WO2021012947A1 - FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 - Google Patents
FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 Download PDFInfo
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Definitions
- the present invention belongs to the technical field of proteins and polypeptides, and more specifically, relates to a FGF21 Fc fusion protein, a GLP-1 Fc fusion protein, and a combination therapeutic agent containing them, for the prevention or treatment of cardiovascular and/or metabolic Diseases, including but not limited to obesity, hyperlipidemia, atherosclerosis, non-alcoholic fatty liver disease, diabetes, diabetic cardiomyopathy, coronary atherosclerotic heart disease and other diseases related to insulin resistance.
- cardiovascular and/or metabolic Diseases including but not limited to obesity, hyperlipidemia, atherosclerosis, non-alcoholic fatty liver disease, diabetes, diabetic cardiomyopathy, coronary atherosclerotic heart disease and other diseases related to insulin resistance.
- Fibroblast growth factor-21 belongs to the FGF family, which is mainly synthesized by the liver and enters the circulation in the form of endocrine. Its C-terminus is combined with the effector organ ⁇ -klotho transmembrane protein and then passes through the N-terminus and FGFR1c Specific binding to form a stable FGF21/ ⁇ -klotho/FGFR complex, which then activates downstream related molecular signals.
- FGF21 has various physiological activities such as promoting glucose utilization, increasing insulin sensitivity, promoting fatty acid decomposition, reducing lipid regeneration, and regulating cholesterol balance. It has shown great potential for application in cardiovascular and metabolic diseases.
- long-acting GLP-1 receptor agonists are a class of GLP-1 or Exendin-4 analogues obtained by structural modification of a class of in vivo half-life and bioavailability greatly improved , Protein products with reduced injection frequency.
- long-acting GLP-1 receptor agonists such as Eli Lilly’s dulaglutide and Novo Nordisk’s semaglutide are in the marketing stage, and they are in clinical application with traditional oral hypoglycemic drugs.
- Short-acting GLP-1 receptor agonists or insulin products show significant superiority in blood sugar control or patient compliance.
- GLP-1 receptor agonists play an effective role mainly by promoting the secretion and release of insulin under glucose stimulation.
- Their physiological functions in glucose metabolism mainly depend on insulin activity.
- diseases such as insulin resistance, obesity, non-alcoholic fatty liver disease, or hyperlipidemia, which are commonly coexisting in diabetic patients through a mechanism of action independent of weight loss.
- This type of product can exert a certain weight loss effect by inhibiting the patient's food intake, but its effect is mostly dependent on the gastrointestinal side effects of the product itself.
- cardiovascular and metabolic diseases are manifested with multiple diseases such as hyperlipidemia, obesity, hyperglycemia, fatty liver, and atherosclerosis.
- diseases such as hyperlipidemia, obesity, hyperglycemia, fatty liver, and atherosclerosis.
- epidemiological results show that obese patients account for about 60% of type 2 diabetes, about 50% of patients with non-alcoholic liver disease, and more than 70% of patients with diabetes have abnormal blood lipid levels; the risk of cardiovascular disease in patients with diabetes is 2-4 times that of diabetic patients, and cardiovascular events have become the first element of all-cause death in diabetic patients; cardiovascular events are the second cause of death in non-alcoholic fatty liver patients.
- multiple drug combination therapies are clinically recommended to control the course of multiple diseases at the same time.
- the purpose of the present invention is to provide a FGF21 Fc fusion protein, a GLP-1 Fc fusion protein, and a combination therapeutic agent using them as FGF21R/GLP-1R dual long-acting agonists for the prevention and treatment of cardiovascular and/or Metabolic diseases, especially for patients with multiple cardiovascular or metabolic diseases, provide a comprehensive management and prevention method.
- the FGF21 Fc fusion protein and GLP-1 Fc fusion protein also provided by the present invention are administered in combination in animal models of diseases such as obesity, diabetes, hyperlipidemia, non-alcoholic fatty liver disease, atherosclerosis, and diabetic cardiomyopathy. , All unexpectedly showed significant synergistic effects.
