 1M guanidine.
  • reaction solution was purified using SOURCE S under the following conditions, thereby obtaining an oxyntomodulin mono-pegylated into the cysteine: column: SOURCE S, flow rate: 2.0 ml/min, flow rate: A 0 ⁇ 100% 50 min B (A: 20 mM Na-citrate, pH 3.0 + 45% ethanol, B: A + 1M KCl).
  • the purified mono-pegylated oxyntomodulin derivative (SEQ ID NO: 25) and immunoglobulin Fc were allowed to react with each other at a molar ratio of 1:5 at a protein concentration of 20 mg/ml at 4 °C for 16 hours.
  • the reaction was performed in 100 mM potassium phosphate buffer (pH 6.0) containing 20mM SCB as a reducing agent.
  • the reaction solution was purified under the following conditions, thereby obtaining a conjugate comprising the oxyntomodulin derivative (SEQ ID NO: 25) and immunoglobulin:
  • SOURCE 15Q column SOURCE 15Q, flow rate: 2.0 ml/min, flow rate: A 0 ⁇ 4% 1 min B ⁇ 20% 80 min B (A: 20 mM Tris-HCl, pH 7.5, B: A + 1M NaCl); and Source ISO column: SOURCE ISO, flow rate: 2.0 ml/min, flow rate: B 0 ⁇ 100% 100 min A (A: 20mM Tris-HCl, pH 7.5, B: A + 1.1M AS).
  • Example 5 Effect of long-acting oxyntomodulin on reduction in lipid in hyperlipidemia model hamsters
  • Example 5-1 Grouping of test animals
  • hamsters 8 week-old male hamsters (Golden Syrian hamsters, 120-130 g) were purchased from Vital River China. It is known that hamsters show blood lipid profiles similar to humans, unlike other rodents, and are sensitive to high-fat diets.
  • the animals were allowed access to a sterilized high-fat diet (Purina 5001 containing 11.5% maize oil, 11.5% coconut oil, 0.5% cholesterol, and 0.25% deoxycholate; Dyets, Bethlehem, PA) or a standard rodent diet (low fat, 2018; Harlan Teklad, Madison, WI).
  • a normal diet group was allowed access to filtered and UV-sterilized tap water, and a high-fat diet group was allowed access to water containing 10% fructose.
  • the animals were kept in a breeding chamber satisfying GLP standards under a 12-hr light/12-hr dark cycle (lighting: am 6 to pm 6), and all the experimental procedures were performed according to the standard guideline for animal experiments.
  • group 1 normal group was fed with a normal feed and administered subcutaneously with 5 ml/kg of Dulbecco's phosphate buffered saline (DPBS, Sigma) once or more a week.
  • DPBS Dulbecco's phosphate buffered saline
  • Group 2 hyperlipidemia-induced group was fed with a high-fat diet to induce hyperlipidemia, and then administered subcutaneously with 5 ml/kg of Dulbecco's phosphate buffered saline (DPBS, Sigma) once or more a week.
  • DPBS Dulbecco's phosphate buffered saline
  • Group 3 hyperlipidemia-induced group + group administered with 3.25 nmol/kg of SEQ ID NO: 25-Fc conjugate
  • Group 3 was fed with a high-fat diet to induce hyperlipidemia, and then administered with 3.25 nmol/kg of the SEQ ID NO: 25-Fc conjugate (prepared in Example 4) once a week at an injection dose of 5 ml/kg.
  • Group 4 hyperlipidemia-induced group + group administered with 8.96 nmol/kg of SEQ ID NO: 23-Fc conjugate
  • Group 4 was fed with a high-fat diet to induce hyperlipidemia, and then administered with 8.96 nmol/kg of the SEQ ID NO: 23-Fc conjugate (prepared in Example 3) once a week at an injection dose of 5 ml/kg.
  • Example 5-2 Analysis of effect of long-acting oxyntomodulin derivative conjugate on reduction in lipid levels
  • FIGS. 1 to 5 show the change in blood triglyceride levels (FIG. 1), the change in blood total cholesterol levels (FIG. 2), the change in LDL-cholesterol levels (FIG. 3), blood HDL-cholesterol levels (FIG. 4), and the change in the blood HDL/LDL-cholesterol ratio (FIG. 5).
  • the obtained results were statistically processed, and the mean values and the standard deviations of the mean values were calculated.
  • data were statistically processed using Dunnett's test of one-way ANOVA, and a value of p ⁇ 0.05 was considered statistically significant.
  • the group administered with the SEQ ID NO: 25-Fc conjugate or the SEQ ID NO: 23-Fc conjugate showed a significant increase in the blood HDL-cholesterol levels compared to the high-fat diet hamster group (FIG. 4).
  • the group administered with the SEQ ID NO: 25-Fc conjugate or the SEQ ID NO: 23-Fc conjugate showed a significant increase in the blood HDL/LDL-cholesterol ratio compared to the high-fat diet hamster group (FIG. 5).
  • the inventive oxyntomodulin derivative conjugate comprising the immunoglobulin Fc region covalently linked to the oxyntomodulin derivative by PEG prevents the accumulation of blood triglyceride and low-density (LDL) cholesterol, and thus can be effectively used for the treatment of hyperlipidemia or related fatty liver disease or arteriosclerosis.
  • LDL low-density
  • VICTOZA ® is a long-acting glucagon-like peptide-1, GLP-1 analog which is currently marketed as an agent for treating diabetes and is known to have the effects of treating obesity and increasing HDL cholesterol levels.
