WO2023277620A1 - 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체를 포함하는 조합물의 치료학적 용도 - Google Patents

글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체를 포함하는 조합물의 치료학적 용도 Download PDF

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WO2023277620A1
WO2023277620A1 PCT/KR2022/009449 KR2022009449W WO2023277620A1 WO 2023277620 A1 WO2023277620 A1 WO 2023277620A1 KR 2022009449 W KR2022009449 W KR 2022009449W WO 2023277620 A1 WO2023277620 A1 WO 2023277620A1
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Prior art keywords
peptide
conjugate
present
composition
immunoglobulin
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Ceased
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PCT/KR2022/009449
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English (en)
French (fr)
Korean (ko)
Inventor
이종석
김요한
김정국
이상현
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Priority to CA3216330A priority Critical patent/CA3216330A1/en
Priority to EP22833674.9A priority patent/EP4364750A4/en
Priority to CN202280042772.4A priority patent/CN117615775A/zh
Priority to US18/565,628 priority patent/US20240293512A1/en
Priority to MX2023012935A priority patent/MX2023012935A/es
Priority to BR112023022445A priority patent/BR112023022445A2/pt
Priority to IL308347A priority patent/IL308347A/en
Priority to AU2022302809A priority patent/AU2022302809A1/en
Priority to JP2023566569A priority patent/JP2024527220A/ja
Publication of WO2023277620A1 publication Critical patent/WO2023277620A1/ko
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
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    • 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
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    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Definitions

  • the present invention provides a combination comprising peptides having activity on both glucagon, GLP-1 and GIP receptors; or the use of a combination comprising said peptide and a SGLT-2 inhibitor.
  • Glucagon is produced and secreted in the pancreas when blood sugar is lowered due to various causes such as drug treatment, disease, hormone or enzyme deficiency, etc. It is known that the secreted glucagon acts on the liver to break down glycogen and induce the release of glucose, eventually raising the blood sugar level to a normal level. Glucagon exerts its activity by acting on glucagon receptors.
  • GLP-1 Glucagon-like peptide-1
  • GIP Glucose-dependent insuliontropic polypeptide
  • glucagon receptors As well as glucagon-like peptide-1 (GLP-1) and GIP (Glucose-dependent insulinotropic polypeptide) receptors to increase efficacy or improve side effects.
  • GLP-1 glucagon-like peptide-1
  • GIP Glucose-dependent insulinotropic polypeptide
  • Diabetes is a type of metabolic disease in which the secretion of insulin is insufficient or normal function is not performed. It is characterized by hyperglycemia in which the concentration of glucose in the blood increases. .
  • diabetes One of the main causes of diabetes is overweight or obesity, and obesity is known to cause increased insulin resistance and decreased secretion of insulin to be a factor in the development of diabetes.
  • the association between diabetes and obesity is due to the irregular secretion of adipokines and free fatty acids, resulting in lipotoxicity due to accumulation of fatty acids in insulin-sensitive tissues such as beta cells, kidney, liver, and heart. because bet
  • obesity itself is one of the metabolic diseases, it is known to cause diabetic complications in diabetic patients, and is known as a factor that not only causes diabetes, but also makes the prognosis of diabetic patients serious.
  • diabetic patients accompanied by obesity, the risk of stroke, vascular complications, heart attack, diabetic retinopathy, renal dysfunction, chronic renal disease, neuropathy, diabetic foot ulcer, and cardiovascular disease increases, so effective treatment of diabetic patients is required. Weight control is also required.
  • drugs such as insulin, insulin secretion stimulants, insulin sensitivity improvers, and hypoglycemic agents.
  • Insulin a common antidiabetic drug, is prescribed when the target of blood sugar control is not reached despite treatment with oral hypoglycemic agents or when hyperglycemia is severe.
  • side effects such as hypoglycemia and weight gain as side effects.
  • SGLT-2 Sodium-Glucose Cotransporter 2 inhibitors, one of the hypoglycemic agents, is an oral diabetes treatment mainly used to control blood sugar in type 2 diabetic patients. By doing so, it is known that glucose lowering effect can be obtained by inhibiting glucose reabsorption in the kidney and excreting glucose. In particular, since it acts as a target for glucose and can act independently of insulin, it has the advantage of being able to be prescribed regardless of beta cell function or insulin resistance.
  • diabetes treatment requires not only blood sugar control but also weight control
  • diabetic patients are required to consume an appropriate amount of food for treatment, making it difficult to lose weight through diet or exercise therapy.
  • Administration of antidiabetic drugs promotes fat formation in the process of insulin regulation, resulting in obesity, or when blood sugar is controlled, symptoms of nutrient leakage through urine are improved, resulting in weight gain.
  • One object of the present invention is a pharmaceutical composition for the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infectious disease, including a peptide or a conjugate having activity on both glucagon, GLP-1 and GIP receptors, It is to provide a pharmaceutical composition characterized in that it is used in combination with a sodium-glucose cotransporter 2 (SGLT-2) inhibitor.
  • SGLT-2 sodium-glucose cotransporter 2
  • Another object of the present invention is a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; and a SGLT-2 inhibitor.
  • Another object of the present invention is a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; And to provide a pharmaceutical kit for the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infectious disease including an SGLT-2 inhibitor.
  • Another object of the present invention is to provide a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; Alternatively, to provide a method for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection comprising the step of administering a pharmaceutical composition containing the same together with an SGLT-2 inhibitor to a subject in need thereof.
  • Another object of the present invention is metabolic syndrome, liver disease, lung disease, or respiratory disease comprising the step of administering and / or using the combination, the pharmaceutical composition, or the pharmaceutical kit to a subject in need thereof. It is to provide a method for preventing or treating infectious diseases.
  • Another object of the present invention is the use of the combination, pharmaceutical composition, or pharmaceutical kit for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease and/or metabolic syndrome, liver disease, lung disease , Or to provide a use for the manufacture of a medicament for the prevention or treatment of respiratory infections.
  • Another object of the present invention is to provide a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; And to provide a pharmaceutical composition for the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infectious disease containing an SGLT-2 inhibitor.
  • Peptides having activity on all of the glucagon, GLP-1 and GIP receptors of the present invention can be used as an effective administration regimen for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease.
  • 1 is a diagram confirming the effect of reducing blood sugar and weight by co-administering the long-acting conjugate of SEQ ID NO: 42 with empagliflozin.
  • FIG. 2 is a diagram showing the results of analysis by quantifying the blood sugar reducing effect of co-administration of the long-acting conjugate of SEQ ID NO: 42 with empagliflozin by AUC (area under curve).
  • One aspect embodying the present invention is a composition comprising a peptide or conjugate having activity on all of glucagon, GLP-1 and GIP receptors.
  • a composition according to one embodiment comprising a pharmaceutically effective amount of a peptide having activity on both glucagon, GLP-1 and GIP receptors; And a pharmaceutical composition for the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infection disease comprising a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor and It is characterized by being used together.
  • SGLT-2 sodium-glucose cotransporter 2
  • the peptide having activity on all of the glucagon, GLP-1 and GIP receptors is characterized in that it is a peptide comprising any one of the amino acid sequences of SEQ ID NOs: 1 to 102.
  • X is a peptide comprising any one of the amino acid sequences of SEQ ID NOs: 1 to 102;
  • L is a linker containing an ethylene glycol repeating unit
  • F is an immunoglobulin Fc region
  • the metabolic syndrome is characterized in that at least one selected from the group consisting of diabetes, obesity, hyperlipidemia and dyslipidemia.
  • sergle In the group consisting of riflozin, ipragliflozin, tofogliflozin, luceogliflozin, sotagliflozin, bexagliflozin, artigliflozin, and ertugliflozin It is characterized in that at least one selected.
  • composition according to any one of the preceding embodiments, characterized in that the composition has an effect of reducing body weight and/or lowering blood sugar.
  • composition according to any one of the preceding embodiments, characterized in that the composition has a hypoglycemic effect in overweight or obese diabetic patients.
  • composition according to any one of the preceding embodiments, characterized in that the composition has a hypoglycemic effect in obese patients with hyperglycemia or diabetes.
  • the peptide is characterized in that the C-terminus is unmodified or amidated.
  • the peptide is characterized in that a ring is formed between amino acid residues.
  • composition according to any one of the preceding embodiments, wherein the immunoglobulin Fc region is aglycosylated.
  • the immunoglobulin Fc region comprises (a) a CH1 domain, a CH2 domain, a CH3 domain and a CH4 domain; (b) a CH1 domain and a CH2 domain; (c) a CH1 domain and a CH3 domain; (d) a CH2 domain and a CH3 domain; (e) a combination of one or more of the CH1 domain, CH2 domain, CH3 domain and CH4 domain with an immunoglobulin hinge region or a portion of a hinge region; And (f) characterized in that it is selected from the group consisting of a dimer of each domain of the heavy chain constant region and the light chain constant region.
  • ADCC antibody dependent cell mediated cytotoxicity
  • composition according to any one of the preceding embodiments, wherein the immunoglobulin Fc region is derived from IgG, IgA, IgD, IgE or IgM.
  • composition according to any one of the preceding embodiments, wherein the immunoglobulin Fc region is a hybrid of domains having different origins derived from immunoglobulins selected from the group consisting of IgG, IgA, IgD, IgE, and IgM.
  • composition according to any one of the preceding embodiments, wherein the immunoglobulin Fc region is in a dimeric form.
  • composition according to any one of the preceding embodiments, wherein the immunoglobulin Fc region is an IgG4 Fc region.
  • composition according to any one of the preceding embodiments, wherein the immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4.
  • composition according to any one of the preceding embodiments, characterized in that the formula weight of the ethylene glycol repeating unit portion in L is in the range of 1 to 100 kDa. composition.
  • composition according to any one of the preceding embodiments, characterized in that the composition has a weight reducing effect in an obese subject.
  • the value of n is characterized in that the average molecular weight of the [OCH 2 CH 2 ]n site in the peptide conjugate, for example, the number average molecular weight, is determined to be 10 kDa.
  • Another aspect of the present invention is a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; and a SGLT-2 inhibitor.
  • Another aspect of the present invention is a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; and a pharmaceutical kit for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease, including an SGLT-2 inhibitor.
  • the metabolic syndrome is a pharmaceutical kit of any one or more selected from the group consisting of diabetes, obesity, hyperlipidemia and dyslipidemia.