- the present invention provides a FGF21 Fc fusion protein, the amino acid sequence of which is:
- the present invention provides a GLP-1 Fc fusion protein, the amino acid sequence of which is:
- the present invention provides a combination therapeutic agent, which consists of a first pharmaceutical composition comprising a long-acting FGF21 Fc fusion protein and a second pharmaceutical composition comprising a long-acting GLP-1 Fc fusion protein; And the amino acid sequence of the long-acting FGF21 Fc fusion protein is selected from SEQ ID NO: 4 or is substantially the same as any of the above sequences (for example, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%).
- amino acid sequence of the long-acting GLP-1 Fc fusion protein is selected from SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7 or substantially the same as any of the above sequences (e.g. at least 80%, 85%, 90%, 92%, 95%, 97%, 98% , 99% more highly similar or with one or more amino acid substitutions (eg conservative substitutions), deletions and/or additions.
- first pharmaceutical composition and the second pharmaceutical composition further comprise a pharmaceutically acceptable carrier, and/or excipient and/or stabilizer.
- the FGF21 Fc fusion protein and GLP-1 Fc fusion protein can be included in the pharmaceutical composition in a preventively effective amount or a therapeutically effective amount; wherein, the preventive or therapeutically effective amount depends on the purpose of treatment or the purpose of prevention , Such as the condition of the patient in need of treatment, the required route of administration, etc.
- first pharmaceutical composition and the second pharmaceutical composition are formulated into a dosage form suitable for oral administration or injection.
- first pharmaceutical composition and the second pharmaceutical composition are respectively formulated into dosage forms suitable for oral administration or injection.
- the present invention also provides the use of the combined therapeutic agent in the preparation of drugs for the prevention or treatment of cardiovascular and/or metabolic diseases.
- cardiovascular and/or metabolic diseases include but are not limited to obesity, hyperlipidemia, atherosclerosis, non-alcoholic fatty liver disease, diabetes, diabetic cardiomyopathy, coronary atherosclerotic heart Diseases and other diseases related to insulin resistance.
- the present invention provides a method for the combination therapeutic agent to prevent and treat the aforementioned diseases.
- the method comprises jointly administering to the subject or patient a preventive or therapeutically effective amount of the first pharmaceutical composition and the second pharmaceutical composition; wherein the preventive or therapeutically effective amount is determined according to the purpose of treatment or the purpose of prevention , Such as the condition of the patient in need of treatment, the required route of administration, etc.
- first pharmaceutical composition and the second pharmaceutical composition are administered in combination, the two are administered together at the same time, but at the same time but separately or at different times; the different time administration is consecutively or at intervals of time.
- first pharmaceutical composition and the second pharmaceutical composition can be administered in any manner known in the art, such as injection, such as intravenous (i.v.) or subcutaneous (s.c) injection.
- injection such as intravenous (i.v.) or subcutaneous (s.c) injection.
- the advantages of the present invention are that, on the one hand, starting from the actual clinical therapeutic effect and the mechanism of action of the drug, the application of the FGF21R/GLP-1R dual agonist combination copes with the complexity of the disease mechanism, meets the diversity of treatment needs, and is fully studied by scientific experiments To clarify the superiority and feasibility of the long-acting FGF21 Fc fusion protein combined with the long-acting GLP-1 Fc fusion protein.
- the treatment method provided by the present invention optimizes the current clinical treatment methods for cardiovascular and metabolic diseases; in particular, it provides a more effective and comprehensive combination treatment plan for patients with multiple cardiovascular or metabolic diseases; on the other hand, the present invention chooses
- the active ingredients of the combined therapeutics are long-acting protein drugs, which can be administered clinically once a week, and their patient acceptance is much higher than other insulin or GLP-1 analog products.
- FGF21 refers to natural human FGF21 and its analogs and derivatives that maintain FGF21 activity.
- the sequence of the natural human FGF21 protein can be obtained from the UNIPROT database under the accession number Q9NSA1.
