US20150182593A1 - Composition for treating hyperlipidemia comprising oxyntomodulin derivative - Google Patents

Composition for treating hyperlipidemia comprising oxyntomodulin derivative Download PDF

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Publication number
US20150182593A1
US20150182593A1 US14/415,200 US201314415200A US2015182593A1 US 20150182593 A1 US20150182593 A1 US 20150182593A1 US 201314415200 A US201314415200 A US 201314415200A US 2015182593 A1 US2015182593 A1 US 2015182593A1
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Prior art keywords
seq
fatty liver
liver disease
oxyntomodulin
group
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US14/415,200
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Inventor
Sung youb Jung
Jin-Sun Kim
Myung Hyun Jang
Sang Hyun Lee
In Young Choi
Se Chang Kwon
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Hanmi Pharmaceutical Co Ltd
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Hanmi Pharmaceutical Co Ltd
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Application filed by Hanmi Pharmaceutical Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Assigned to HANMI PHARM. CO., LTD. reassignment HANMI PHARM. CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHOI, IN YOUNG, JANG, MYUNG HYUN, JUNG, SUNG YOUB, KIM, JIN-SUN, KWON, SE CHANG, LEE, SANG HYUN
Publication of US20150182593A1 publication Critical patent/US20150182593A1/en
Priority to US15/846,395 priority Critical patent/US10493132B2/en
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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;
  • X3 is leucine or tyrosine
  • X5 is lysine or arginine
  • X6 is glutamine or tyrosine
  • 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.
  • 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-C1), 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 SQGTFTSDYSKYLDSRRAQD-FVQWLMNT (SEQ ID NO: 41), SQGTFTSDYSKYLDEEAVRLFIEWLMNT (SEQ ID NO: 42), SQGTFTSDYSKYLDERRAQDFVAWLKNT (SEQ ID NO: 43), GQGTFTSDYSRYLEEEAVRLFIEWLKNG (SEQ ID NO: 44), GQGTFTSDYS-RQMEEEAVRLFIEWLKNG (SEQ ID NO: 45), GEGTFTSDL-SRQMEEEAVRLFIEWAA (SEQ ID NO: 46), and SQGTFTSDYSRQMEEEAVRL-FIEWLMNG (SEQ ID NO: 47);
  • SQGTFTSDYSKYLDSRRAQD-FVQWLMNT SEQ ID NO: 41
  • SQGTFTSDYSKYLDEEAVRLFIEWLMNT SEQ ID NO: 42
  • SQGTFTSDYSKYLDERRAQDFVAWLKNT SEQ ID NO: 43
  • GQGTFTSDYSRYLEEEAVRLFIEWLKNG SEQ ID NO: 44
  • GQGTFTSDYS-RQMEEEAVRLFIEWLKNG SEQ ID NO: 45
  • GEGTFTSDL-SRQMEEEAVRLFIEWAA SEQ ID NO: 46
  • SQGTFTSDYSRQMEEEAVRL-FIEWLMNG 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 en-capsulated 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.
  • 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 ab-normally 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 en-dothelial 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 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 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, intra-venously, 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.
  • 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, methylhy-droxybenzoate, 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 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 de-veloping the above disease. In addition, the subject may be any subject that can be treated by the oxyntomodulin derivative of the present invention.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 ⁇ 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 incubator at 37° 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.
  • 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 3 mg/ml at room temperature for 3 hours.
  • the reaction was performed in 50 mM 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 20 mM 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: 20 mM 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: 20 mM Tris-HCl, pH 7.5, B: A+1.1M AS).
  • 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 50 mM 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 20 mM 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: 20 mM Tris-HCl, pH 7.5, B: A+1.1M AS).
  • 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, Wis.).
  • 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.