  • Another aspect of the present invention is metabolic syndrome, liver disease, lung disease, or respiratory disease comprising the step of administering and / or using the combination, the pharmaceutical composition, or the pharmaceutical kit to a subject in need thereof. It is a method for preventing or treating an infectious disease.
  • the metabolic syndrome is a method of at least one selected from the group consisting of diabetes, obesity, hyperlipidemia and dyslipidemia.
  • Another aspect of the present invention is a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; Or a method for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection comprising administering a pharmaceutical composition containing the same together with an SGLT-2 inhibitor to a subject in need thereof.
  • the metabolic syndrome is a method of at least one selected from the group consisting of diabetes, obesity, hyperlipidemia and dyslipidemia.
  • Another aspect of the present invention is the use of the combination, pharmaceutical composition, or pharmaceutical kit for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease and/or metabolic syndrome, liver disease, lung disease , or for the preparation of a medicament for the prevention or treatment of respiratory infections.
  • the metabolic syndrome is the use of any one or more selected from the group consisting of diabetes, obesity, hyperlipidemia and dyslipidemia.
  • Another aspect of the present invention is a peptide or conjugate having activity on both glucagon, GLP-1 and GIP receptors; And a pharmaceutical composition for the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infectious disease, including an SGLT-2 inhibitor.
  • the metabolic syndrome is a composition of any one or more selected from the group consisting of diabetes, obesity, hyperlipidemia and dyslipidemia.
  • Aib may be used interchangeably with “2-aminoisobutyric acid” or “aminoisobutyric acid”, and 2-aminoisobutyric acid and aminoisobutyric acid Butyric acid (aminoisobutyric acid) may be used in combination.
  • compositions comprising a peptide or a conjugate having activity against glucagon receptors, glucagon-like peptide-1 (GLP-1) receptors, and glucose-dependent insulinotropic polypeptide (GIP) receptors.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic polypeptide
  • the composition is a pharmaceutical composition for the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infection including the peptide or a conjugate thereof.
  • the metabolic syndrome include, but are not limited to, diabetes, obesity, hyperlipidemia and dyslipidemia.
  • One specific aspect of the present invention is a composition comprising a peptide or a conjugate having activity against a glucagon receptor, a glucagon-like peptide-1 (GLP-1) receptor, and a glucose-dependent insulinotropic polypeptide (GIP) receptor, which is useful for treating diabetes and / or a pharmaceutical composition for preventing or treating obesity.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic polypeptide
  • the peptide may include, consist essentially of, or consist of any one amino acid sequence of SEQ ID NOs: 1 to 102.
  • the composition may be a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 102 or a conjugate thereof in a pharmaceutically effective amount.
  • a composition containing the peptide or a conjugate thereof according to the present invention as an active ingredient may be used in combination with a sodium-glucose cotransporter (SGLT-2) inhibitor.
  • SGLT-2 sodium-glucose cotransporter
  • composition of the present invention can exhibit not only a hypoglycemic effect but also a weight loss effect by being administered in combination with an SGLT-2 inhibitor, diabetic patients requiring both blood sugar control and weight control (eg, overweight or obese diabetics) patients) or obese patients (eg, obese patients with hyperglycemia or diabetes).
  • the peptide or its conjugate of the present invention since a composition containing the same has anti-inflammatory and/or anti-fibrotic effects, it can be effective even in liver diseases, lung diseases, or respiratory infections by administering it in combination with an SGLT-2 inhibitor.
  • “combined administration”, “combined use” and “combined use” refer to the peptide or conjugate thereof according to the present invention; Or, it means administering a composition containing it as an active ingredient together with an SGLT-2 inhibitor to a subject, which means not only simultaneous administration of concomitant drugs, but also glucagon receptors, GLP-1 receptors, and GIP receptors. It should be understood as a dosage form in which a peptide or a conjugate thereof having activity against and an SGLT-2 inhibitor act together on a subject so that each substance can perform a level equal to or higher than its original function.
  • the term "combination” is to be understood as referring to simultaneous, separate, sequential, or reverse order administration, in any order.
  • the order of administration is not particularly limited, but the interval between administration of the second component should be such that the beneficial effect of the combination is not lost.
  • SGLT-2 inhibitor may be administered in the form of, but not limited to:
  • SGLT-2 inhibitor may be administered in a separate form, but is not limited thereto.
  • the conjugate thereof and the SGLT-2 inhibitor may be formulated as separate preparations and administered simultaneously, separately, sequentially, or in reverse order.
  • a peptide having activity on glucagon receptor, GLP-1 receptor, and GIP receptor or a conjugate thereof is additionally included and used in combination with an SGLT-2 inhibitor, blood sugar lowering effect and weight reduction effect can be obtained at the same time. , It was confirmed that the preventive or therapeutic effect of diabetes and/or obesity was remarkably improved, and the combination therapy was provided.
  • SGLT-2 inhibitor when used in combination by further including an SGLT-2 inhibitor in peptides or conjugates having activity on glucagon receptors, GLP-1 receptors, and GIP receptors, metabolic syndrome, liver disease, lung disease , or preventive or therapeutic effects of respiratory infectious diseases can be obtained.
  • lowering blood sugar means lowering the blood sugar level.
  • Blood glucose homeostasis is maintained in the body by insulin and glucagon, and diabetes occurs when blood sugar levels exceed the normal range and remain high.
  • SGLT-2 inhibitors an oral antidiabetic drug, act to lower blood sugar levels by stimulating the excretion of glucose.
  • the combined administration of the peptide or the conjugate thereof according to the present invention and the SGLT-2 inhibitor can reduce the patient's weight as well as lower blood sugar, thereby treating obesity that causes diabetes along with diabetes and preventing diabetic complications. It can be an advantageous treatment regimen in that it is present. In addition, even in obese patients with hyperglycemia or diabetes, it can be an effective treatment regimen because it shows the effect of lowering blood sugar and reducing weight.
  • peptide having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor may also be used interchangeably with the name “triple active body” or “peptide” in the present invention.
  • Such peptides include various substances, such as various peptides, that have significant levels of activity on glucagon, GLP-1, and GIP receptors.
  • the peptide having a significant level of activity for the glucagon, GLP-1, and GIP receptors is one or more of the glucagon, GLP-1, and GIP receptors, specifically two or more Receptors, more specifically, for all three receptors, the in vitro activity is about 0.001% or more, about 0.01% or more, about 0.1% or more compared to the native ligands (native-type glucagon, native-type GLP-1, and native-type GIP) of the corresponding receptor.
  • % or more about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10 % or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 150 % or more, may represent about 200% or more, but a significantly increased range is included without limitation.
  • the activity for the receptor is about 0.001% or more, 0.01% or more, 0.1% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, compared to the native type. , 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90 For example, % or more, 100% or more, or about 200% or more. However, it is not limited thereto.
  • the term "about” is a range including ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, ⁇ 0.1, etc., and includes all numerical values in a range equivalent to or similar to the numerical value following the term about, but, therefore, Not limited.
  • the peptide is characterized in that it possesses one or more, two or more, specifically three activities, specifically significant activities among the following i) to iii):
  • activating the receptor means that the in vitro activity against the native receptor is about 0.001% or more, about 0.01% or more, about 0.1% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more. % or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50 % or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 150% or more, or about 200% or more. However, it is not limited thereto.
  • the peptide may have an increased in vivo half-life compared to any one of native GLP-1, native glucagon, and native GIP, but is not particularly limited thereto.
  • the peptide of the present invention comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 102, consists (essentially) of the amino acid sequence of any one of SEQ ID NOs: 1 to 102, or any one of SEQ ID NOs: 1 to 102 At least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or more of any one amino acid sequence , or may also include a peptide having a sequence identity of 95% or more, and for the purpose of the present invention, it is not limited to a specific sequence as long as it has an effect of lowering blood sugar and reducing body weight by co-administered with an SGLT-2 inhibitor.
  • the peptide may include or (essentially) consist of any one amino acid sequence of SEQ ID NOs: 21, 22, 42, 43, 50, 77, and 96, but is not limited thereto.
  • the term 'homology' or 'identity' refers to the degree to which two given amino acid sequences or base sequences are related to each other and can be expressed as a percentage.
  • Whether any two peptide sequences have homology, similarity or identity can be determined, for example, by Pearson et al (1988) [Proc. Natl. Acad. Sci. USA 85]: can be determined using known computer algorithms such as the “FASTA” program using default parameters as in 2444. or, as performed in the Needleman program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16: 276-277) (version 5.0.0 or later), It can be determined using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443-453).
  • GCG program package (Devereux, J., et al, Nucleic Acids Research 12: 387 (1984)), BLASTP, BLASTN, FASTA (Atschul, [S.] [F.,] [ET AL, J MOLEC BIOL 215] : 403 (1990);Guide to Huge Computers, Martin J. Bishop, [ED.,] Academic Press, San Diego, 1994, and [CARILLO ETA/.] (1988) SIAM J Applied Math 48: 1073) Homology, similarity or identity can be determined using, for example, BLAST of the National Center for Biotechnology Information Database, or ClustalW.
  • GAP program defines the total number of symbols in the shorter of the two sequences divided by the number of similarly aligned symbols (ie amino acids).
  • the default parameters for the GAP program are (1) a binary comparison matrix (containing values of 1 for identity and 0 for non-identity) and Schwartz and Dayhoff, eds., Atlas Of Protein Sequence And Structure, National Biomedical Research Foundation, pp.
  • the peptide of the present invention may include an intramolecular bridge (eg, a covalent bridge or a non-covalent bridge), and may specifically include a ring, for example, at positions 16 and 20 of the peptide. It may be in the form of a ring formed between amino acids, but is not particularly limited thereto.
  • amino acid 16 may be glutamic acid and amino acid 20 may be lysine, but are not limited thereto.
  • Non-limiting examples of the ring may include a lactam bridge (or lactam ring).
  • the above-described peptides include those modified to include an amino acid capable of forming a ring at a desired position to include a ring.
  • amino acid pairs at positions 16 and 20 of the peptide may be substituted with glutamic acid or lysine capable of forming a ring, respectively, but is not limited thereto.
  • Such a ring may be formed between amino acid side chains in the peptide, and for example, a lactam ring may be formed between a side chain of lysine and a side chain of glutamic acid, but is not particularly limited thereto.
  • the amino acid sequence is different from that of native glucagon by one or more, and the alpha-carbon of the amino acid residue at the N-terminus is removed.
  • peptides having, but not limited thereto, and peptides applicable to the present invention can be prepared by a combination of several methods for analog production.