- the precursor protein is composed of 209 amino acids, including signal peptide (amino acids 1-28) and mature protein (amino acids 29-209).
- natural human FGF21 includes SEQ ID NO: 1 and L174P or G141S substitution isoforms.
- the mature protein partial sequence (amino acids 29-209) shown after removing the leader peptide; in addition, it also includes these sequences before adding the above 27 or 28 The full-length sequence of the precursor protein of a signal peptide with three amino acids.
- GLP-1 refers to human GLP-1 (7-37) (SEQ ID NO: 2 amino acids 1-31), Exendin-4 (7-45) (SEQ ID NO: 3) 1-39 amino acids) and its analogues and derivatives that maintain GLP-1 activity.
- FGF21 analogs and "GLP-1 analogs” refer to the following polypeptides, which can be deduced or derived from the respective FGF21 of SEQ ID NOs: 1, 2 and 3 by modifying its amino acid sequence or by modifying its amino acid sequence. , GLP-1 and Exendin-4 (Exendin-4) sequence. Such modifications may include substitutions, deletions and/or additions of one or more amino acids. For example, amino acids may be added and/or deleted at the C-terminus, N-terminus, or within the amino acid sequence. Preferably, amino acids are added and/or deleted at the C-terminus and/or N-terminus, more preferably at the N-terminus. Amino acid sequences with C-terminal or N-terminal deleted amino acids can also be referred to as truncated sequences, as known in the art.
- the pharmaceutical composition comprising the FGF21 Fc fusion protein and the GLP-1 fusion protein of the present invention may further comprise a pharmaceutically acceptable carrier.
- the carrier may be water or physiological saline, for example.
- Other pharmaceutically acceptable substances may also be used, such as diluents and appropriate buffers.
- other pharmaceutically acceptable substances such as emulsifiers, suspending agents, solvents, fillers, bulking agents, adjuvants, preservatives, antioxidants, coloring agents and/or flavoring agents may also be used.
- the FGF21 Fc fusion protein and GLP-1 Fc fusion protein can be used in the form of purified polypeptides, or formulated with suitable pharmaceutically acceptable excipients, as known in the art.
- the pharmaceutical composition can be administered in any manner known in the art, such as injection, such as intravenous (i.v.) or subcutaneous (s.c) injection.
- the FGF21 Fc fusion protein and GLP-1 Fc fusion protein can be included in the pharmaceutical composition in a therapeutically effective amount or a preventively effective amount.
- the effective amount depends on the purpose of treatment or prevention, such as the condition of the patient to be treated, the required route of administration, and the like.
- insulin resistance refers to a state where the normal dose of insulin produces lower than normal biological effects, which slows down the glucose uptake of fat and skeletal muscle, but increases the release of glucose from the liver and the release of free fatty acids from adipose tissue .
- the first response of insulin resistance is the compensatory production and secretion of insulin to compensate for the reduced sensitivity of the body, leading to hyperinsulinemia. In this way, high insulin levels and reduced responsiveness of tissues to clear glucose from the bloodstream are characteristic of insulin resistance.
- Insulin resistance is the main event that leads to a series of metabolic changes, including compensatory hyperinsulinemia, dyslipidemia, hypocompensated pancreatic ⁇ -cells, and hyperglycemia.
- IMS insulin resistance syndrome
- type 2 diabetes impaired glucose tolerance
- metabolic syndrome hyperglycemia
- hyperinsulinemia hyperinsulinemia
- arteriosclerosis hypercholesterolemia
- high glycerol Triesteremia hyperlipidemia
- dyslipidemia obesity
- central obesity polycystic ovary syndrome
- rapid coagulation hypertension
- microalbuminuria a measure of insulin resistance syndrome
- diabetes is an endocrine and metabolic disease caused by absolute or relative insufficient insulin secretion.
- the pathogenesis of type 2 diabetes includes the gradual development of insulin resistance in the liver and peripheral tissues, accompanied by defective insulin secretion in pancreatic beta cells, leading to obvious hyperglycemia (abnormally high blood glucose content).