  • hamsters were divided into a normal hamster group and hamster groups fed with a high-fat diet.
  • the normal hamster group was administered subcutaneously with 5 ml/kg of DPBS once or more a week.
  • the hamster groups fed with high-fat diet were divided into a group administered subcutaneously with 5 ml/kg of DPBS once or more a week, a group administered subcutaneously with 35.5 nmol/kg of VICTOZA ® once or more a week,a group administered subcutaneously with 3.25 nmol/kg of the SEQ ID NO: 25-Fc conjugate,and a group administered subcutaneously with 8.96 nmol/kg ofthe SEQ ID NO:23-Fc conjugate,and the blood lipid levels of the groups were analyzed.
  • inventive long-acting oxyntomodulin derivative conjugate (SEQ ID NO: 25-Fc conjugate or SEQ ID NO: 23-Fc conjugate) showed increases in blood HDL-cholesterol levels and the HDL/LDL-cholesterol ratio compared to administration of VICTOZA ® (FIGS.8 and 9).
  • the long-acting SEQ ID NO: 25-Fc conjugate showed significant increases in blood HDL-cholesterol levels and the HDL/LDL-cholesterol ratio compared to VICTOZA ® .
  • inventive long-acting oxyntomodulin derivative conjugate (SEQ ID NO: 25-Fc conjugate or SEQ ID NO: 23-Fc conjugate) showed a decrease in blood triglyceride levels compared to administration of VICTOZA ® .
  • the long-acting oxyntomodulin derivative conjugate of the present invention exhibits a lipid-lowering effect that is equal to or higher than that of known VICTOZA ® , and thus the conjugate can be effectively used as an agent for treating hyperlipidemia, fatty liver disease or arteriosclerosis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Toxicology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biotechnology (AREA)
PCT/KR2013/006668 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative Ceased WO2014017843A1 (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
BR112015001596-4A BR112015001596B1 (pt) 2012-07-25 2013-07-25 Uso de uma composição compreendendo um derivado de oxintomodulina como um ingrediente ativo e uso de um derivado de oxintomodulina
EP20188520.9A EP3766520A1 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
MX2015001218A MX360024B (es) 2012-07-25 2013-07-25 Composicion para el tratamiento de la hiperlipidemia que comprende un derivado de oxintomodulina.
BR122022025353-9A BR122022025353B1 (pt) 2012-07-25 2013-07-25 Composição e uso de conjugado de derivado de oxintomodulina para a prevenção ou tratamento de hiperlipidemia, doença hepática gordurosa ou arteriosclerose
RU2015104492A RU2642267C2 (ru) 2012-07-25 2013-07-25 Композиция для лечения гиперлипидемии, содержащая производное оксинтомодулина
US14/415,200 US20150182593A1 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
CN201380039596.XA CN104507492B (zh) 2012-07-25 2013-07-25 治疗高脂血症的包含泌酸调节肽衍生物的组合物
JP2015524182A JP2015524427A (ja) 2012-07-25 2013-07-25 オキシントモジュリン誘導体を含む高脂血症の治療のための組成物
AU2013293714A AU2013293714B2 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
CA2888407A CA2888407C (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
EP18169490.2A EP3384925B1 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
EP13823727.6A EP2884994B1 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
UAA201501078A UA118177C2 (uk) 2012-07-25 2013-07-25 Композиція для лікування гіперліпідемії, яка містить похідну оксинтомодуліну
ES13823727T ES2942187T3 (es) 2012-07-25 2013-07-25 Composición para tratar la hiperlipidemia que comprende un derivado de oxintomodulina
SG11201500519UA SG11201500519UA (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
NZ705384A NZ705384A (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
HK15107083.6A HK1206280B (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
PH12015500158A PH12015500158B1 (en) 2012-07-25 2015-01-23 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
IL236913A IL236913B (en) 2012-07-25 2015-01-25 The composition containing an oxyntomodulin derivative for the treatment of hyperlipidemia
ZA2015/01238A ZA201501238B (en) 2012-07-25 2015-02-24 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
US15/086,499 US9901621B2 (en) 2012-07-25 2016-03-31 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
US15/846,395 US10493132B2 (en) 2012-07-25 2017-12-19 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
AU2018203729A AU2018203729B2 (en) 2012-07-25 2018-05-28 Composition For Treating Hyperlipidemia Comprising Oxyntomodulin Derivative
PH12019501131A PH12019501131A1 (en) 2012-07-25 2019-05-21 Composition for treating hyperlipidemia comprising oxytomodulin derivative
IL274106A IL274106B2 (en) 2012-07-25 2020-04-21 The composition containing an oxyntomodulin derivative for the treatment of hyperlipidemia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2012-0081475 2012-07-25
KR1020120081475A KR101968344B1 (ko) 2012-07-25 2012-07-25 옥신토모듈린 유도체를 포함하는 고지혈증 치료용 조성물