  • amino acids of the peptides of the present invention may be substituted with other amino acids or non-natural compounds in order to avoid the recognition of activator degrading enzymes in order to increase the half-life in the body.
  • it may be a peptide that increases the half-life in the body by avoiding the recognition action of the degradation enzyme through substitution of the second amino acid sequence of the amino acid sequence of the peptide, but amino acid substitution or change to avoid the recognition action of the degradation enzyme in the body included without limitation.
  • modifications for producing peptides include modifications using L- or D-type amino acids, and/or non-natural amino acids; and/or modification of the native sequence, e.g., modification of side chain functional groups, intramolecular covalent linkages such as inter-side chain ring formation, methylation, acylation, ubiquitination, phosphorylation, aminohexaylation, biotinylation, etc. including all that
  • the substituted or added amino acids may be 20 amino acids commonly observed in human proteins as well as atypical or non-naturally occurring amino acids.
  • Commercial sources of atypical amino acids include Sigma-Aldrich, ChemPep and Genzyme pharmaceuticals. Peptides containing these amino acids and typical peptide sequences can be synthesized and purchased through commercialized peptide synthesis companies, such as American Peptide Company or Bachem in the US or Anygen in Korea.
  • Amino acid derivatives can also be obtained in the same way, and examples thereof include 4-imidazoacetic acid and the like.
  • the peptide according to the present invention is chemically modified at its N-terminus and/or C-terminus, protected with an organic group, or amino acids at the end of the peptide in order to protect it from protein cleavage enzymes in vivo and increase stability. It may be added and modified form.
  • the N-terminus is acetylated and/or the C-terminus is amidated to remove these charges. It may be, but is not particularly limited thereto.
  • the N-terminus or C-terminus of the peptide of the present invention may have an amine group (-NH2) or a carboxyl group (-COOH), but is not limited thereto.
  • the peptide of the present invention can be synthesized according to its length by a method well known in the art, for example, an automatic peptide synthesizer, or can be produced by genetic engineering technology.
  • the peptides of the present invention can be prepared by standard synthetic methods, recombinant expression systems, or any other art method.
  • the peptides according to the present invention can be synthesized in a number of ways, including, for example, methods comprising:
  • a method of obtaining a peptide fragment by any combination of (a), (b) and (c), then linking the fragments to obtain a peptide, and recovering the peptide.
  • the peptides having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor are biocompatible to increase the in vivo half-life of the peptide having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor It may be in the form of a long-acting assemblage in which substances are bound.
  • the biocompatible material may be mixed with a carrier.
  • the peptide conjugate may exhibit increased durability compared to the peptide to which the carrier is not bound, and in the present invention, such conjugate is referred to as a "long-acting conjugate".
  • long-acting conjugate or “conjugate” of the present invention has a structure in which the peptide and the biocompatible material are bound, and may exhibit increased durability compared to the peptide to which the biocompatible material is not bound.
  • the biocompatible material may be covalently linked to the peptide, but is not particularly limited thereto.
  • the peptide which is one component of the conjugate, is a peptide having activity against glucagon receptors, GLP-1 receptors, and GIP receptors, specifically peptides comprising any one of the amino acid sequences of SEQ ID NOs: 1 to 102 Or it may be a fragment, and the biocompatible material is a material capable of increasing the half-life of the peptide, and corresponds to one component of the moiety constituting the conjugate of the present invention.
  • the peptide included in the conjugate may be a peptide including or (essentially) consisting of any one amino acid sequence of SEQ ID NOs: 1 to 102.
  • the half-life may be increased without losing activity by binding to a biocompatible material, but as long as it is administered in combination with an SGLT-2 inhibitor to lower blood sugar and reduce body weight, it is one component of the conjugate of the present invention without limitation. element can be used.
  • biocompatible material refers to a material that is bound to the peptide of the present invention, which is a physiologically active material, and can increase the durability of the effect of the physiologically active material compared to a physiologically active material that is not bound to a biocompatible material part or a carrier. refers to The biocompatible material may be covalently linked to a physiologically active material (eg, a peptide), but is not particularly limited thereto.
  • the biocompatible material may be an immunoglobulin Fc region, more specifically an IgG Fc region, but is not particularly limited thereto.
  • One or more amino acid side chains within the peptides of the present invention may be conjugated to such biocompatible materials to increase solubility and/or half-life in vivo and/or to increase bioavailability. Such modifications may also reduce clearance of therapeutic proteins and peptides.
  • the aforementioned biocompatible materials may be water soluble (amphiphilic or hydrophilic) and/or non-toxic and/or pharmaceutically acceptable.
  • conjugates may be non-naturally occurring.
  • the long-acting conjugate or conjugate may be represented by Formula 1 below, but is not limited thereto:
  • X is a peptide comprising any one of the amino acid sequences of SEQ ID NOs: 1 to 102;
  • L is a linker containing an ethylene glycol repeating unit
  • F is an immunoglobulin Fc region or a derivative thereof
  • the conjugate of the present invention can exhibit significant activity on glucagon receptors, GLP-1 receptors, and GIP receptors even in the form of a conjugate, and therefore, when co-administered with an SGLT-2 inhibitor, it can also exert blood sugar lowering and weight reducing effects.
  • the conjugate of the present invention has an in vitro activity of about 0.001% or more, 0.01% or more, 0.1% or more, 0.1% or more, or 0.2% or more of glucagon receptor, GLP-1 receptor, and/or GIP receptor activity compared to the wild type. , 0.5% or more, 0.7% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 20 % or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% or more, but is not limited thereto.
  • the peptide or its conjugate has an activity of about 0.001% or more, 0.01% or more, 0.1% or more, 1% or more, 2 % or more, 3% or more, 4% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more , but may be 100% or more, but is not limited thereto.
  • X may include any one amino acid sequence of the amino acid sequences of SEQ ID NOs: 1 to 102, or may consist essentially of or consist of any one of the amino acid sequences of SEQ ID NOs: 1 to 102, specifically , SEQ ID NO: 21, 22, 42, 43, 50, 77, and 96 comprising any one of the amino acid sequence, or SEQ ID NO: 21, 22, 42, 43, 50, 77, and any one of the amino acid sequence of 96 It may be essentially configured or configured, but is not limited thereto.
  • F in the conjugate increases the half-life of X, that is, a peptide having activity against glucagon receptors, GLP-1 receptors, and GIP receptors, specifically, peptides comprising any one of the amino acid sequences of SEQ ID NOs: 1 to 102 As a material that can be used, it corresponds to one component of the moiety constituting the conjugate of the present invention.
  • the F may be bonded to X through a covalent chemical bond or a non-covalent chemical bond, and F and X may be bonded to each other through L through a covalent chemical bond, a non-covalent chemical bond, or a combination thereof.
  • X and L and L and F may be linked to each other through a covalent bond, and in this case, the conjugate is a conjugate in which X, L, and F are linked through a covalent bond, respectively, in the order of Formula 1.
  • the F may be an immunoglobulin Fc region, and more specifically, the immunoglobulin Fc region may be derived from IgG, but is not particularly limited thereto.
  • immunoglobulin Fc region refers to a region including heavy chain constant region 2 (CH2) and/or heavy chain constant region 3 (CH3), excluding the heavy chain and light chain variable regions of immunoglobulin.
  • the immunoglobulin Fc region may be one constituent of the moiety of the conjugate of the present invention.
  • the Fc region refers to a natural sequence obtained from papain digestion of immunoglobulin as well as a derivative thereof, such as one or more amino acid residues in the natural sequence, which are transformed by deletion, insertion, non-conservative or conservative substitution, or a combination thereof. It includes even the sequence that is different from the form.
  • the F is a structure in which two polypeptide chains are connected by a disulfide bond, and may be a structure in which only one chain of the two chains is connected through a nitrogen atom, but is not limited thereto.
  • the nitrogen atom may be connected to the epsilon amino atom or the N-terminal amino group of lysine through reductive amination.
  • the reductive amination reaction refers to a reaction in which an amine group or an amino group of a reactant reacts with an aldehyde (ie, a functional group capable of reductive amination) of another reactant to generate an amine, and then a reduction reaction forms an amine bond, It is an organic synthesis reaction widely known in the art.
  • the F may be connected through the nitrogen atom of the N-terminal proline, but is not limited thereto.
  • the immunoglobulin Fc region constitutes a moiety of the conjugate of Formula 1 of the present invention, and may specifically correspond to F in Formula 1 above.
  • Such an immunoglobulin Fc region may include a hinge portion in a heavy chain constant region, but is not limited thereto.
  • the immunoglobulin Fc region may include a specific hinge sequence at the N-terminus.
  • flankinge sequence refers to a region located in a heavy chain to form a dimer of an immunoglobulin Fc region through an inter disulfide bond.
  • the hinge sequence may be mutated to have only one cysteine residue by deleting a part of the hinge sequence having the following amino acid sequence, but is not limited thereto:
  • the hinge sequence may include only one cysteine residue by deletion of the 8th or 11th cysteine residue of the hinge sequence of SEQ ID NO: 119.
  • the hinge sequence of the present invention may consist of 3 to 12 amino acids including only one cysteine residue, but is not limited thereto.
  • the hinge sequence of the present invention may have the following sequences: Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Pro-Ser-Cys-Pro (SEQ ID NO: 104), Glu-Ser- Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser-Pro (SEQ ID NO: 105), Glu-Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser (SEQ ID NO: 106), Glu- Ser-Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Pro (SEQ ID NO: 107), Lys-Tyr-Gly-Pro-Pro-Cys-Pro-Ser (SEQ ID NO: 108), Glu-Ser-Lys- Tyr-Gly-Pro-Pro-Cys (SEQ ID NO: 109), Glu-Lys-Tyr-Gly-Pro-Pro-Cys (SEQ ID
  • the hinge sequence may include the amino acid sequence of SEQ ID NO: 113 (Pro-Ser-Cys-Pro) or SEQ ID NO: 122 (Ser-Cys-Pro), but is not limited thereto.
  • the immunoglobulin Fc region of the present invention may be in the form of a dimer formed by two molecules of the immunoglobulin Fc chain due to the presence of a hinge sequence, and in the conjugate of Formula 1 of the present invention, one end of the linker is a dimer immunoglobulin It may be linked to one chain of the Fc region, but is not limited thereto.
  • N-terminus refers to the amino terminus of a protein or polypeptide, one, two, three, four, five, six, It may contain up to 7, 8, 9, or 10 or more amino acids.