- diabetes is a dysfunction of other parts of the body caused by chronic hyperglycemia, such as diabetic nephropathy, diabetic neuropathy, diabetic foot (foot ulcers and low circulation), and eye disease (retinopathy). Diabetes also increases the risk of heart disease and bone and joint disorders. Other long-term complications of diabetes include skin problems, digestive problems, sexual dysfunction, and teeth and gum problems.
- diabetes refers to a myocardial disease that occurs in diabetic patients and cannot be explained by hypertensive heart disease, coronary atherosclerotic heart disease, and other heart diseases.
- the disease caused extensive focal necrosis of the myocardium on the basis of metabolic disorders and microvascular disease, with subclinical cardiac dysfunction, and eventually progressed to severe patients with heart failure, arrhythmia, and cardiogenic shock and even sudden death.
- coronary atherosclerotic heart disease is a heart disease caused by atherosclerotic lesions in the coronary arteries that cause vascular lumen to be narrowed or blocked, resulting in myocardial ischemia, hypoxia or necrosis.
- Dyslipidemia is a disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency. Dyslipidemia can be manifested as an increase in the concentration of total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides in the blood, and a decrease in the concentration of high-density lipoprotein (HDL) cholesterol.
- LDL low-density lipoprotein
- HDL high-density lipoprotein
- non-alcoholic fatty liver disease refers to all diseases of the liver caused by steatosis rather than excessive drinking.
- NAFLDs include but are not limited to simple non-alcoholic fatty liver (“NAFL”), non-alcoholic steatohepatitis (“NASH”), NAFL with liver fibrosis, NAFL with liver cirrhosis, and liver fibrosis NASH, NASH with liver cirrhosis and caused by hepatitis, obesity, diabetes, insulin resistance, hypertriglyceridemia, lipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, pregnancy Or fatty liver disease caused by lipodystrophy.
- non-alcoholic steatohepatitis is a liver disease unrelated to alcohol consumption, which is characterized by fatty degeneration of liver cells, accompanied by inflammation and fibrosis in the lobules.
- Atherosclerosis is a systemic disease related to lipid metabolism disorders. Its pathological feature is that lipids in the blood enter the arterial wall and deposit on the intima to form atherosclerotic plaques. Causes arteries to thicken and harden. AS mainly affects the large and medium arteries.
- the basic pathology is lipid deposition in the arterial intima, focal fibrosis of the intima, atherosclerotic plaque formation, hardening of the vessel wall, stenosis of the official cavity, and a series of secondary diseases, especially It occurs in the heart, brain, kidney and other organs, causing ischemic changes.
- pharmaceutically acceptable carrier and/or excipient and/or stabilizer refers to a carrier and/or excipient/or that is pharmacologically and/or physiologically compatible with the subject and the active ingredient Stabilizers, they are non-toxic to cells or mammals exposed to them at the dose and concentration used.
- pH adjusting agents include, but are not limited to, phosphate buffer.
- surfactants include but are not limited to cationic, anionic or nonionic surfactants, such as Tween-80.
- Ionic strength enhancers include, but are not limited to, sodium chloride.
- Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like.
- Agents for maintaining osmotic pressure include but are not limited to sugar, NaCl and the like.
- Agents that delay absorption include, but are not limited to, monostearate and gelatin.
- Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol) and the like.
- Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, paraben, chlorobutanol, phenol, sorbic acid and the like.
- Stabilizers have the meaning commonly understood by those skilled in the art, which can stabilize the desired activity of the active ingredients in the drug, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose) , Lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin or casein) or their degradation products (such as lactalbumin hydrolysate).
- patient refers to any human or non-human animal, especially a human, who receives prophylactic or therapeutic treatment.
- the combination therapeutic agents and methods described herein can be used to treat subjects with diabetes, NASA, NAFLD, or atherosclerotic disease.
- non-human animals includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, reptiles, and the like.
- an effective amount refers to an amount sufficient to obtain or at least partially obtain the desired effect.