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/415,200 A-371-Of-International US20150182593A1 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative
US15/086,499 Division US9901621B2 (en) 2012-07-25 2016-03-31 Composition for treating hyperlipidemia comprising oxyntomodulin derivative

Publications (1)

Publication Number Publication Date
WO2014017843A1 true WO2014017843A1 (en) 2014-01-30

Family

ID=49997578

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2013/006668 Ceased WO2014017843A1 (en) 2012-07-25 2013-07-25 Composition for treating hyperlipidemia comprising oxyntomodulin derivative

Country Status (24)

Country Link
US (3) US20150182593A1 (enExample)
EP (3) EP2884994B1 (enExample)
JP (4) JP2015524427A (enExample)
KR (1) KR101968344B1 (enExample)
CN (2) CN104507492B (enExample)
AR (1) AR091903A1 (enExample)
AU (2) AU2013293714B2 (enExample)
BR (2) BR122022025353B1 (enExample)
CA (2) CA2888407C (enExample)
CL (4) CL2015000177A1 (enExample)
DK (1) DK3384925T3 (enExample)
ES (2) ES2942187T3 (enExample)
IL (2) IL236913B (enExample)
MX (2) MX360024B (enExample)
MY (2) MY171493A (enExample)
NZ (2) NZ731657A (enExample)
PE (1) PE20150633A1 (enExample)
PH (2) PH12015500158B1 (enExample)
RU (2) RU2768853C1 (enExample)
SG (2) SG11201500519UA (enExample)
TW (3) TWI661837B (enExample)
UA (2) UA118177C2 (enExample)
WO (1) WO2014017843A1 (enExample)
ZA (2) ZA201501238B (enExample)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015183054A1 (en) 2014-05-30 2015-12-03 Hanmi Pharm. Co., Ltd. Composition for treating diabetes mellitus comprising insulin and a glp-1/glucagon dual agonist
US9365632B2 (en) 2012-10-09 2016-06-14 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
WO2016198628A1 (en) 2015-06-12 2016-12-15 Sanofi Non-acylated exendin-4 derivatives as dual glp-1/glucagon receptor agonists
WO2016198624A1 (en) 2015-06-12 2016-12-15 Sanofi Exendin-4 derivatives as trigonal glp-1/glucagon/gip receptor agonists
US9522946B2 (en) 2011-06-10 2016-12-20 Hanmi Science Co., Ltd. Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9724420B2 (en) 2012-11-06 2017-08-08 Hanmi Pharm. Co., Ltd. Liquid formulation of protein conjugate comprising an oxyntomodulin derivative covalently linked to a non-peptidyl polymer to an immunoglobulin FC region
US9731031B2 (en) 2011-06-17 2017-08-15 Hanmi Science Co., Ltd. Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof
CN107106660A (zh) * 2014-09-16 2017-08-29 韩美药品株式会社 长效glp‑1/胰高血糖素受体双激动剂对于治疗非酒精性脂肪肝疾病的应用
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9901621B2 (en) 2012-07-25 2018-02-27 Hanmi Pharm. Co., Ltd. Composition for treating hyperlipidemia comprising oxyntomodulin derivative
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
WO2018069422A1 (en) * 2016-10-12 2018-04-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of non-alcoholic fatty liver disease
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10017557B2 (en) 2015-08-28 2018-07-10 Hanmi Pharm. Co., Ltd. Insulin analogs and use thereof
US10159715B2 (en) 2014-05-29 2018-12-25 Hanmi Pharm. Co., Ltd Method for treating diabetes comprising long-acting insulin analogue conjugate and long-acting insulinotropic peptide conjugate
US10253082B2 (en) 2014-01-20 2019-04-09 Hanmi Pharm. Co., Ltd Long-acting insulin and use thereof
CN109641035A (zh) * 2016-06-29 2019-04-16 韩美药品株式会社 胰高血糖素衍生物、其缀合物、包含其的组合物、和其治疗用途
US10370426B2 (en) 2015-12-31 2019-08-06 Hanmi Pharm. Co., Ltd Triple glucagon/GLP-1/GIP receptor agonist
WO2019171352A3 (en) * 2018-03-08 2019-11-07 Janssen Pharmaceutica Nv Methods of treating severe non-diabetic obesity
WO2020017916A1 (en) 2018-07-19 2020-01-23 D&D Pharmatech Inc. Pharmaceutical composition comprising polypeptide
US10696725B2 (en) 2015-06-30 2020-06-30 Hanmi Pharm. Co., Ltd. Glucagon derivative and a composition comprising a long acting conjugate of the same
WO2020128967A3 (en) * 2018-12-19 2020-07-30 Janssen Pharmaceutica Nv Efinopegdutide for use in the treatment of severe non-diabetic obesity
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
WO2021148664A1 (en) * 2020-01-24 2021-07-29 Keybioscience Ag Oxyntomodulin mimetics
EP3708577A4 (en) * 2017-11-06 2021-09-01 Shenzhen Turier Biotech Co., Ltd. TREATMENT OF BILARY CIRROUS BASED ON AN OXYNTOMODULIN ANALOGUE GLP-1R / GCGR DUAL-TARGET ANGONIST PEPTID
US11135271B2 (en) 2014-12-30 2021-10-05 Hanmi Pharm. Co., Ltd. Glucagon derivatives with improved stability
EP3670529A4 (en) * 2017-08-16 2021-11-03 Dong-A St Co., Ltd. ACYLATED OXYNTOMODULIN PEPTIDE ANALOG
US11254724B2 (en) 2014-12-30 2022-02-22 Hanmi Pharm. Co., Ltd. Glucagon derivatives
US11396534B2 (en) 2016-09-23 2022-07-26 Hanmi Pharm. Co., Ltd. Insulin analogs with reduced affinity to insulin receptor and use thereof
US11752216B2 (en) 2017-03-23 2023-09-12 Hanmi Pharm. Co., Ltd. Insulin analog complex with reduced affinity for insulin receptor and use thereof

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20130049671A (ko) 2011-11-04 2013-05-14 한미사이언스 주식회사 생리활성 폴리펩타이드 결합체 제조 방법
AR090281A1 (es) 2012-03-08 2014-10-29 Hanmi Science Co Ltd Proceso mejorado para la preparacion de un complejo polipeptidico fisiologicamente activo
KR101993393B1 (ko) 2012-11-06 2019-10-01 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 당뇨병 또는 비만성 당뇨병 치료용 조성물
AR098616A1 (es) * 2013-12-18 2016-06-01 Lilly Co Eli Péptido para el tratamiento de hipoglicemia severa
DK3127923T3 (da) * 2014-03-31 2021-11-22 Hanmi Pharm Ind Co Ltd Fremgangsmåde til forbedring af oppløselighed af protein og peptid ved hjælp af immunoglobulin-fc-fragment-binding
AR107823A1 (es) * 2016-03-07 2018-06-06 Hanmi Pharm Ind Co Ltd Derivados de polietilenglicol y uso de los mismos
EA201891946A1 (ru) * 2016-03-10 2019-04-30 Медиммун Лимитед Коагонисты глюкагона и glp-1 для лечения ожирения
CN106046145B (zh) 2016-04-22 2022-11-04 深圳市图微安创科技开发有限公司 Glp-1r/gcgr双靶点激动剂多肽治疗脂肪肝病、高脂血症和动脉硬化
CN110545852B (zh) 2017-02-07 2023-05-26 韩美药品株式会社 非肽聚合物接头化合物、包含该接头化合物的缀合物及制备该接头化合物和缀合物的方法
KR102686854B1 (ko) * 2017-08-09 2024-07-18 사노피 지방간 질환 및 지방간염의 치료에서의 glp-1/글루카곤 수용체 작용제
KR20200135618A (ko) * 2019-05-23 2020-12-03 ㈜ 디앤디파마텍 폴리펩티드를 포함하는 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물
WO2020017919A1 (ko) * 2018-07-19 2020-01-23 한미정밀화학주식회사 생리활성 폴리펩타이드에 사용되는 신규한 중간체 및 이의 제조방법
US12441776B2 (en) 2018-11-30 2025-10-14 Eirgen Pharma Ltd. Oxyntomodulin peptide analog formulations
EP3939990A4 (en) * 2019-02-15 2023-05-24 Hanmi Fine Chemical Co., Ltd. NOVEL INTERMEDIATE FOR BIOLOGICALLY ACTIVE POLYPEPTIDE AND PROCESS FOR THE PRODUCTION THEREOF
KR20220050820A (ko) * 2020-10-16 2022-04-25 한미약품 주식회사 Glp-1/gip 이중작용제, 이의 지속형 결합체, 및 이를 포함하는 약학적 조성물