  • the immunoglobulin Fc region of the present invention may include a hinge sequence at the N-terminus, but is not limited thereto.
  • the immunoglobulin Fc region of the present invention except for the heavy chain and light chain variable regions of the immunoglobulin, part or all of the heavy chain constant region 1 (CH1) and / or light chain constant region, as long as it has substantially equivalent or improved effects to the native type, 1 (CL1) may be an extended Fc region. In addition, it may be a region in which a part of a fairly long amino acid sequence corresponding to CH2 and/or CH3 is removed.
  • the immunoglobulin Fc region of the present invention includes 1) CH1 domain, CH2 domain, CH3 domain and CH4 domain, 2) CH1 domain and CH2 domain, 3) CH1 domain and CH3 domain, 4) CH2 domain and CH3 domain, 5) It may be a combination of one or two or more domains of the CH1 domain, CH2 domain, CH3 domain, and CH4 domain with an immunoglobulin hinge region (or part of the hinge region), 6) a dimer of each domain of the heavy chain constant region and the light chain constant region. .
  • an immunoglobulin hinge region or part of the hinge region
  • the immunoglobulin Fc region F is a dimer (dimer dimer) composed of two polypeptide chains, wherein the Fc region dimer F and X are ethylene glycol They are covalently linked through one and the same linker L containing repeating units.
  • X is covalently linked through a linker L to only one polypeptide chain of the two polypeptide chains of the Fc region dimer F.
  • only X of one molecule is covalently linked via L to one polypeptide chain to which X is linked among the two polypeptide chains of the Fc region dimer F.
  • the F is a homodimer.
  • the immunoglobulin Fc region F is a dimer composed of two polypeptide chains, and one end of L may be linked to only one polypeptide chain of the two polypeptide chains, but is not limited thereto.
  • the long-acting conjugate of the present invention it is also possible for two X molecules to bind symmetrically to one Fc region in the form of a dimer.
  • the immunoglobulins Fc and X may be connected to each other by a non-peptide linker.
  • a non-peptide linker it is not limited to the examples described above.
  • the immunoglobulin Fc region of the present invention includes a native amino acid sequence as well as a sequence derivative thereof.
  • An amino acid sequence derivative means that one or more amino acid residues in a natural amino acid sequence have a different sequence by deletion, insertion, non-conservative or conservative substitution, or a combination thereof.
  • amino acid residues from 214 to 238, from 297 to 299, from 318 to 322, or from 327 to 331 known to be important for binding in the case of IgG Fc can be used as suitable sites for modification.
  • various types of derivatives are possible, such as removal of a site capable of forming a disulfide bond, removal of some amino acids at the N-terminus of native Fc, or addition of a methionine residue to the N-terminus of native Fc.
  • a complement binding site eg, a C1q binding site
  • ADCC antibody dependent cell mediated cytotoxicity
  • Amino acid exchanges in proteins and peptides that do not entirely alter the activity of the molecule are known in the art (H. Neurath, R.L. Hill, The Proteins, Academic Press, New York, 1979).
  • the most commonly occurring exchanges are amino acid residues Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/ Exchange between Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly.
  • it is modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, acetylation, and amidation. may be modified.
  • the above-described Fc derivative may exhibit biological activity equivalent to that of the Fc region of the present invention and may have increased structural stability of the Fc region against heat and pH.
  • an Fc region may be obtained from a natural form isolated in vivo from an animal such as human, cow, goat, pig, mouse, rabbit, hamster, rat or guinea pig, or obtained from transformed animal cells or microorganisms. It may be recombinant or a derivative thereof.
  • the method of obtaining from the natural form may be a method of obtaining whole immunoglobulin by isolating it from a human or animal living body and then treating it with a proteolytic enzyme. When treated with papain, it is cleaved into Fab and Fc, and when treated with pepsin, it is cleaved into pF'c and F(ab)2. Fc or pF'c can be separated from this using size-exclusion chromatography or the like.
  • the human-derived Fc region is a recombinant immunoglobulin Fc region obtained from a microorganism.
  • the immunoglobulin Fc region may be a native type sugar chain, an increased sugar chain compared to the native type, a reduced sugar chain compared to the natural type, or a form in which the sugar chain has been removed.
  • Conventional methods such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms may be used to increase or decrease immunoglobulin Fc sugar chains.
  • the immunoglobulin Fc region in which sugar chains are removed from Fc has significantly reduced binding ability to complement (c1q), and antibody-dependent cytotoxicity or complement-dependent cytotoxicity is reduced or eliminated, so that unnecessary immune responses are not induced in vivo.
  • a form more suitable for its original purpose as a drug carrier will be referred to as an immunoglobulin Fc region in which sugar chains are removed or non-glycosylated.
  • deglycosylation refers to an Fc region from which sugars are removed by an enzyme
  • aglycosylation refers to a prokaryotic animal, in a more specific embodiment, refers to an Fc region that is not glycosylated produced by Escherichia coli. .
  • the immunoglobulin Fc region may be of human origin or animal origin such as cow, goat, pig, mouse, rabbit, hamster, rat, guinea pig, etc., and in a more specific embodiment, it is of human origin.
  • the immunoglobulin Fc region may be an Fc region derived from IgG, IgA, IgD, IgE, or IgM, a combination thereof, or a hybrid thereof. In a more specific embodiment, it is derived from IgG or IgM, which is most abundant in human blood, and in a more specific embodiment, it is derived from IgG known to improve the half-life of ligand binding proteins. In a more specific embodiment, the immunoglobulin Fc region is an IgG4 Fc region, and in the most specific embodiment, the immunoglobulin Fc region is a non-glycosylated Fc region derived from human IgG4, but is not limited thereto.
  • the immunoglobulin Fc fragment is a region of human IgG4 Fc, in which two monomers are linked through a disulfide bond (inter-chain form) between cysteine, which is the 3rd amino acid of each monomer. It may be in the form of a homodimer, wherein each monomer of the homodimer independently has an internal disulfide bond between cysteines 35 and 95 and an internal disulfide bond between cysteines 141 and 199, that is, two internal Has/can have disulfide bonds (intra-chain form).
  • the number of amino acids of each monomer may consist of 221 amino acids, and amino acids forming a homodimer may consist of a total of 442 amino acids, but are not limited thereto.
  • two monomers having the amino acid sequence of SEQ ID NO: 123 (consisting of 221 amino acids) form a homodimer through a disulfide bond between cysteine, the 3rd amino acid of each monomer, and the homodimer
  • the monomers of may each independently form an internal disulfide bond between cysteines at positions 35 and 95 and an internal disulfide bond between cysteines at positions 141 and 199, but are not limited thereto.
  • F in Formula 1 may include a monomer having an amino acid sequence of SEQ ID NO: 123, and F may be a homodimer of a monomer having an amino acid sequence of SEQ ID NO: 123, but is not limited thereto.
  • the immunoglobulin Fc fragment may be a homodimer including the amino acid sequence of SEQ ID NO: 123 (consisting of 442 amino acids), but is not limited thereto.
  • “combination" related to the immunoglobulin Fc region means that a polypeptide encoding a single-chain immunoglobulin Fc region of the same origin binds to a single-chain polypeptide of a different origin when forming a dimer or multimer.
  • a dimer or a multimer can be prepared from two or more regions selected from the group consisting of IgG Fc, IgA Fc, IgM Fc, IgD Fc, and IgE Fc region.
  • hybrid is a term meaning that sequences corresponding to immunoglobulin Fc regions of two or more different origins exist in a single-chain immunoglobulin constant region.
  • various types of hybrids are possible. That is, a hybrid of one to four domains from the group consisting of CH1, CH2, CH3, and CH4 of IgG Fc, IgM Fc, IgA Fc, IgE Fc, and IgD Fc is possible, and may include a hinge.
  • IgG can also be divided into subclasses of IgG1, IgG2, IgG3 and IgG4, and combinations thereof or hybridization thereof are also possible in the present invention. Specifically, it is an IgG2 and IgG4 subclass, and most specifically, it is an Fc fragment of IgG4 that has little effector function such as complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • conjugates may have increased efficacy compared to native GLP-1, GIP, or glucagon, or compared to X with unmodified F. It includes, but is not limited to, forms encapsulated in particles.
  • L may be a non-peptide linker, for example, a linker containing an ethylene glycol repeating unit.
  • the "non-peptide linker” includes a biocompatible polymer in which two or more repeating units are bonded.
  • the repeating units are connected to each other through any covalent bond other than a peptide bond.
  • the non-peptide linker may be one constituent of the moiety of the conjugate of the present invention, and corresponds to L in Formula 1 above.
  • Non-peptide linkers that can be used in the present invention can be used without limitation as long as they are polymers resistant to in vivo proteolytic enzymes.
  • the non-peptide linker may be used in combination with a non-peptide polymer.
  • the non-peptidyl linker includes a reactive group at its end, and may form a conjugate through reaction with other components constituting the conjugate.
  • a non-peptide linker having reactive functional groups at both ends binds to X and F of Formula 1 through each reactive group to form a conjugate
  • the non-peptide linker or non-peptide polymer is a non-peptide polymer linker moiety) or a non-peptide linker linkage.
  • non-peptide linker may be a linker containing an ethylene glycol repeating unit, for example, polyethylene glycol, and derivatives thereof already known in the art and readily available at the level of skill in the art. Derivatives that can be prepared are also included in the scope of the present invention.
  • the repeating unit of the non-peptide linker may be an ethylene glycol repeating unit, and specifically, the non-peptide linker may include an ethylene glycol repeating unit and include a functional group used for preparing a conjugate at a terminal thereof.
  • the long-acting conjugate according to the present invention may be a form in which X and F are linked through the functional group, but is not limited thereto.
  • the non-peptide linker may include two or three or more functional groups, and each functional group may be the same or different from each other, but is not limited thereto.
  • the linker L including the ethylene glycol repeating unit may include a functional group used for preparing the conjugate before being formed as a conjugate at its terminal.
  • the long-acting conjugate according to the present invention may be a form in which X and F are linked through the functional group, but is not limited thereto.
  • the linker containing the ethylene glycol repeating unit may include two or three or more functional groups, and each functional group may be the same or different from each other, but is not limited thereto.
  • the linker may be polyethylene glycol (PEG) represented by Formula 2 below, but is not limited thereto:
  • the PEG moiety may include not only a -(CH2CH2O)n- structure but also an oxygen atom intervening between the linking element and the -(CH2CH2O)n-, but is not limited thereto.