- an effective amount for preventing diseases refers to, when used alone or in combination with another or more therapeutic agents, sufficient to prevent, prevent, or delay the occurrence of diseases (e.g., tumors or infections)
- An effective amount for treating a disease refers to an amount sufficient to cure or at least partially prevent the disease and its complications in patients who have already suffered from the disease when used alone or in combination with another or more therapeutic agents. It is completely within the abilities of those skilled in the art to determine such an effective amount.
- the effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient’s own immune system, the patient’s general conditions such as age, weight and sex, the way the drug is administered, and other treatments that are simultaneously administered and many more.
- the terms "effective” and “effectiveness” with respect to treatment include both pharmacological effectiveness and physiological safety.
- Pharmacological effectiveness refers to the ability of a drug to promote the resolution of a patient's illness or symptoms.
- Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cell, organ, and/or biological level caused by drug administration.
- Treatment or “therapy” for a subject means to reverse, reduce, ameliorate, inhibit, slow down, or prevent the appearance, progression, development, severity or recurrence of disease-related symptoms, complications, disorders or biochemical indicators
- Treatment or “therapy” for a subject means to reverse, reduce, ameliorate, inhibit, slow down, or prevent the appearance, progression, development, severity or recurrence of disease-related symptoms, complications, disorders or biochemical indicators
- Figure 1 The effect of combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on the body weight of obese mice (means ⁇ SEM); Note for statistical differences: Comparing with the vehicle control group Ratio, ## P ⁇ 0.01; Compared with the corresponding GLP-1 Fc fusion protein single-use group, **P ⁇ 0.01; Compared with FP4I single-use group, ⁇ P ⁇ 0.01.
- FIG. 1 The effect of the combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on the serum liver function of obese mice (means ⁇ SEM); Note for statistical differences: Compared with vehicle Compared with the group, ## P ⁇ 0.01; compared with the corresponding GLP-1 Fc fusion protein single-use group, ** P ⁇ 0.01; compared with the FP4I single-use group, ⁇ P ⁇ 0.01.
- Figure 3 The effect of the combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on the liver triglyceride content of obese mice (means ⁇ SEM); statistical difference mark annotation: with vehicle Compared with the control group, ## P ⁇ 0.01; compared with the corresponding GLP-1 Fc fusion protein single-use group, ** P ⁇ 0.01; compared with the FP4I single-use group, ⁇ P ⁇ 0.01.
- FIG. 4 Histopathological picture of liver in obese mice after combined use of FP4I and GLP-1 Fc fusion protein dulaglutide, FP-B or FP-A.
- FIG. 5 The effect of the combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on the serum insulin content of obese mice (means ⁇ SEM); Note for statistical differences: Compared with vehicle Compared with the group, ## P ⁇ 0.01; compared with the corresponding GLP-1 Fc fusion protein single-use group, ** P ⁇ 0.01; compared with the FP4I single-use group, ⁇ P ⁇ 0.01.
- Figure 6 The effect of combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on serum liver function in mice with non-alcoholic steatohepatitis (means ⁇ SEM); statistical difference marker annotation : Compared with the vehicle control group, ## P ⁇ 0.01; compared with the corresponding GLP-1 Fc fusion protein single-use group, ** P ⁇ 0.01; compared with the FP4I single-use group, ⁇ P ⁇ 0.01.
- Figure 7 The effect of combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on the liver triglyceride content of mice with nonalcoholic steatohepatitis (means ⁇ SEM); statistical difference Mark annotation: Compared with the vehicle control group, ## P ⁇ 0.01; compared with the corresponding GLP-1 Fc fusion protein single-use group, * P ⁇ 0.05; compared with the FP4I single-use group, ⁇ P ⁇ 0.05.
- FIG. 8 Histopathological picture of liver in mice with non-alcoholic steatohepatitis after FP4I and GLP-1 Fc fusion protein dulaglutide, FP-B and FP-A were used in combination.