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032478A1 (en) 1995-04-14 1996-10-17 Genentech, Inc. Altered polypeptides with increased half-life
WO1997034631A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
WO2009033756A2 (en) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2010107256A2 (en) * 2009-03-20 2010-09-23 Hanmi Pharm. Co., Ltd. Method for preparing a site-specific physiologically active polypeptide conjugate
US7928058B2 (en) * 2006-02-22 2011-04-19 Merck Sharp & Dohme Corp. Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition
WO2011071957A1 (en) * 2009-12-07 2011-06-16 Sea Lane Biotechnologies, Llc Conjugates comprising an antibody surrogate scaffold with improved pharmacokinetic properties
EP1891105B1 (en) * 2005-06-13 2012-04-11 Imperial Innovations Limited Oxyntomodulin analogues and their effects on feeding behaviour
WO2012173422A1 (en) * 2011-06-17 2012-12-20 Hanmi Science Co., Ltd. A conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof

Family Cites Families (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1060746A4 (en) 1998-03-06 2002-06-19 Chugai Pharmaceutical Co Ltd PROTEIN-FREE PREPARATIONS
US6660843B1 (en) 1998-10-23 2003-12-09 Amgen Inc. Modified peptides as therapeutic agents
US6677136B2 (en) 2000-05-03 2004-01-13 Amgen Inc. Glucagon antagonists
GB0121709D0 (en) * 2001-09-07 2001-10-31 Imp College Innovations Ltd Food inhibition agent
US7217845B2 (en) 2002-11-25 2007-05-15 Sun Bio, Inc. Bifunctional polyethylene glycol derivatives
GB0300571D0 (en) 2003-01-10 2003-02-12 Imp College Innovations Ltd Modification of feeding behaviour
CA2513213C (en) 2003-01-22 2013-07-30 Human Genome Sciences, Inc. Albumin fusion proteins
US7772188B2 (en) * 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2005035761A1 (en) 2003-10-16 2005-04-21 Compugen Ltd. Splice variants of preproglucagon, glucagon-like peptide-1 and oxyntomodulin
US8263084B2 (en) * 2003-11-13 2012-09-11 Hanmi Science Co., Ltd Pharmaceutical composition for treating obesity-related disease comprising insulinotropic peptide conjugate
US20090238838A1 (en) 2003-11-13 2009-09-24 Hanmi Pharm. Ind. Co. Ltd. Insulinotropic peptide conjugate using an immunoglobulin fc
KR101135244B1 (ko) 2007-11-29 2012-04-24 한미사이언스 주식회사 인슐린 분비 펩타이드 결합체를 포함하는 비만 관련질환 치료용 조성물
BRPI0406606A (pt) 2003-11-13 2005-12-06 Hanmi Pharm Ind Co Ltd Composição farmacêutica compreendendo uma região fc de imunoglobulina como um veìculo
CA2589800A1 (en) 2004-12-02 2006-06-08 Domantis Limited Bispecific domain antibodies targeting serum albumin and glp-1 or pyy
WO2006086769A2 (en) 2005-02-11 2006-08-17 Amylin Pharmaceuticals, Inc. Gip analog and hybrid polypeptides with selectable properties
KR100754667B1 (ko) 2005-04-08 2007-09-03 한미약품 주식회사 비펩타이드성 중합체로 개질된 면역글로불린 Ｆｃ 단편 및이를 포함하는 약제학적 조성물
GB0511986D0 (en) 2005-06-13 2005-07-20 Imp College Innovations Ltd Novel compounds and their effects on feeding behaviour
EP2330124B1 (en) 2005-08-11 2015-02-25 Amylin Pharmaceuticals, LLC Hybrid polypeptides with selectable properties
EP2046367A4 (en) 2006-06-07 2009-11-11 Human Genome Sciences Inc ALBUM INFUSION PROTEINS
TWI428346B (zh) 2006-12-13 2014-03-01 Imp Innovations Ltd 新穎化合物及其等對進食行為影響
GB0624868D0 (en) 2006-12-13 2007-01-24 Imp Innovations Ltd Novel compounds and their effects on feeding behaviour
US20090098130A1 (en) 2007-01-05 2009-04-16 Bradshaw Curt W Glucagon-like protein-1 receptor (glp-1r) agonist compounds
JP2008169195A (ja) 2007-01-05 2008-07-24 Hanmi Pharmaceutical Co Ltd キャリア物質を用いたインスリン分泌ペプチド薬物結合体
EA017849B1 (ru) 2007-02-15 2013-03-29 Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн Соагонисты глюкагоновых/glp-1-рецепторов
EA201070121A1 (ru) 2007-07-10 2010-06-30 Эли Лилли Энд Компани Лекарственная форма, содержащая слитый белок glp-1-fc
WO2009058734A1 (en) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Compounds exhibiting glucagon antagonist and glp-1 agonist activity
JP2011511778A (ja) 2008-01-30 2011-04-14 インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーション エステルに基づいたペプチドプロドラッグ
US8450270B2 (en) 2008-06-17 2013-05-28 Indiana University Research And Technology Corporation Glucagon analogs exhibiting enhanced solubility and stability in physiological pH buffers
PA8830501A1 (es) 2008-06-17 2010-07-27 Univ Indiana Res & Tech Corp Co-agonistas del receptor de glucagon/glp-1
WO2010013012A2 (en) 2008-08-01 2010-02-04 Lund University Bioscience Ab Novel polypeptides and uses thereof
MX2011003117A (es) 2008-09-19 2011-04-21 Nektar Therapeutics Conjugados polimericos de peptidos terapeuticos.
WO2010033220A2 (en) 2008-09-19 2010-03-25 Nektar Therapeutics Modified therapeutics peptides, methods of their preparation and use
ES2439499T3 (es) 2008-12-15 2014-01-23 Zealand Pharma A/S Análogos de glucagón