  • 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 of the 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.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3428147A4 (en) * 2016-03-07 2019-08-28 Hanmi Pharm. Co., Ltd. Polyethylene glycol derivative and use thereof
WO2020109526A2 (en) 2018-11-30 2020-06-04 Opko Ireland Global Holdings, Ltd. Oxyntomodulin peptide analog formulations

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3434687B1 (en) 2011-06-10 2021-03-10 Hanmi Science Co., Ltd. Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
TR201901402T4 (tr) 2011-06-17 2019-02-21 Hanmi Science Co Ltd Oksintomodulin ve bir immünoglobulin fragmanı içeren bir konjugat ve onun kullanımı.
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
KR101968344B1 (ko) 2012-07-25 2019-04-12 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 고지혈증 치료용 조성물
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
PH12018501454A1 (en) 2012-11-06 2020-02-17 Hanmi Pharm Ind Co Ltd Liquid formulation of protein conjugate comprising the oxyntomodulin and an immunoglubin fragment
KR101993393B1 (ko) * 2012-11-06 2019-10-01 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 당뇨병 또는 비만성 당뇨병 치료용 조성물
CN104870009B (zh) 2012-12-21 2021-05-18 赛诺菲 官能化的毒蜥外泌肽-4衍生物
TW201609795A (zh) 2013-12-13 2016-03-16 賽諾菲公司 作為雙重ｇｌｐ－１／ｇｉｐ受體促效劑的艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物
EP3080154B1 (en) 2013-12-13 2018-02-07 Sanofi Dual glp-1/gip receptor agonists
EP3080152A1 (en) 2013-12-13 2016-10-19 Sanofi Non-acylated exendin-4 peptide analogues
EP3080149A1 (en) 2013-12-13 2016-10-19 Sanofi Dual glp-1/glucagon receptor agonists
AR098616A1 (es) * 2013-12-18 2016-06-01 Lilly Co Eli Péptido para el tratamiento de hipoglicemia severa
MX369656B (es) 2014-01-20 2019-11-15 Hanmi Pharm Ind Co Ltd Insulina de accion prolongada y uso de la misma.
KR102385120B1 (ko) * 2014-03-31 2022-04-12 한미약품 주식회사 면역글로불린 Fc 단편 결합을 이용한 단백질 및 펩타이드의 용해도를 개선시키는 방법
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
AR100639A1 (es) 2014-05-29 2016-10-19 Hanmi Pharm Ind Co Ltd Composición para tratar diabetes que comprende conjugados de análogos de insulina de acción prolongada y conjugados de péptidos insulinotrópicos de acción prolongada
TWI684458B (zh) * 2014-05-30 2020-02-11 南韓商韓美藥品股份有限公司 包含胰島素及ｇｌｐ-１/昇糖素雙重促效劑之治療糖尿病之組成物
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
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KR102418477B1 (ko) 2014-12-30 2022-07-08 한미약품 주식회사 글루카곤 유도체
WO2016108586A1 (ko) 2014-12-30 2016-07-07 한미약품 주식회사 안정성이 증가된 글루카곤 유도체
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
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
PE20180449A1 (es) 2015-06-30 2018-03-05 Hanmi Pharm Ind Co Ltd Derivado de glucagon y una composicion que comprende un conjugado de accion prolongada del mismo
TW201706291A (zh) 2015-07-10 2017-02-16 賽諾菲公司 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物
UY36870A (es) 2015-08-28 2017-03-31 Hanmi Pharm Ind Co Ltd Análogos de insulina novedosos
HRP20220995T1 (hr) * 2015-12-31 2022-11-11 Hanmi Pharm. Co., Ltd. Trostruki aktivator koji aktivira glukagonski, glp-1 i gip receptore
WO2017153575A1 (en) * 2016-03-10 2017-09-14 Medimmune Limited Glucagon and glp-1 co-agonists for the treatment of obesity
CN115181175A (zh) * 2016-04-22 2022-10-14 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