  • the conjugate is covalently bonded to a peptide (X) comprising an amino acid sequence of any one of SEQ ID NOs: 1 to 102 and an immunoglobulin Fc region (F) via a linker containing an ethylene glycol repeating unit It may be a structure connected to, but is not limited thereto.
  • the polyethylene glycol is a term encompassing all types of ethylene glycol homopolymers, PEG copolymers, and monomethyl-substituted PEG polymers (mPEG), but is not particularly limited thereto.
  • the ethylene glycol repeating unit may be represented by, for example, [OCH 2 CH 2 ]n, where n is a natural number and is the average molecular weight of the [OCH 2 CH 2 ]n site in the peptide conjugate, such as number It can be set to have an average molecular weight of greater than 0 to about 100 kDa, but is not limited thereto.
  • the n value is a natural number and the average molecular weight of the [OCH 2 CH 2 ]n site in the peptide conjugate, for example, the number average molecular weight is about 1 to about 100 kDa, about 1 to about 80 kDa, about 1 to about 50 kDa, about 1 to about 30 kDa, about 1 to about 25 kDa, about 1 to about 20 kDa, about 1 to about 15 kDa, about 1 to about 13 kDa, about 1 to about 11 kDa, about 1 to about 10 kDa, about 1 to about 8 kDa, about 1 to about 5 kDa, about 1 to about 3.4 kDa, about 3 to about 30 kDa, about 3 to about 27 kDa, about 3 to about 25 kDa, about 3 to about 22 kDa , about 3 to about 20 kDa, about 3 to about 18 kDa, about 3 to about 16 kDa, about 3
  • both ends of the linker may bind to a thiol group, an amino group, a hydroxyl group of an immunoglobulin Fc region, and a thiol group, an amino group, an azide group, or a hydroxyl group of a peptide, but is not limited thereto. .
  • the linker includes, at both ends, a reactive group capable of binding to an immunoglobulin Fc region and a peptide, specifically, a thiol group of cysteine of an immunoglobulin Fc region; an amino group located at the N-terminus, lysine, arginine, glutamine and/or histidine; And/or bonded to a hydroxyl group located at the C-terminus, and a thiol group of cysteine of a peptide; amino groups of lysine, arginine, glutamine and/or histidine; the azide group of azidoricin; And / or may include a reactive group capable of bonding with a hydroxyl group, but is not limited thereto.
  • the reactive group of the linker may be at least one selected from the group consisting of an aldehyde group, a maleimide group, and a succinimide derivative, but is not limited thereto.
  • examples of the aldehyde group include a propion aldehyde group or a butyl aldehyde group, but are not limited thereto.
  • both ends of the non-peptide linker may bind to an amine or thiol group of F, for example, an amine or thiol group of an immunoglobulin Fc region and an amine or thiol group of X, respectively.
  • the non-peptide polymer is a reactive group capable of binding to F (eg, immunoglobulin Fc region) and X at both ends, specifically, X, or the N-terminus of F (eg, immunoglobulin Fc region) or a reactive group capable of bonding with an amine group located on lysine or a thiol group of cysteine, but is not limited thereto.
  • the reactive group of the non-peptide polymer that can bind to F may be selected from the group consisting of an aldehyde group, a maleimide group, and a succinimide derivative, but is not limited thereto.
  • examples of the aldehyde group include a propion aldehyde group or a butyl aldehyde group, but are not limited thereto.
  • succinimide derivatives include succinimidyl valerate, succinimidyl methylbutanoate, succinimidyl methylpropionate, succinimidyl butanoate, succinimidyl propionate, N-hydroxysuccini Mead, hydroxy succinimidyl, succinimidyl carboxymethyl or succinimidyl carbonate may be used, but is not limited thereto.
  • the non-peptide linker may be connected to X and F through such a reactive group and converted into a non-peptide linker linkage, but is not particularly limited thereto.
  • the end product produced by reductive amination by aldehyde linkage is much more stable than that linked by amide linkage.
  • the aldehyde reactive group reacts selectively at the N-terminus at low pH and can form a covalent bond with a lysine residue at high pH, for example, pH 9.0.
  • the reactive groups at both ends of the non-peptide linker may be the same or different from each other, for example, having an aldehyde group at both ends, or a maleimide group at one end and an aldehyde group at the other end, It may have a propionic aldehyde group or a butyl aldehyde group.
  • F specifically, an immunoglobulin Fc region and X can be coupled to each end of the non-peptide linker, it is not particularly limited thereto.
  • a maleimide group as a reactive group may be included at one end of the non-peptide linker, and an aldehyde group, propion aldehyde group, or butyl aldehyde group may be included at the other end.
  • the hydroxy group can be activated with various reactive groups by known chemical reactions, or commercially available polyethylene glycols having modified reactive groups can be used to obtain this
  • the long-acting protein conjugate of the invention can be prepared.
  • the non-peptidyl polymer may be linked to a cysteine residue of X, more specifically, a -SH group of cysteine, but is not limited thereto.
  • cysteine residues 10-13 15, 17, 19, 21, 24, 28, 29 The non-peptide polymer may be linked to cysteine residue 1, cysteine 30, cysteine 31, cysteine 40, or cysteine 41, but is not particularly limited thereto.
  • a reactive group of a non-peptide polymer may be connected to the -SH group of the cysteine residue, and all of the above descriptions apply to the reactive group.
  • maleimide-PEG-aldehyde is used, the maleimide group is connected to the -SH group of X through a thioether bond, and the aldehyde group is subjected to a reductive amination reaction with F, specifically -NH 2 group of immunoglobulin Fc It can be connected through, but is not limited thereto, and this corresponds to one example.
  • the N-terminal amino group of the immunoglobulin Fc region is linked to an oxygen atom located at one end of PEG, a non-peptide polymer, through a linker functional group having a structure of -CH 2 CH 2 CH 2 - ,
  • a peptide capable of forming a structure such as -PEG-O-CH 2 CH 2 CH 2 NH-immunoglobulin Fc and having one end of PEG containing the sequence of any one of SEQ ID NOs: 1 to 102 through a thioether bond It can form a structure linked to the sulfur atom located on the cysteine of
  • the above-mentioned thioether bond is may contain the structure of
  • the non-peptide polymer may be linked to a lysine residue of X, more specifically, to an amino group of lysine, but is not limited thereto.
  • the reactive group of the non-peptide polymer may be linked to -NH2 located at the N-terminus of the immunoglobulin Fc region, but this corresponds to one example.
  • the peptide may be connected to a linker having a reactive group through the C-terminus, but this corresponds to one example.
  • C-terminus refers to the carboxy terminal of a peptide, and refers to a position capable of binding to a linker for the purpose of the present invention.
  • it may include not only the most terminal amino acid residue at the C-terminus but also all of the amino acid residues around the C-terminus, and specifically include the first to twentieth amino acid residues from the terminal end. It can, but is not limited thereto.
  • F is an immunoglobulin Fc region, in which one or more amino acid residues in the native sequence as well as the native sequence obtained from immunoglobulin digestion with papain, as well as derivatives, substitutions, such as deletion, insertion, non-conservative or conservative substitution, or combinations thereof It includes even variants such as sequences that have been converted and are different from the natural type.
  • the above derivatives, substituents and variants are premised on having the ability to bind to FcRn.
  • the F is a structure in which two polypeptide chains are connected by a disulfide bond, and may be a structure in which only one chain of the two chains is connected through a nitrogen atom, but is not limited thereto. Connection through the nitrogen atom may be connected to the epsilon amino atom of lysine or the N-terminal amino group through reductive amination, but is not limited thereto.
  • the reductive amination reaction refers to a reaction in which an amine group or an amino group of a reactant reacts with an aldehyde (ie, a functional group capable of reductive amination) of another reactant to generate an amine, and then a reduction reaction forms an amine bond, It is an organic synthesis reaction widely known in the art.
  • the F may be connected through the nitrogen atom of the N-terminal proline, but is not limited thereto.
  • the type of salt is not particularly limited. However, it is preferably in a form that is safe and effective for an individual, such as a mammal, but is not particularly limited thereto.
  • pharmaceutically acceptable refers to a substance that can be effectively used for a desired purpose without causing excessive toxicity, irritation, or allergic reaction within the scope of medical or pharmaceutical judgment.
  • the term "pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
  • suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid.
  • Salts derived from suitable bases may include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium.
  • solvate used in the present invention refers to the formation of a complex between the peptide or its salt according to the present invention and solvent molecules.
  • the sodium-glucose cotransporter 2 (SGLT-2) inhibitor administered in combination with the peptide or its conjugate is also referred to as sodium-glucose cotransporter 2, specifically empagliflozin, dapagliflozin, Canagliflozin, Remogliflozin, Remogliflozin Etabonate, Sergliflozin, Ifragliflozin, Topogliflozin, Luseogliflozin, Sotagliflozin, It may be any one or more selected from the group consisting of bexagliflozin, artigliflozin and ertugliflozin, but is not limited thereto.
  • a blood glucose lowering effect can be obtained by administering the peptide or a conjugate thereof according to the present invention in combination with an SGLT-2 inhibitor.
  • the "diabetes” is a kind of metabolic disease such as lack of insulin secretion or normal function, characterized by hyperglycemia in which the concentration of glucose in the blood increases, and causes various symptoms and signs due to hyperglycemia A disease in which glucose is excreted in the urine.
  • Diabetes can be classified into type 1 diabetes and type 2 diabetes, and the peptide or its conjugate according to the present invention can be administered in combination with an SGLT-2 inhibitor as long as it can reduce blood sugar as well as reduce body weight.
  • diabetes may include obese diabetes and diabetic complications.
  • the "obesity diabetes” refers to diabetes accompanied by obesity symptoms that cause diabetes, particularly type 2 diabetes, or obesity symptoms generally accompanied by type 2 diabetes patients. About 80-90% of type 2 diabetic patients are known to be accompanied by obesity symptoms. In the present invention, the obese diabetes may be caused by obesity.
  • diabetes complications refers to various pathological symptoms accompanying the body while maintaining a high blood sugar state for a long period of time, for example, stroke, vascular complications, heart attack, diabetic retinopathy, renal dysfunction, chronic renal disease, neuropathy, Diabetic foot ulcers, and cardiovascular diseases may be mentioned, but are not limited thereto. If the hyperglycemic state is maintained for a long period of time, the risk of the diabetic complications increases, so effective blood sugar management and weight control are essential to prevent these complications.