US8680049B2 (en) * 2008-12-15 2014-03-25 Zealand Pharma A/S Glucagon analogues
CN102325539A (zh) 2008-12-19 2012-01-18 印第安纳大学研究及科技有限公司 基于酰胺的胰高血糖素超家族肽前药
WO2010096052A1 (en) 2009-02-19 2010-08-26 Merck Sharp & Dohme Corp. Oxyntomodulin analogs
CA2755133A1 (en) 2009-03-20 2010-09-23 Amgen Inc. Selective and potent peptide inhibitors of kv1.3
CN102459325B (zh) 2009-06-16 2015-03-25 印第安纳大学科技研究有限公司 胃抑胜肽受体活化的胰高血糖素化合物
PT2454282E (pt) 2009-07-13 2015-06-23 Zealand Pharma As Análogos de glucagão acilados
US20120294855A1 (en) 2009-11-03 2012-11-22 Eli Lilly & Company Glp-1 receptor agonist compounds for obstructive sleep apnea
US8703701B2 (en) * 2009-12-18 2014-04-22 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
AR079344A1 (es) 2009-12-22 2012-01-18 Lilly Co Eli Analogo peptidico de oxintomodulina, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para tratar diabetes no insulinodependiente y/u obesidad
AR079345A1 (es) * 2009-12-22 2012-01-18 Lilly Co Eli Analogo peptidico de oxintomodulina
BR112012024379A2 (pt) 2010-03-26 2017-01-10 Novo Nordisk As "peptídeos glucagon, seu uso, bem como composição farmacêutica"
CN103179976A (zh) * 2010-05-13 2013-06-26 印第安纳大学研究及科技有限公司 呈现g蛋白偶联受体活性的胰高血糖素超家族肽
RU2580317C2 (ru) 2010-06-24 2016-04-10 Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн Пептидные пролекарства, принадлежащие к суперсемейству амид-содержащих глюкагонов
KR101382593B1 (ko) 2010-07-21 2014-04-10 한미사이언스 주식회사 신규한 지속형 글루카곤 결합체 및 이를 포함하는 비만 예방 및 치료용 약학적 조성물
CN101974077A (zh) * 2010-09-15 2011-02-16 南京瑞年天平医药科技有限公司 一种新颖的多肽化合物
KR101303388B1 (ko) 2010-10-26 2013-09-03 한미사이언스 주식회사 지속형 인터페론 알파 결합체의 액상 제제
KR101767570B1 (ko) * 2010-10-26 2017-08-14 한미사이언스 주식회사 항 비만 펩타이드의 지속형 결합체
CN102010473A (zh) 2010-11-10 2011-04-13 曹鹏 重组胃泌酸调节素融合蛋白及其制备和应用
AR084558A1 (es) 2010-12-22 2013-05-22 Marcadia Biotech Metodos para tratar trastornos metabolicos y obesidad con peptidos basados en glucagon activos para el receptor de peptido insulinotropico dependiente de glucosa (gip)/peptido-1 similar al glucagon (glp-1)
EP2492749A1 (en) 2011-02-28 2012-08-29 Rohm and Haas Electronic Materials LLC Photoresist compositions and methods of forming photolithographic patterns
KR101161526B1 (ko) 2011-05-16 2012-07-02 숭실대학교산학협력단 연료전지용 촉매전극을 위한 코어/쉘 구조의 나노 지지체 및 그 제조방법
RU2739209C2 (ru) 2011-06-10 2020-12-21 Ханми Сайенс Ко., Лтд. Новые производные оксинтомодулина и содержащая их фармацевтическая композиция для лечения ожирения
CA2839867A1 (en) 2011-06-22 2012-12-27 Indiana University Research And Technology Corporation Glucagon/glp-1 receptor co-agonists
KR101665009B1 (ko) 2012-03-09 2016-10-11 한미사이언스 주식회사 비알콜성 지방간 질환의 예방 또는 치료용 약학적 조성물
WO2013157002A1 (en) 2012-04-19 2013-10-24 Prolor Biotech Inc. Long-acting oxyntomodulin variants and methods of producing same
JP6311708B2 (ja) 2012-06-21 2018-04-18 インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ Ｇｉｐ受容体活性を示すグルカゴンアナローグ
KR101968344B1 (ko) * 2012-07-25 2019-04-12 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 고지혈증 치료용 조성물
AR092873A1 (es) 2012-09-26 2015-05-06 Cadila Healthcare Ltd Peptidos como agonistas triples de los receptores de gip, glp-1 y glugagon
US9724420B2 (en) * 2012-11-06 2017-08-08 Hanmi Pharm. Co., Ltd. Liquid formulation of protein conjugate comprising an oxyntomodulin derivative covalently linked to a non-peptidyl polymer to an immunoglobulin FC region
KR101993393B1 (ko) 2012-11-06 2019-10-01 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 당뇨병 또는 비만성 당뇨병 치료용 조성물
JP6137046B2 (ja) 2014-05-09 2017-05-31 信越化学工業株式会社 単量体、高分子化合物、レジスト材料及びパターン形成方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032478A1 (en) 1995-04-14 1996-10-17 Genentech, Inc. Altered polypeptides with increased half-life
WO1997034631A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
EP1891105B1 (en) * 2005-06-13 2012-04-11 Imperial Innovations Limited Oxyntomodulin analogues and their effects on feeding behaviour
US7928058B2 (en) * 2006-02-22 2011-04-19 Merck Sharp & Dohme Corp. Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition
WO2009033756A2 (en) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
WO2010107256A2 (en) * 2009-03-20 2010-09-23 Hanmi Pharm. Co., Ltd. Method for preparing a site-specific physiologically active polypeptide conjugate
WO2011071957A1 (en) * 2009-12-07 2011-06-16 Sea Lane Biotechnologies, Llc Conjugates comprising an antibody surrogate scaffold with improved pharmacokinetic properties
WO2012173422A1 (en) * 2011-06-17 2012-12-20 Hanmi Science Co., Ltd. A conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ASSMAN ET AL., AM. J. CARD, 1996
E. FALK ET AL., CIRCULATION, 1995
H. NEURATH; R. L. HILL: "The Proteins", 1979, ACADEMIC PRESS, NEW YORK
See also references of EP2884994A4