TN2018000452A1 (en) * 2016-06-29 2020-06-15 Hanmi Pharm Ind Co Ltd Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof
KR20180033105A (ko) 2016-09-23 2018-04-02 한미약품 주식회사 인슐린 수용체와의 결합력이 감소된, 인슐린 아날로그 및 이의 용도
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
WO2018147641A1 (ko) 2017-02-07 2018-08-16 한미약품 주식회사 비펩티드성 중합체 링커 화합물, 그 링커 화합물을 포함하는 결합체, 및 이들의 제조방법
EP3604328A4 (en) 2017-03-23 2021-01-06 Hanmi Pharm. Co., Ltd. REDUCED INSULIN ANALOGUE COMPLEX FOR INSULIN RECEPTOR AND ITS USE
CA3072118A1 (en) * 2017-08-09 2019-02-14 Sanofi Glp-1/glucagon receptor agonists in the treatment of fatty liver disease and steatohepatitis
ES2973986T3 (es) * 2017-08-16 2024-06-25 Dong A St Co Ltd Análogo peptídico acilado de oxintomodulina
CN114920818B (zh) 2017-11-06 2024-02-27 深圳市图微安创科技开发有限公司 基于胃泌酸调节素类似物glp-1r/gcgr双靶点激动剂多肽治疗胆汁性肝硬化
WO2019171352A2 (en) * 2018-03-08 2019-09-12 Janssen Pharmaceutica Nv Methods of treating severe non-diabetic obesity
WO2020017919A1 (ko) * 2018-07-19 2020-01-23 한미정밀화학주식회사 생리활성 폴리펩타이드에 사용되는 신규한 중간체 및 이의 제조방법
JP2021530533A (ja) * 2018-07-19 2021-11-11 ディーアンドディー ファーマテック インコーポレイテッド ポリペプチドを含む医薬組成物
KR20200135618A (ko) * 2019-05-23 2020-12-03 ㈜ 디앤디파마텍 폴리펩티드를 포함하는 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물
WO2020128967A2 (en) * 2018-12-19 2020-06-25 Janssen Pharmaceutica Nv Methods of treating severe non-diabetic obesity
US20220242913A1 (en) * 2019-02-15 2022-08-04 Hanmi Fine Chemical Co., Ltd. Novel intermediate used for biologically active polypeptide and method for preparing same
GB202001024D0 (en) * 2020-01-24 2020-03-11 Key Bioscience Ag Oxyntomodulin mimetics

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100330108A1 (en) * 2003-11-13 2010-12-30 Hanmi Pharmaceutical Co., Ltd. Pharmaceutical composition for treating obesity-related disease comprising insulinotropic peptide conjugate

Family Cites Families (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096871A (en) 1995-04-14 2000-08-01 Genentech, Inc. Polypeptides altered to contain an epitope from the Fc region of an IgG molecule for 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
US6776983B1 (en) 1998-03-06 2004-08-17 Chugai Seiyaku Kabushiki Kaisha Protein free formulations
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
US7737260B2 (en) 2003-11-13 2010-06-15 Hanmi Pharm. Co., Ltd Protein complex using an immunoglobulin fragment and method for the preparation thereof
WO2005003296A2 (en) 2003-01-22 2005-01-13 Human Genome Sciences, Inc. Albumin fusion proteins
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
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
KR101135244B1 (ko) 2007-11-29 2012-04-24 한미사이언스 주식회사 인슐린 분비 펩타이드 결합체를 포함하는 비만 관련질환 치료용 조성물
US20090238838A1 (en) 2003-11-13 2009-09-24 Hanmi Pharm. Ind. Co. Ltd. Insulinotropic peptide conjugate using an immunoglobulin fc
NZ555464A (en) 2004-12-02 2010-03-26 Domantis Ltd Bispecific domain antibodies targeting serum albumin and glp-1 or pyy
EP2390264A1 (en) 2005-02-11 2011-11-30 Amylin Pharmaceuticals Inc. GIP analog and hybrid polypeptides with selectable propperties
US20090286723A1 (en) 2005-02-11 2009-11-19 Amylin Pharmaceuticals, Inc. 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
ATE553124T1 (de) * 2005-06-13 2012-04-15 Imp Innovations Ltd Oxyntomodulinanaloga und ihre wirkungen auf das fressverhalten