- Figure 9 The effect of combined use of FP4I and GLP-1 Fc fusion proteins dulaglutide, FP-B and FP-A on the whole heart mass of db/db mice (means ⁇ SEM); statistical difference mark annotation: and Compared with the normal control group, ## P ⁇ 0.01; compared with the vehicle control group, ** P ⁇ 0.01.
- the present invention selects a long-acting FGF21-Fc fusion protein (named FP4I, see Chinese Patent CN107995914A) and the long-acting GLP-1 Fc fusion protein dulaglutide (trade name: Trulicity) or Ex(1-39)- L3-CTP 1 -vFc ⁇ 2-3 (named FP-A, see Chinese patent CN106117370B), or Ex-(1-45)-L-vFc (named FP-B, see Chinese patent CN106279430B) used in combination to Obesity, hyperlipidemia, non-alcoholic fatty liver disease or diabetes animal models are the research objects, fully clarifying the therapeutic advantages of the combination of the two types of products and providing a more effective and comprehensive approach for the comprehensive management and prevention of cardiovascular and metabolic diseases s solution.
- FP4I long-acting FGF21-Fc fusion protein
- GLP-1 Fc fusion protein dulaglutide trade name: Trulicity
- Example 1 The effect of combined use on the treatment of obesity, lipid metabolism disorder and fatty liver in mice induced by high-fat diet
- mice Male C57BL/6J mice, 8 weeks old, were purchased from Shanghai Slack Laboratory Animal Co., Ltd. The breeding environment is 22-24°C, the relative humidity is 45-65%, and the lighting time is 12h/day. After being fed with D12492 feed (60% fat calories, American Research Diets) for 20 weeks, the mice were randomly divided into vehicle control group, FP4I-5mg/kg group (FP4I group for short), dulaglutide- 1.5mg/kg group (referred to as dulaglutide group), FP-B-1.5mg/kg group (referred to as FP-B group), FP-A-1.5mg/kg group (referred to as FP-A group), FP4I- 5mg+duraglutide-1.5mg/kg group (abbreviated as FP4I+duraglutide group), FP4I-5mg/kg+FP-B-1.5mg/kg group (abbreviated as FP4I+FP-B group) and FP4I-5mg+ FP-A
- the vehicle control group and the single-agent treatment group were given the corresponding protein solution or buffer by subcutaneous injection on the back of the neck; the combination group was given FP4I by subcutaneous injection on the back of the neck, and dulaglutide, FP-A or FP-B were given by subcutaneous injection on the abdomen. It is administered once every 6 days for a total of 4 administrations. After the last dosing cycle, the mice in each group fasted for 16 hours, and the whole blood was taken from the orbit, centrifuged at 2000g for 15 minutes, and the serum samples were separated. The liver tissue was separated, weighed, and the left outer lobe of the liver was quickly frozen in liquid nitrogen and then transferred to a -80°C refrigerator for storage, and the right lobe of the liver was stored in 10% formalin solution.
- the automatic biochemical analyzer (Ouba XL-200 automatic biochemical analyzer, the product of Germany Ouba company) and its supporting kit (the product of Ningbo Meikang Biotechnology Co., Ltd.) detect mouse serum ALT, AST, TG, TC, LDL-c, HDL-c content.
- ELISA method mouse hypersensitive insulin ELISA test kit, American ALPCO company product detects the insulin content in fasting serum of mice. Approximately 55 mg of left outer lobe tissue of mouse liver was taken, and the content of triglyceride per unit liver mass was measured by Floch method. Take the right lobe of the mouse liver, HE stain, and carry out histopathological examination.
- the data is expressed in the form of mean ⁇ standard error (means ⁇ SEM), and SPSS 18.0 statistical software is used to analyze the data.
- Normal distribution single-factor analysis of variance is used for mean difference between multiple groups, LSD test is used for homogeneity of variance, Dunnet T3 test is used for uneven variance; non-parametric test is used for non-normal distribution, P ⁇ 0.05 indicates significant statistics difference.
- the histopathological results showed that the liver of the mice in the vehicle control group showed mixed fatty degeneration of bullae and vesicles, and the fat was fused into flakes.