Cited By (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9522946B2 (en) 2011-06-10 2016-12-20 Hanmi Science Co., Ltd. Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
US9527898B2 (en) 2011-06-10 2016-12-27 Hanmi Science Co., Ltd. Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
US9765131B2 (en) 2011-06-10 2017-09-19 Hanmi Science Co., Ltd. Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
US9731031B2 (en) 2011-06-17 2017-08-15 Hanmi Science Co., Ltd. Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof
US11872283B2 (en) 2011-06-17 2024-01-16 Hanmi Science Co., Ltd Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof
US10363320B2 (en) 2011-06-17 2019-07-30 Hanmi Science Co., Ltd. Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof
US9901621B2 (en) 2012-07-25 2018-02-27 Hanmi Pharm. Co., Ltd. Composition for treating hyperlipidemia comprising oxyntomodulin derivative
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9365632B2 (en) 2012-10-09 2016-06-14 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US11071785B2 (en) 2012-11-06 2021-07-27 Hanmi Pharm. Co., Ltd. Liquid formulation of long-lasting protein conjugate comprising the oxyntomodulin and an immunoglobulin Fc region
US9724420B2 (en) 2012-11-06 2017-08-08 Hanmi Pharm. Co., Ltd. Liquid formulation of protein conjugate comprising an oxyntomodulin derivative covalently linked to a non-peptidyl polymer to an immunoglobulin FC region
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US10253082B2 (en) 2014-01-20 2019-04-09 Hanmi Pharm. Co., Ltd Long-acting insulin and use thereof
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US10159715B2 (en) 2014-05-29 2018-12-25 Hanmi Pharm. Co., Ltd Method for treating diabetes comprising long-acting insulin analogue conjugate and long-acting insulinotropic peptide conjugate
EP3148571A4 (en) * 2014-05-30 2017-12-20 Hanmi Pharm. Co., Ltd. Composition for treating diabetes mellitus comprising insulin and a glp-1/glucagon dual agonist
JP2017518298A (ja) * 2014-05-30 2017-07-06 ハンミ ファーマシューティカル カンパニー リミテッド インスリン及びｇｌｐ−１／グルカゴン二重アゴニストを含む糖尿病治療用組成物
JP2020164534A (ja) * 2014-05-30 2020-10-08 ハンミ ファーマシューティカル カンパニー リミテッド インスリン及びｇｌｐ−１／グルカゴン二重アゴニストを含む糖尿病治療用組成物
KR102429920B1 (ko) * 2014-05-30 2022-08-09 한미약품 주식회사 인슐린 및 glp-1/글루카곤 이중작용제를 포함하는 당뇨병 치료용 조성물
KR20150138119A (ko) * 2014-05-30 2015-12-09 한미약품 주식회사 인슐린 및 glp-1/글루카곤 이중작용제를 포함하는 당뇨병 치료용 조성물
WO2015183054A1 (en) 2014-05-30 2015-12-03 Hanmi Pharm. Co., Ltd. Composition for treating diabetes mellitus comprising insulin and a glp-1/glucagon dual agonist
US10188703B2 (en) 2014-05-30 2019-01-29 Hanmi Pharm. Co., Ltd. Method for treating diabetes mellitus by a composition comprising insulin and a GLP-1/glucagon dual agonist
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
JP2017529354A (ja) * 2014-09-16 2017-10-05 ハンミ ファーマシューティカル カンパニー リミテッド 非アルコール性脂肪性肝疾患を治療するための長時間作用性ｇｌｐ−１／グルカゴン受容体デュアルアゴニストの使用
US10233230B2 (en) * 2014-09-16 2019-03-19 Hanmi Pharm. Co., Ltd. Use of a long acting GLP-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease
CN107106660B (zh) * 2014-09-16 2021-10-22 韩美药品株式会社 长效glp-1/胰高血糖素受体双激动剂对于治疗非酒精性脂肪肝疾病的应用
US10435459B2 (en) 2014-09-16 2019-10-08 Hanmi Pharm. Co., Ltd. Use of a long acting GLP-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease
JP2021035942A (ja) * 2014-09-16 2021-03-04 ハンミ ファーマシューティカル カンパニー リミテッド 非アルコール性脂肪性肝疾患を治療するための長時間作用性ｇｌｐ−１／グルカゴン受容体デュアルアゴニストの使用
EP3197483A4 (en) * 2014-09-16 2018-05-09 Hanmi Pharm. Co., Ltd. Use of a long acting glp-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease
CN107106660A (zh) * 2014-09-16 2017-08-29 韩美药品株式会社 长效glp‑1/胰高血糖素受体双激动剂对于治疗非酒精性脂肪肝疾病的应用
US11254724B2 (en) 2014-12-30 2022-02-22 Hanmi Pharm. Co., Ltd. Glucagon derivatives
US12018060B2 (en) 2014-12-30 2024-06-25 Hanmi Pharm Co., Ltd. Glucagon derivatives
US11135271B2 (en) 2014-12-30 2021-10-05 Hanmi Pharm. Co., Ltd. Glucagon derivatives with improved stability
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