EP2471810A1 (en) * 2006-02-22 2012-07-04 Merck Sharp & Dohme Corporation Oxyntomodulin derivatives
BRPI0712383A2 (pt) 2006-06-07 2012-07-10 Human Genome Sciences Inc proteìnas de fusão da albumina
GB0624868D0 (en) 2006-12-13 2007-01-24 Imp Innovations Ltd Novel compounds and their effects on feeding behaviour
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
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
US20090098130A1 (en) 2007-01-05 2009-04-16 Bradshaw Curt W Glucagon-like protein-1 receptor (glp-1r) agonist compounds
BRPI0807728A2 (pt) 2007-02-15 2012-04-17 Univ Indiana Res & Tech Corp co-agonistas de receptor glucagon/glp-1
BRPI0813699B1 (pt) 2007-07-10 2021-06-22 Eli Lilly And Company Formulação de proteína de fusão glp-1-fc
CA2698690A1 (en) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Thyrotropin releasing hormone for therapeutic applications
ES2558155T3 (es) 2007-10-30 2016-02-02 Indiana University Research And Technology Corporation Compuestos que muestran actividad antagonista de glucacón y agonista de GLP-1
CA2713348C (en) 2008-01-30 2018-10-09 Indiana University Research And Technology Corporation Ester-based peptide prodrugs
AU2009260302B2 (en) 2008-06-17 2014-10-23 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
CN102088989B (zh) 2008-06-17 2014-11-26 印第安纳大学研究及科技有限公司 在生理pH缓冲液中具有增强的溶解性和稳定性的胰高血糖素类似物
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.
EP2344200A2 (en) 2008-09-19 2011-07-20 Nektar Therapeutics Modified therapeutics peptides, methods of their preparation and use
BRPI0823377A2 (pt) * 2008-12-15 2016-09-27 Zealand Pharma As análogos de glucagon
BRPI0823379A2 (pt) 2008-12-15 2015-07-14 Zealand Pharma As Análogos de glucagon
PE20120332A1 (es) 2008-12-19 2012-04-14 Univ Indiana Res & Tech Corp Profarmacos de peptido de la superfamilia de glucagon basado en amida
WO2010096052A1 (en) * 2009-02-19 2010-08-26 Merck Sharp & Dohme Corp. Oxyntomodulin analogs
ES2587397T3 (es) * 2009-03-20 2016-10-24 Hanmi Science Co., Ltd. Procedimiento para preparar un conjugado específico de sitio de un polipéptido fisiológicamente activo
MX347291B (es) 2009-03-20 2017-04-17 Amgen Inc Inmunoglobulinas portadoras y usos de las mismas.
MX2011013625A (es) 2009-06-16 2012-01-20 Univ Indiana Res & Tech Corp Compuestos glucagon activo de receptor de gip.
DK2454282T3 (da) 2009-07-13 2015-05-04 Zealand Pharma As Acetylerede glucagonanaloger
US20120294855A1 (en) 2009-11-03 2012-11-22 Eli Lilly & Company Glp-1 receptor agonist compounds for obstructive sleep apnea
EP2509997B1 (en) * 2009-12-07 2017-08-30 i2 Pharmaceuticals, Inc. Conjugates comprising an antibody surrogate scaffold with improved pharmacokinetic properties
US8703701B2 (en) * 2009-12-18 2014-04-22 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
AR079345A1 (es) 2009-12-22 2012-01-18 Lilly Co Eli Analogo peptidico de oxintomodulina
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
CA2792663A1 (en) 2010-03-26 2011-09-29 Novo Nordisk A/S Novel glucagon analogues
WO2011143208A1 (en) * 2010-05-13 2011-11-17 Indiana University Research And Technology Corporation Glucagon superfamily peptides exhibiting g protein-coupled receptor activity
MX2012014576A (es) 2010-06-24 2013-02-21 Univ Indiana Res & Tech Corp Profarmacos de peptido de la superfamilia de glucagon basado en amida.