  • obesity means a state of being overweight (Body Mass Index of 25.0 or more), and is also a major cause of diabetes. Since obesity is closely related to diabetes, weight loss has significance not only as a therapeutic effect on obesity, but also has important significance in the treatment of diabetes.
  • an SGLT-2 inhibitor When the peptide or conjugate thereof of the present invention is administered in combination with an SGLT-2 inhibitor, not only blood glucose lowering but also an effect of weight loss can be obtained. It can be used for prevention or treatment, specifically for treatment of hyperglycemic or diabetic obese patients. Alternatively, excellent preventive or therapeutic effects can be obtained in diabetic patients, particularly overweight or obese diabetic patients.
  • compositions comprising a peptide or a conjugate thereof, administered in combination with the SGLT-2 inhibitor of the present invention, can be used in diabetic and/or obese patients, eg, overweight or obese diabetic patients; Alternatively, it may be administered to an obese patient with diabetes to exhibit blood sugar lowering and weight reduction effects, thereby preventing or treating diabetes and/or obesity, but is not limited thereto.
  • the effect of such combined administration can be exerted not only in diabetes and obesity, but also in various diseases caused by weight gain and glycemic dysregulation, for example, patients with metabolic syndrome.
  • the metabolic syndrome collectively refers to various metabolic diseases, and examples of the metabolic syndrome include diabetes, obesity, hyperlipidemia and dyslipidemia, but are not limited thereto. Representative causes of such metabolic syndrome include insulin resistance, overweight, and the like.
  • Diabetes and obesity are as described above.
  • hyperlipidemia refers to a disease in which low-density lipoprotein cholesterol and/or triglycerides are high in the blood. It can be.
  • dyslipidemia refers to a state in which the levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and triglyceride in the blood are out of the normal range.
  • composition containing the peptide or its conjugate administered in combination with the SGLT-2 inhibitor according to the present invention also has anti-inflammatory and anti-fibrotic effects, so it can prevent or treat liver diseases, lung diseases, or respiratory infections.
  • liver disease may include uncomplicated steatosis, non-alcoholic fatty liver, liver inflammation, non-alcoholic steatohepatitis, metabolic liver disease, cholestatic liver disease, liver fibrosis, cirrhosis, liver failure and liver cancer, but is not limited thereto.
  • lung diseases include interstitial lung disease, progressive fibrotic interstitial lung disease, idiopathic interstitial pneumonia, nonspecific interstitial pneumonia, pulmonary fibrosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, alveolitis, pneumonia, emphysema, bronchitis, These include chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), and asthma.
  • COPD chronic obstructive pulmonary disease
  • CPFE combined pulmonary fibrosis and emphysema
  • the main pathological mechanisms include the development of inflammation and tissue damage and consequent fibrosis. Since the composition containing the peptide or its conjugate administered in combination with the SGLT-2 inhibitor according to the present invention has anti-inflammatory and anti-fibrotic effects, it can also exhibit effects on liver and lung diseases.
  • the respiratory infectious disease of the present invention is a respiratory disease caused by infection with a pathogen (virus, bacteria, fungus, etc.), and a representative cause of infection is a respiratory virus.
  • respiratory virus infection means a respiratory disease caused by a pathogenic virus infection
  • the respiratory virus is adenovirus, vaccinia virus, herpes simplex virus, parainfluenza virus (parainfluenza virus), rhinovirus, varicella zoster virus, measle virus, respiratory syncytial virus, dengue virus, human immunodeficiency virus (HIV), influenza virus, which may be, but is not limited to, a coronavirus, severe acute respiratory syndrome associated virus (SARS-associated virus), or middle east respiratory syndrome coronavirus (MERS-CoV). It doesn't work.
  • coronavirus is SARS-CoV-2, and SARS-CoV-2 infection can cause coronavirus disease 2019 (COVID-19).
  • COVID-19 is a viral infectious disease caused by corona virus (2019-nCoV or SARS-CoV-2) infection, and although a clear source and route of infection have not yet been identified, the transmission power is very strong and spread worldwide. caused a pandemic.
  • the respiratory infectious disease of the present invention may include sequelae of respiratory infectious diseases.
  • the sequelae of respiratory infectious diseases of the present invention refers to abnormal symptoms that appear independently of respiratory infections in patients with respiratory infectious diseases.
  • the sequelae of respiratory infectious diseases in the present invention may mean sequelae of respiratory viral infections, more specifically, sequelae of coronavirus infection-19 (COVID-19), but are not limited thereto.
  • COVID-19 sequelae refers to sequelae that appear in patients after SARS-CoV-2 infection.
  • COVID-19 sequelae may include, but is not limited to, shortness of breath, cough, pneumonia, pulmonary fibrosis, pain, inflammation, and nervous system disorders, etc. Difficulty breathing, cough, chronic fatigue, pain, pneumonia, Fibrosis and the like may be caused by reduced function and/or damage of the respiratory tract, particularly the lungs, but are not limited thereto.
  • prevention refers to the peptide (e.g., the peptide itself or a long-acting conjugate form in which a biocompatible material is bound thereto) or a composition containing the same and the combined administration of an SGLT-2 inhibitor to prevent metabolic syndrome, liver disease, lung disease , or any action that suppresses or delays respiratory infections.
  • treatment refers to the peptide (eg, the peptide itself or a long-acting conjugate form in which a biocompatible material is bound thereto) or a composition containing the peptide and a SGLT-2 inhibitor are administered in combination to treat metabolic syndrome, liver disease, and lung disease. , or any action that improves or benefits the symptoms of a respiratory infection.
  • composition according to the present invention may contain a peptide (triple active compound) or a conjugate thereof, and specifically may contain a pharmacologically effective amount of a peptide or a conjugate thereof.
  • a pharmaceutically acceptable excipient may be further included.
  • the composition of the present invention may be used for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection, or may be used for lowering blood sugar, but is not limited thereto.
  • the composition according to the present invention may also have a use for weight loss.
  • the term "pharmaceutically acceptable” means an amount sufficient to exhibit a therapeutic effect and not causing side effects, and the type of disease, age, weight, health, sex, and sensitivity of the patient to the drug , It can be easily determined by a person skilled in the art according to factors well known in the medical field, such as an administration route, an administration method, the number of administrations, a treatment period, combination or drugs used simultaneously.
  • compositions of the present invention include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments and flavors for oral administration, and buffers, preservatives, and painless agents for injections.
  • a topical agent, a solubilizing agent, an isotonic agent, and a stabilizer may be mixed and used, and in the case of topical administration, a base, an excipient, a lubricant, and a preservative may be used.
  • the dosage form of the composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable excipients as described above.
  • oral administration it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses.
  • it can be formulated into solutions, suspensions, tablets, pills, capsules, and sustained-release preparations.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers and preservatives may be further included.
  • composition of the present invention is any one formulation selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, freeze-dried formulations, and suppositories.
  • the peptide or conjugate may be mixed with various pharmaceutically acceptable carriers such as physiological saline or organic solvents, and carbohydrates such as glucose, sucrose or dextran, ascorbic acid to increase stability or absorption
  • various pharmaceutically acceptable carriers such as physiological saline or organic solvents, and carbohydrates such as glucose, sucrose or dextran, ascorbic acid to increase stability or absorption
  • Antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins or other stabilizers may be used as drugs.
  • composition of the present invention are determined according to the type of drug as an active ingredient, as well as various related 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 composition of the present invention may contain the peptide or its conjugate in a pharmaceutically effective amount, but is not limited thereto.
  • Inclusion of the peptide or its conjugate in a pharmaceutically effective amount means the extent to which the desired pharmacological activity (eg, blood sugar lowering and/or weight loss) can be obtained due to the peptide or its conjugate, and also the administered subject Toxicity or side effects do not occur or it may mean a pharmaceutically acceptable level as an insignificant level, but is not limited thereto.
  • a pharmaceutically effective amount may be determined by comprehensively considering the number of administrations, patients, dosage forms, and the like.
  • the pharmaceutical composition of the present invention may contain the ingredient (active ingredient) in an amount of 0.01 to 99% by weight by volume.
  • the total effective amount of the composition of the present invention can be administered to the patient in a single dose or by a fractionated treatment protocol in which multiple doses are administered over a long period of time.
  • the composition of the present invention may vary the content of the active ingredient according to the severity of the disease.
  • a preferred total dose of the peptide of the present invention or a long-acting conjugate thereof may be about 0.0001 mg to 500 mg per 1 kg of the patient's body weight per day.
  • the dosage of the peptide or its long-acting conjugate is determined for the patient in consideration of various factors such as the patient's age, weight, health condition, sex, severity of disease, diet and excretion rate, as well as the route of administration of the pharmaceutical composition and the number of treatments.
  • the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as it exhibits the effects of the present invention.
  • composition of the present invention may be administered once every 3 days, once a week, once every 2 weeks, once every 4 weeks, or once a month, but is not limited thereto.
  • composition of the present invention may be administered to mammals, including rats, livestock, etc., including humans, in need of blood sugar lowering and/or weight loss, specifically, diabetic and/or obese patients, more specifically, overweight or obese people. It can be administered to diabetic patients or obese patients with hyperglycemia or diabetes, but the subject of administration is not limited as long as beneficial effects can be obtained due to blood sugar lowering and weight loss.
  • the composition of the present invention may be administered to patients with metabolic syndrome, liver disease, lung disease, or respiratory infection, but is not limited thereto.
  • the peptide of the present invention or a long-acting conjugate thereof administered in combination with an SGLT-2 inhibitor may have anti-inflammatory and anti-fibrotic effects and exhibit excellent preventive or therapeutic effects in patients with liver diseases, lung diseases, or respiratory infections.
  • the SGLT-2 inhibitor may be formulated into a formulation suitable for co-administration, for example, tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, lyophilized formulations, and It may have any one formulation selected from the group consisting of suppositories, but is not limited thereto.
  • the SGLT-2 inhibitor may be administered by an appropriate route of administration for concomitant administration, for example, oral or dermal, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal It may be administered by a parenteral administration route including intranasal, intranasal, intragastrointestinal, topical, sublingual, intravaginal or rectal routes, but is not limited thereto.
  • the peptide of the present invention or a long-acting conjugate thereof may be co-administered with an SGLT-2 inhibitor in an appropriate ratio.
  • the peptide of the present invention or a long-acting conjugate thereof is 0.1 to 100 mg, 0.5 to 80 mg, 1 to 60 mg, 1 to 25 mg, 5 to 20 mg, or 10 to 15 mg.