WO2016198624A1 (en) 2015-06-12 2016-12-15 Sanofi Exendin-4 derivatives as trigonal glp-1/glucagon/gip receptor agonists
WO2016198628A1 (en) 2015-06-12 2016-12-15 Sanofi Non-acylated exendin-4 derivatives as dual glp-1/glucagon receptor agonists
EP4523705A3 (en) * 2015-06-30 2025-06-11 Hanmi Pharm. Co., Ltd. Glucagon derivative and a composition comprising a long acting conjugate of the same
US10696725B2 (en) 2015-06-30 2020-06-30 Hanmi Pharm. Co., Ltd. Glucagon derivative and a composition comprising a long acting conjugate of the same
US11261227B2 (en) 2015-06-30 2022-03-01 Hanmi Pharm. Co., Ltd. Glucagon derivative and a composition comprising a long acting conjugate of the same
JP2023062043A (ja) * 2015-06-30 2023-05-02 ハンミ ファーマシューティカル カンパニー リミテッド グルカゴン誘導体及びその持続型結合体を含む組成物
US11667688B2 (en) 2015-06-30 2023-06-06 Hanmi Pharm. Co., Ltd. Glucagon derivative and a composition comprising a long acting conjugate of the same
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10647753B2 (en) 2015-08-28 2020-05-12 Hanmi Pharm. Co., Ltd. Insulin analogs and use thereof
US10017557B2 (en) 2015-08-28 2018-07-10 Hanmi Pharm. Co., Ltd. Insulin analogs and use thereof
US10370426B2 (en) 2015-12-31 2019-08-06 Hanmi Pharm. Co., Ltd Triple glucagon/GLP-1/GIP receptor agonist
US10400020B2 (en) 2015-12-31 2019-09-03 Hanmi Pharm. Co., Ltd. Long-acting conjugate of triple glucagon/GLP-1/GIP receptor agonist
US11332508B2 (en) 2015-12-31 2022-05-17 Hanmi Pharm. Co., Ltd. Triple glucagon/GLP-1/GIP receptor agonist
US10981967B2 (en) 2015-12-31 2021-04-20 Hanmi Pharm. Co., Ltd. Long-acting conjugate of triple glucagon/GLP-1/GIP receptor agonist
US11142559B2 (en) 2016-06-29 2021-10-12 Hanmi Pharm. Co., Ltd. Glucagon derivative, conjugate thereof, composition comprising same, and therapeutic use thereof
CN109641035A (zh) * 2016-06-29 2019-04-16 韩美药品株式会社 胰高血糖素衍生物、其缀合物、包含其的组合物、和其治疗用途
EP3479841A4 (en) * 2016-06-29 2020-03-04 Hanmi Pharm. Co., Ltd. GLUCAGON DERIVATIVE, CONJUGATE THEREOF, COMPOSITION THEREOF AND THERAPEUTIC USE THEREOF
IL263934B2 (en) * 2016-06-29 2023-10-01 Hanmi Pharm Ind Co Ltd Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof
AU2017289014B2 (en) * 2016-06-29 2019-12-05 Hanmi Pharm. Co., Ltd. Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof
IL263934B1 (en) * 2016-06-29 2023-06-01 Hanmi Pharm Ind Co Ltd A derivative of glucagon, its conjugate, a preparation containing it and its medical use
US11396534B2 (en) 2016-09-23 2022-07-26 Hanmi Pharm. Co., Ltd. Insulin analogs with reduced affinity to insulin receptor and use thereof
WO2018069422A1 (en) * 2016-10-12 2018-04-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of non-alcoholic fatty liver disease
US11752216B2 (en) 2017-03-23 2023-09-12 Hanmi Pharm. Co., Ltd. Insulin analog complex with reduced affinity for insulin receptor and use thereof
EP3670529A4 (en) * 2017-08-16 2021-11-03 Dong-A St Co., Ltd. ACYLATED OXYNTOMODULIN PEPTIDE ANALOG
EP4079757A1 (en) * 2017-08-16 2022-10-26 Dong-A St Co., Ltd. Acylated oxyntomodulin peptide analog
US11419918B2 (en) 2017-11-06 2022-08-23 Shenzhen Turier Biotech Co., Ltd. Treatment of biliary cirrhosis based on oxyntomodulin analogue GLP-1R/GCGR dual-target agonist peptide
EP3708577A4 (en) * 2017-11-06 2021-09-01 Shenzhen Turier Biotech Co., Ltd. TREATMENT OF BILARY CIRROUS BASED ON AN OXYNTOMODULIN ANALOGUE GLP-1R / GCGR DUAL-TARGET ANGONIST PEPTID
WO2019171352A3 (en) * 2018-03-08 2019-11-07 Janssen Pharmaceutica Nv Methods of treating severe non-diabetic obesity
WO2020017916A1 (en) 2018-07-19 2020-01-23 D&D Pharmatech Inc. Pharmaceutical composition comprising polypeptide
AU2019308089B2 (en) * 2018-07-19 2025-04-10 D&D Pharmatech Inc. Pharmaceutical composition comprising polypeptide
US12338270B2 (en) 2018-07-19 2025-06-24 D&D Pharmatech Inc. Pharmaceutical composition comprising polypeptide
WO2020128967A3 (en) * 2018-12-19 2020-07-30 Janssen Pharmaceutica Nv Efinopegdutide for use in the treatment of severe non-diabetic obesity
WO2021148664A1 (en) * 2020-01-24 2021-07-29 Keybioscience Ag Oxyntomodulin mimetics