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
KR101767570B1 (ko) * 2010-10-26 2017-08-14 한미사이언스 주식회사 항 비만 펩타이드의 지속형 결합체
KR101303388B1 (ko) 2010-10-26 2013-09-03 한미사이언스 주식회사 지속형 인터페론 알파 결합체의 액상 제제
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
AU2011348202A1 (en) 2010-12-22 2013-07-04 Marcadia Biotech, Inc. Methods for treating metabolic disorders and obesity with GIP and GLP-1 receptor-active glucagon-based peptides
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
EP3434687B1 (en) 2011-06-10 2021-03-10 Hanmi Science Co., Ltd. Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
TR201901402T4 (tr) 2011-06-17 2019-02-21 Hanmi Science Co Ltd Oksintomodulin ve bir immünoglobulin fragmanı içeren bir konjugat ve onun kullanımı.
JP6184404B2 (ja) 2011-06-22 2017-08-23 インディアナ ユニヴァーシティ リサーチ アンド テクノロジー コーポレイション グルカゴン／ｇｌｐ−１レセプターコアゴニスト
KR101665009B1 (ko) 2012-03-09 2016-10-11 한미사이언스 주식회사 비알콜성 지방간 질환의 예방 또는 치료용 약학적 조성물
JP2015520128A (ja) 2012-04-19 2015-07-16 オプコ バイオロジクス リミテッド 長時間作用性オキシントモジュリン変異体とその作製方法
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
PH12018501454A1 (en) * 2012-11-06 2020-02-17 Hanmi Pharm Ind Co Ltd Liquid formulation of protein conjugate comprising the oxyntomodulin and an immunoglubin fragment
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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100330108A1 (en) * 2003-11-13 2010-12-30 Hanmi Pharmaceutical Co., Ltd. Pharmaceutical composition for treating obesity-related disease comprising insulinotropic peptide conjugate

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
Atherosclerosis, from http://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis, pages 1-14, accessed 12/29/2015. *
Day et al, Optimization of Co-Agonism at GLP-1 and Glucagon Receptors to Safely Maximize Weight Reduction in DIO-Rodents, Peptide Science, 2012, 98, pages 443-450, published online 4/14/2012. *
Definition of Arteriosclerosis, from http://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/defi..., page 1, accessed 12/29/2015. *
Ding et al, Exendin-4, a Glucagon-Like Protein-1 (GLP-1) Receptor Agonist, Reverses Hepatic Steatosis in ob/ob Mice, HEPATOLOGY, 2006, 43, pages 173-181. *
Dyslipidemia, from http://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/lipid-dis..., pages 1-11, accessed 12/29/2015. *
Exendin-4 sequence, from http://www.sigmaaldrich.com/catalog/product/sigma/e7144?lang=en&region=US, page 1, accessed 12/28/2015. *
Fatty Liver Disease, from http://www.webmd.com/hepatitis/fatty-liver-disease?page=2&print=true, pages 1-4, accessed 12/29/2015. *
Nonatheromatous Arteriosclerosis, from http://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/non..., pages 1-2, accessed 12/29/2015. *
Vitamins & Supplements Search, from http://www.webmd.com/vitamins-supplements/condition-1275-Hyperlipidemia.aspx, pages 1-3, accessed 12/29/2015. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3428147A4 (en) * 2016-03-07 2019-08-28 Hanmi Pharm. Co., Ltd. Polyethylene glycol derivative and use thereof
US11603346B2 (en) 2016-03-07 2023-03-14 Hanmi Pharm. Co., Ltd. Polyethylene glycol derivative and use thereof
WO2020109526A2 (en) 2018-11-30 2020-06-04 Opko Ireland Global Holdings, Ltd. Oxyntomodulin peptide analog formulations

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