  • the SGLT-2 inhibitor may be administered at a dose of 1 to 50 mg, 3 to 30 mg, or 5 to 25 mg, but is not limited thereto.
  • the peptide of the present invention or a long-acting conjugate thereof can be administered in combination with an SGLT-2 inhibitor at an appropriate ratio to exhibit an excellent blood sugar control effect and a weight loss effect. If an overdose of the peptide or its long-acting conjugate is administered, there is a high risk of not having a level of blood sugar control effect that can treat diabetic patients, and when an SGLT-2 inhibitor is overdose, the risk of side effects such as weight gain There is this high problem.
  • composition containing the SGLT-2 inhibitor may be administered together with the SGLT-2 inhibitor at regular administration intervals, or may be administered separately at different frequencies, and the administration time is not limited as long as the combined administration of the two components has an effect.
  • the frequency of administration of the SGLT-2 inhibitor may be administered each independently once every 3 days, once a week, once every 2 weeks, once every 4 weeks, or once a month, peptides or long-acting conjugates thereof;
  • the administration interval between the composition containing the same and the SGLT-2 inhibitor may be 1 to 10 days, 1 to 5 days, or 1 to 3 days, but is not limited thereto.
  • Another aspect embodying the present invention is a peptide or conjugate having activity against glucagon receptors, GLP-1 receptors, and GIP receptors; and a combination, pharmaceutical composition, or kit comprising an SGLT-2 inhibitor.
  • it is a combination, pharmaceutical composition, or kit for preventing or treating liver disease, lung disease, or respiratory infection disease.
  • it is a combination, pharmaceutical composition, or kit for preventing or treating diabetes and/or obesity.
  • the peptide, its conjugate, composition, liver disease, lung disease, or respiratory infection disease, diabetes, obesity, SGLT-2 inhibitor, concomitant administration, prevention, and treatment are as described above.
  • composition, combination, or kit of the present invention comprises (i) a peptide having activity against the glucagon receptor, the GLP-1 receptor, and the GIP receptor, or (ii) the glucagon receptor, the GLP-1 receptor, and the GIP receptor It may include a long-acting conjugate of a peptide having an activity, and may additionally/optionally include an SGLT-2 inhibitor, but is not limited thereto.
  • the compositions, combinations and kits of the present invention may be administered/used to patients with metabolic syndrome, liver disease, lung disease, or respiratory infection to exhibit preventive or therapeutic effects, but are not limited thereto.
  • the compositions, combinations and kits of the present invention may be administered/used to diabetic patients, obese patients, overweight or obese diabetic patients, or diabetic obese patients to exhibit blood sugar lowering and weight reducing effects, but are not limited thereto.
  • the term “combination” refers to a peptide or a conjugate thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors; And as having a combined administration use of the SGLT-2 inhibitor, it can be understood as the same meaning as “combined use”. These include peptides with activity against glucagon receptors, GLP-1 receptors, and GIP receptors; And a pharmaceutical composition form characterized in that the SGLT-2 inhibitor is used in combination, but is not limited thereto.
  • SGLT-2 inhibitor may be administered in a separate form, but is not limited thereto.
  • the conjugate thereof and the SGLT-2 inhibitor may be formulated as separate preparations and administered simultaneously, separately, sequentially, or in reverse order.
  • a composition comprising a peptide or a conjugate thereof having activity on glucagon receptor, GLP-1 receptor, and GIP receptor, which is co-administered with the SGLT-2 inhibitor of the present invention, may include the above combination.
  • composition comprising a combination refers to a combination including a peptide or a conjugate thereof having activity on the glucagon receptor, GLP-1 receptor, and GIP receptor, and an SGLT-2 inhibitor itself, or , including these, may have therapeutic uses, but are not limited thereto.
  • it may be used for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease, but is not limited thereto.
  • it may be used for preventing or treating diabetes and/or obesity, but is not limited thereto.
  • composition comprising a combination may be used interchangeably with “composition”.
  • a composition comprising the combination according to the present invention is for co-administration of a peptide or conjugate thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors, and an SGLT-2 inhibitor.
  • a peptide or conjugate thereof having activity against GIP receptors; and the SGLT-2 inhibitor may be formulated as one formulation or individually formulated.
  • peptides or conjugates thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors; and SGLT-2 inhibitor may be administered simultaneously, separately, sequentially, or in reverse order, but is not limited thereto.
  • the term "kit” refers to peptides or conjugates thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors; and peptides or conjugates thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors according to the present invention for concomitant administration of SGLT-2 inhibitors; and SGLT-2 inhibitors.
  • the kit according to the present invention includes peptides or conjugates thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors formulated as one formulation; and an SGLT-2 inhibitor, or the peptide or a conjugate thereof; and individual formulations of the SGLT-2 inhibitor, and may additionally include substances necessary for the combined administration of the two substances, but are not limited thereto.
  • the administration/use of the combination, composition, or kit of the present invention can reduce body weight and lower blood sugar levels, thereby helping patients with metabolic syndrome, specifically diabetic patients, especially diabetic patients with overweight or obesity; Alternatively, an excellent preventive or therapeutic effect of diabetes and/or obesity may be obtained in obese patients, particularly diabetic obese patients.
  • combination, composition, and kit of the present invention can be administered/used to reduce weight and lower blood sugar, as well as anti-inflammatory and anti-fibrotic effects, so that patients with liver disease, lung disease, or respiratory infection disease may have preventive or therapeutic effects.
  • compositions and kits of the present invention include peptides or conjugates thereof having activity against glucagon receptors, GLP-1 receptors, and GIP receptors; And it may be used for concomitant administration of an SGLT-2 inhibitor.
  • Another aspect embodying the present invention is a method for preventing or treating diabetes and/or obesity, or a method for lowering blood sugar, comprising administering a peptide, a conjugate thereof, or a composition containing the same to a subject in need thereof.
  • Another aspect embodying the present invention is the prevention or treatment of metabolic syndrome, liver disease, lung disease, or respiratory infection comprising the step of administering a peptide, a conjugate thereof, or a composition containing the same to a subject in need thereof method or blood sugar lowering method.
  • the methods of the invention may further comprise administering an SGLT-2 inhibitor to an individual in need thereof.
  • the method of the present invention may be a method of administering a peptide or a conjugate thereof in combination with an SGLT-2 inhibitor, but is not limited thereto.
  • the peptide, its conjugate, composition, SGLT-2 inhibitor, concomitant administration, diabetes, obesity, metabolic syndrome, liver disease, lung disease, or respiratory infection disease, prevention, treatment, and blood sugar lowering are as described above.
  • the subject is an individual that is beneficial for lowering blood sugar and reducing body weight, and refers to mammals including humans, rats, livestock, etc., but the blood glucose lowering effect due to the peptide or conjugate thereof of the present invention, or a composition containing the same Objects benefiting from this are included without limitation.
  • it may be a subject having diabetes and/or obesity, but is not limited thereto.
  • the subject may be an overweight or obese diabetic patient, or an individual who has or is at risk of having diabetic obesity or diabetic complications, but is not limited thereto.
  • it may be an obese, obese individual with hyperglycemia or diabetes, but is not limited thereto.
  • it may be a subject with metabolic syndrome, liver disease, lung disease, or respiratory infection disease, but is not limited thereto.
  • the term "administration" means introducing a predetermined substance to a patient (subject) by any suitable method, and includes the peptide, its conjugate, or composition;
  • the route of administration of the SGLT-2 inhibitor is not particularly limited thereto, but the peptide, its conjugate or composition;
  • the SGLT-2 inhibitor can be administered through any general route that can reach the target in vivo, for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration , intranasal administration, intrapulmonary administration, intrarectal administration, and the like.
  • the peptide or its conjugate; and the SGLT-2 inhibitor may be administered by the same route of administration or by different routes of administration, and the route of administration of the concomitantly administered drugs may be independent of each other.
  • the peptide, its conjugate or composition; And the SGLT-2 inhibitor is formulated into a unit dosage form suitable for administration into the body of a patient according to a conventional method in the pharmaceutical field, specifically, a formulation useful for the administration of a protein drug, which is commonly used in the art.
  • it may be administered by a parenteral administration route including a rectal route, but is not limited thereto.
  • the peptide of the present invention, a conjugate thereof, or a composition containing the same may be administered once every 3 days, once a week, once every 2 weeks, once every 4 weeks, or once a month. It may, but is not limited thereto.
  • the frequency of administration is not limited, but, for example, 3 days It may be administered once in a week, once in a week, once in two weeks, once in four weeks, or once in a month. In addition, it is administered at the same interval as the peptide or conjugate thereof, or at a different interval, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days. It may be administered at intervals of one or more days, but is not limited thereto,
  • the method of the present invention comprises a composition comprising the peptide or a conjugate thereof; and administering a pharmaceutically effective amount of an SGLT-2 inhibitor.
  • An appropriate total daily amount can be determined by a treating physician within the scope of sound medical judgment, and can be administered once or divided into several times.
  • a specific therapeutically effective amount for a particular patient is determined by the type and extent of the response to be achieved, the specific composition, including whether other agents are used as the case may be, the patient's age, weight, general state of health, It is preferable to apply differently according to various factors including gender and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used together with or concurrently used with a specific composition, and similar factors well known in the medical field.
  • the peptide or a long-acting conjugate thereof may be co-administered with an SGLT-2 inhibitor in an appropriate ratio.
  • the peptide of the present invention or a long-acting conjugate thereof is 0.1 to 100 mg, 0.5 to 80 mg, 1 to 60 mg, 1 to 25 mg, 5 to 20 mg, or 10 to 15 mg.
  • the SGLT-2 inhibitor may be administered at a dose of 1 to 50 mg, 3 to 30 mg, or 5 to 25 mg, but is not limited thereto.
  • Another aspect embodying the present invention is a method for preventing or treating diabetes and/or obesity comprising administering and/or using the combination, the pharmaceutical composition, or the pharmaceutical kit to a subject in need thereof. is to provide
  • Another aspect embodying the present invention is metabolic syndrome, liver disease, lung disease, or It is to provide a method for preventing or treating respiratory infections.
  • the combination, pharmaceutical composition, pharmaceutical kit, subject, administration, diabetes, obesity, metabolic syndrome, liver disease, lung disease, or respiratory infection disease, combined administration, prevention, and treatment are as described above.
  • the method may be a method of administering a peptide or a conjugate thereof in combination with an SGLT-2 inhibitor, but is not limited thereto.