Also Published As

Publication number Publication date
EP3384925B1 (en) 2020-09-02
EP3384925A1 (en) 2018-10-10
JP6499333B2 (ja) 2019-04-10
TWI661837B (zh) 2019-06-11
DK3384925T3 (da) 2020-12-07
US20160199451A1 (en) 2016-07-14
IL236913B (en) 2020-05-31
AU2013293714A1 (en) 2015-03-12
MX2018012686A (es) 2020-09-02
ES2842881T3 (es) 2021-07-15
IL274106B1 (en) 2023-04-01
BR112015001596B1 (pt) 2023-05-02
EP2884994A1 (en) 2015-06-24
HK1206280A1 (en) 2016-01-08
NZ705384A (en) 2018-01-26
RU2642267C2 (ru) 2018-01-24
ZA201501238B (en) 2019-12-18
CA2888407C (en) 2021-08-03
AU2018203729B2 (en) 2020-05-28
US9901621B2 (en) 2018-02-27
NZ731657A (en) 2020-01-31
AR091903A1 (es) 2015-03-11
PH12019501131A1 (en) 2020-09-14
UA118177C2 (uk) 2018-12-10
ES2942187T3 (es) 2023-05-30
CN104507492A (zh) 2015-04-08
CL2020002262A1 (es) 2020-11-20
SG11201500519UA (en) 2015-02-27
BR112015001596A2 (pt) 2017-08-01
CA2888407A1 (en) 2014-01-30
JP2018090595A (ja) 2018-06-14
KR20140018462A (ko) 2014-02-13
EP3766520A1 (en) 2021-01-20
JP2015524427A (ja) 2015-08-24
PE20150633A1 (es) 2015-05-06
CL2019001115A1 (es) 2019-06-28
TW201416087A (zh) 2014-05-01
SG10201700527UA (en) 2017-02-27
CN104507492B (zh) 2017-11-24
PH12015500158B1 (en) 2022-02-02
JP2021107403A (ja) 2021-07-29
AU2013293714B2 (en) 2018-03-01
EP2884994A4 (en) 2016-07-20
CN107854691B (zh) 2021-04-09
CL2015000177A1 (es) 2015-05-04
MY171493A (en) 2019-10-15
US10493132B2 (en) 2019-12-03
CL2017002432A1 (es) 2018-04-02
JP6903086B2 (ja) 2021-07-14
UA128812C2 (uk) 2024-10-30
US20150182593A1 (en) 2015-07-02
TW202106338A (zh) 2021-02-16
AU2018203729A1 (en) 2018-06-21
IL236913A0 (en) 2015-03-31
US20180177850A1 (en) 2018-06-28
CA3121985A1 (en) 2014-01-30
IL274106A (en) 2020-06-30
MX360024B (es) 2018-10-18
PH12015500158A1 (en) 2015-03-16
RU2015104492A (ru) 2016-09-10
MX2015001218A (es) 2015-09-07
ZA201905331B (en) 2020-05-27
CN107854691A (zh) 2018-03-30
TWI708614B (zh) 2020-11-01
TWI780493B (zh) 2022-10-11
BR122022025353B1 (pt) 2023-11-21
KR101968344B1 (ko) 2019-04-12
MY187988A (en) 2021-11-06
IL274106B2 (en) 2023-08-01
JP2019108394A (ja) 2019-07-04
TW201740980A (zh) 2017-12-01
EP2884994B1 (en) 2023-01-18
RU2768853C1 (ru) 2022-03-25

Similar Documents

Publication Publication Date Title
WO2014017843A1 (en) Composition for treating hyperlipidemia comprising oxyntomodulin derivative
WO2014073845A1 (en) A composition for treating diabetes or diabesity comprising oxyntomodulin analog
WO2014073842A1 (en) Liquid formulation of protein conjugate comprising the oxyntomodulin and an immunoglobulin fragment
WO2012173422A1 (en) A conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof
WO2017003191A1 (en) Glucagon derivative and a composition comprising a long acting conjugate of the same
WO2017052329A1 (en) Protein complex by use of a specific site of an immunoglobulin fragment for linkage
WO2015152618A1 (ko) 면역글로불린 fc 단편 결합을 이용한 단백질 및 펩타이드의 용해도를 개선시키는 방법
WO2018004283A2 (ko) 글루카곤 유도체, 이의 결합체, 및 이를 포함하는 조성물, 및 이의 치료적 용도
WO2010011096A2 (en) A polypeptide complex comprising non-peptidyl polymer having three functional ends
WO2015186988A1 (en) Method for decreasing immunogenicity of protein and peptide
WO2019066586A1 (ko) 글루카곤 유사 펩타이드-2(glp-2) 유도체의 지속형 결합체
WO2020071865A1 (ko) 글루카곤 및 이를 포함하는 조합물의 치료학적 용도
WO2017018742A1 (en) Method of preparing physiologically active polypeptide conjugate
WO2022080987A1 (ko) 글루카곤/glp-1/gip 삼중작용제 또는 이의 지속형 결합체를 포함하는 혈관염 예방 또는 치료용 약학적 조성물
WO2019066603A1 (ko) 효력이 향상된 지속성 단백질 결합체
WO2022164204A1 (en) Liquid formulation of protein and methods of preparing the same
WO2021235907A1 (ko) 글루카곤 유도체의 지속형 결합체의 액상 제제
WO2021182928A1 (ko) 신규 이중 특이성 단백질 및 그의 용도
WO2022015082A1 (ko) 글루카곤 유도체 또는 이의 결합체의 간질환에 대한 치료적 용도
WO2019022563A2 (ko) 이두로네이트 2-설파타제 결합체
WO2022080985A1 (ko) Gip 유도체 또는 이의 지속형 결합체를 포함하는 루푸스-관련 질환의 예방 또는 치료용 약학적 조성물
WO2024107006A1 (en) Dual function proteins and uses thereof
WO2023121370A1 (ko) 간 표적 물질 및 이의 용도
WO2021235915A1 (ko) 액상 제제
WO2022080989A1 (ko) 글루카곤/glp-1/gip 삼중작용제 또는 이의 지속형 결합체를 포함하는 루푸스-관련 질환의 예방 또는 치료용 약학적 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13823727

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 14415200

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2888407

Country of ref document: CA

Ref document number: 2015524182

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2015000177

Country of ref document: CL

Ref document number: 122022025353

Country of ref document: BR

Ref document number: 12015500158

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 236913

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 000094-2015

Country of ref document: PE

Ref document number: MX/A/2015/001218

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: IDP00201500789

Country of ref document: ID

WWE Wipo information: entry into national phase

Ref document number: 2013823727

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2015104492

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2013293714

Country of ref document: AU

Date of ref document: 20130725

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015001596

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112015001596

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150123