  • Another aspect embodying the present invention is a peptide, a conjugate thereof, or a composition containing the same for preventing or treating diabetes and/or obesity, and/or for preparing a medicament for preventing or treating diabetes and/or obesity. to provide a use.
  • Another aspect embodying the present invention is the use of a peptide, a conjugate thereof, or a composition containing the same for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease, and/or metabolic syndrome, liver disease, lung disease , Or to provide a use for the manufacture of a medicament for the prevention or treatment of respiratory infections.
  • the peptide, its conjugate, composition, diabetes, obesity, metabolic syndrome, liver disease, lung disease, or respiratory infection disease, prevention and treatment are as described above.
  • the use may be for co-administration of a peptide or a conjugate thereof with an SGLT-2 inhibitor.
  • Another object of the present invention is to use the combination, pharmaceutical composition, or pharmaceutical kit for the prevention or treatment of diabetes and/or obesity and/or for the preparation of a medicament for the prevention or treatment of diabetes and/or obesity. to provide a use.
  • Another object of the present invention is the use of the combination, pharmaceutical composition, or pharmaceutical kit for preventing or treating metabolic syndrome, liver disease, lung disease, or respiratory infection disease and/or metabolic syndrome, liver disease, lung disease , Or to provide a use for the manufacture of a medicament for the prevention or treatment of respiratory infections.
  • the combination, pharmaceutical composition, pharmaceutical kit, subject, administration, diabetes, obesity, metabolic syndrome, liver disease, lung disease, or respiratory infection disease, prevention, treatment, combined administration, prevention, treatment are as described above. .
  • the use may be for co-administration of a peptide or a conjugate thereof with an SGLT-2 inhibitor.
  • a triple activator exhibiting activity on all of GLP-1, GIP and glucagon receptors was prepared and its sequence is shown in Table 1 below.
  • the amino acid indicated by X is Aib (2-aminoisobutyric acid), which is a non-natural amino acid, and the underlined amino acid indicates that the underlined and bold amino acids form a ring with each other.
  • CA means 4-imidazoacetyl (4-imidazoacetyl)
  • Y means tyrosine.
  • maleimide-PEG-aldehyde 10 kDa PEG having a maleimide group and an aldehyde group at both ends
  • maleimide-PEG-aldehyde 10 kDa, NOF, Japan
  • the triple active compound of Example 1 SEQ ID NOs: 21, 22, 42, 43, 50 , 77, and 96
  • the molar ratio of the triactivator and maleimide-PEG-aldehyde was 1: 1 to 3
  • the protein concentration was 1 to 5 mg/ml at low temperature to 0.5 to 5 mg/ml. Reacted for 3 hours.
  • the reaction was performed in an environment in which 20 to 60% isopropanol was added to 50 mM Tris buffer (pH 7.5). After the reaction was completed, the reaction solution was applied to SP Sepharose HP (GE healthcare, USA) to purify the triactivator mono-PEGylated on cysteine.
  • the purified mono-PEGylated triactivator and immunoglobulin Fc (homodimer of SEQ ID NO: 123) were mixed at a molar ratio of 1: 1 to 5 and 4 to 8 at a protein concentration of 10 to 50 mg/ml. It was reacted for 12 to 18 hours at °C. The reaction was performed in an environment in which 10 to 50 mM sodium cyanoborohydride and 10 to 30% isopropanol as reducing agents were added to 100 mM potassium phosphate buffer (pH 6.0).
  • This purified long-acting conjugate has a structure in which a triactive peptide, a polyethylene glycol (PEG) linker and an Fc dimer are covalently linked in a molar ratio of 1:1:1 within the molecule, and the PEG linker is a structure in which the two polypeptide chains of the Fc dimer are linked together. are connected to only one chain.
  • PEG linker is a structure in which the two polypeptide chains of the Fc dimer are linked together. are connected to only one chain.
  • two monomers having the amino acid sequence of SEQ ID NO: 123 form a homodimer through a disulfide bond between cysteine, amino acid number 3 of each monomer, and the homodimer
  • the monomers of are each independently formed with an internal disulfide bond between cysteines at positions 35 and 95 and an internal disulfide bond between cysteines at positions 141 and 199.
  • conjugate in which the triactivator of SEQ ID NO: 21 and immunoglobulin Fc are linked via a PEG linker was named 'a conjugate comprising SEQ ID NO: 21 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 21', and these They may be used interchangeably herein.
  • conjugate in which the triactivator of SEQ ID NO: 22 and immunoglobulin Fc are linked via a PEG linker was named 'a conjugate comprising SEQ ID NO: 22 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 22', and these They may be used interchangeably herein.
  • conjugate in which the triactivator of SEQ ID NO: 42 and immunoglobulin Fc are linked via PEG was named 'a conjugate comprising SEQ ID NO: 42 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 42'. can be used interchangeably in
  • conjugate in which the triactivator of SEQ ID NO: 43 and immunoglobulin Fc are linked through PEG was named 'a conjugate comprising SEQ ID NO: 43 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 43', and these are described herein. can be used interchangeably in
  • conjugate in which the triactivator of SEQ ID NO: 50 and immunoglobulin Fc are linked through PEG was named 'a conjugate comprising SEQ ID NO: 50 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 50', and these are described herein. can be used interchangeably in
  • conjugate in which the triactivator of SEQ ID NO: 77 and immunoglobulin Fc are linked through PEG was named 'a conjugate comprising SEQ ID NO: 77 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 77', which are described herein. can be used interchangeably in
  • conjugate in which the triactivator of SEQ ID NO: 96 and immunoglobulin Fc are linked via PEG was named 'a conjugate comprising SEQ ID NO: 96 and immunoglobulin Fc' or 'a long-acting conjugate of SEQ ID NO: 96'. can be used interchangeably in
  • Each of the above cell lines was transformed to express human GLP-1 receptor, human GCG receptor, and human GIP receptor genes in Chinese hamster ovary (CHO), respectively, and is suitable for measuring the activities of GLP-1, GCG, and GIP. Therefore, the activity for each part was measured using each transformed cell line.
  • human GLP-1 was serially diluted from 50 nM to 0.000048 nM by 4 folds, and in Examples 1 and 2
  • the prepared triactivator and its long-acting conjugate were serially diluted from 400 nM to 0.00038 nM by 4 folds.
  • the culture medium was removed from the cultured human GLP-1 receptor-expressing CHO cells, 5 ⁇ l of each of the serially diluted substances was added to the cells, and then 5 ⁇ l of buffer containing cAMP antibody was added to the cells, followed by 15 minutes. while incubated at room temperature.
  • human GCG was serially diluted from 50 nM to 0.000048 nM by 4 folds, and the triple activity prepared in Examples 1 and 2
  • the body and its long-acting conjugate were serially diluted from 400 nM to 0.00038 nM by 4 folds.
  • the culture medium was removed from the cultured human GCG receptor-expressing CHO cells, 5 ⁇ l of each of the serially diluted substances was added to the cells, and then 5 ⁇ l of buffer containing cAMP antibody was added to the cells, followed by addition of 5 ⁇ l of buffer solution for 15 minutes at room temperature. cultured in.
  • human GIP was serially diluted from 50 nM to 0.000048 nM by 4 folds, and the triple activity prepared in Examples 1 and 2
  • the body and its long-acting conjugate were serially diluted from 400 nM to 0.00038 nM by 4 folds.
  • the culture medium was removed from the cultured human GIP receptor-expressing CHO cells, 5 ⁇ l of each of the serially diluted substances was added to the cells, and then 5 ⁇ l of buffer containing cAMP antibody was added to the cells, followed by incubation at room temperature for 15 minutes. cultured in.
  • the above triple activator and its conjugate have a function as a triple activator capable of activating all of the GLP-1 receptor, the GIP receptor and the glucagon receptor.
  • the long-acting conjugate of SEQ ID NO: 42 was used as the SGLT-2 inhibitor Empagliple. It was co-administered with rosin for 4 weeks to DIO/STZ rats, which are well known as obesity and diabetes models.
  • the test was conducted in the vehicle control group, the long-acting conjugate of SEQ ID NO: 42 alone administration group (0.163 mg/kg, Q3D), and the empagliflozin alone administration group (10 mg/kg, QD). Then, the long-acting conjugate of SEQ ID NO: 42 (0.163 mg/kg, Q3D) and empagliflozin (10 mg/kg, QD) were divided into a combination administration group, and the substances were repeatedly administered subcutaneously for 4 weeks.

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PCT/KR2022/009449 2021-06-30 2022-06-30 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체를 포함하는 조합물의 치료학적 용도 Ceased WO2023277620A1 (ko)

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CA3216330A CA3216330A1 (en) 2021-06-30 2022-06-30 Therapeutic use of combination including triple agonist having activities to all of glucagon, glp-1, and gip receptors
EP22833674.9A EP4364750A4 (en) 2021-06-30 2022-06-30 THERAPEUTIC USE OF A COMBINATION COMPRISING A TRIPLE ACTIVATOR WITH ACTIVITY ON ALL OF THE FOLLOWING RECEPTORS: GLUCAGON, GLP-1 AND GIP
CN202280042772.4A CN117615775A (zh) 2021-06-30 2022-06-30 包括对胰高血糖素、glp-1和gip受体全部具有活性的三重激动剂的组合的治疗用途
US18/565,628 US20240293512A1 (en) 2021-06-30 2022-06-30 Therapeutic use of combination including triple agonist having activities to all of glucagon, glp-1, and gip receptors
MX2023012935A MX2023012935A (es) 2021-06-30 2022-06-30 Uso terapeutico de una combinacion que incluye triples agonistas que tienen actividades para todos los receptores de glucagon, glp-1 y gip.
BR112023022445A BR112023022445A2 (pt) 2021-06-30 2022-06-30 Composição farmacêutica e uso da combinação farmacêutica
IL308347A IL308347A (en) 2021-06-30 2022-06-30 Therapeutic use of combination including triple agonist having activities to all of glucagon, glp-1, and gip receptors
AU2022302809A AU2022302809A1 (en) 2021-06-30 2022-06-30 Therapeutic use of combination including triple agonist having activities to all of Glucagon, GLP-1, and GIP receptors
JP2023566569A JP2024527220A (ja) 2021-06-30 2022-06-30 グルカゴン、ｇｌｐ－１及びｇｉｐ受容体の全てに対して活性を有する三重活性体を含む組み合わせ物の治療学的用途

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