- the administration of dulaglutide, FP-B, FP-A or FP4I alone can improve liver steatosis in mice.
- the degree of liver lipopathy in mice in the combined drug group was relieved to a greater extent. The results are shown in Figure 4.
- FP4I, dulaglutide, FP-B and FP-A alone can effectively improve the symptoms of hyperinsulinemia in obese mice.
- FP4I is used in combination with the above-mentioned GLP-1 Fc fusion protein, its effect of improving insulin resistance is significantly enhanced.
- the research content of this example shows that, taking obese mice with typical metabolic syndrome characteristics as the research object, the combination of long-acting FGF21 fusion protein and long-acting GLP-1 Fc fusion protein is more effective in reducing weight and reversing Fatty liver and its induced liver damage, alleviation and treatment of vascular disease caused by dyslipidemia, insulin resistance, and elevated low-density lipoprotein show more excellent therapeutic effects.
- Example 2 The therapeutic effect of combined use on non-alcoholic steatohepatitis mice induced by high fructose, high fat and high cholesterol feed
- mice aged 8 weeks Male C57BL/6J mice aged 8 weeks were purchased from Beijing Huafukang Biotechnology Co., Ltd. The breeding environment is 22-24°C, the relative humidity is 45-65%, and the lighting time is 12h/day.
- D09100301 feed fat calorie 40%, fructose calorie 40%, cholesterol mass 2%, product of Research Diets, USA
- mice were randomly divided into vehicle control group, FP4I-5mg/kg group (referred to as FP4I group), dulaglutide-1.5mg/kg group (referred to as dulaglutide group), FP- B-1.5mg/kg group (abbreviated as FP-B group), FP-A-1.5mg/kg group (abbreviated as FP-A group), FP4I-5mg+duraglutide-1.5mg/kg group (abbreviated as FP4I+dura Lutide group), FP4I-5mg/kg+FP-B-1.5mg/kg (referred to as FP4I+FP-B group) and FP4I-5mg+FP-A-1.5mg/kg group (referred to as FP4I+FP-A group) ), 8 mice per group.
- FP4I group dulaglutide-1.5mg/kg group
- dulaglutide group referred to as dulaglutide group
- FP- B-1.5mg/kg group ab
- the vehicle control group and the single-agent treatment group were given the corresponding protein solution or buffer by subcutaneous injection on the back of the neck; the combination group was given FP4I by subcutaneous injection on the back of the neck, and dulaglutide, FP-A or FP-B were given by subcutaneous injection on the abdomen. It is administered once every 6 days for a total of 8 administrations.
- the mice in each group fasted for 16 hours, collected whole blood from the intraocular canthal venous plexus, centrifuged at 2000g for 15 minutes, and separated serum samples.
- the liver tissue was separated, weighed, and the left outer lobe of the liver was quickly frozen in liquid nitrogen and then transferred to a -80°C refrigerator for storage, and the right lobe of the liver was stored in 10% formalin solution.
- the non-alcoholic steatohepatitis scoring system evaluates the treatment effect.
- the standards refer to the guidelines of the National Institutes of Health Pathology Working Group. The specifics are as follows: liver cell steatosis 0 points ( ⁇ 5%), 1 point (5% ⁇ 33%) ), 2 points (34% ⁇ 66%), 3 points (>66%); Inflammation in the lobules under 20x microscope: 0 points (none), 1 point ( ⁇ 2 points), 2 points (2 to 4 points) , 3 points ( ⁇ 4); hepatocyte ballooning: 0 points (none), 1 point (rare), 2 points (more common).
- the methods of serum biochemical detection, liver triglyceride content detection, histopathological examination, and statistical analysis were the same as those in the corresponding parts in Example 1.
- the combined medication group can further improve the liver function of mice with non-alcoholic steatohepatitis and reduce the liver triglyceride content.
- the research content of this example shows that the combined use of FGF21 Fc fusion protein and GLP-1 Fc fusion protein shows a more active therapeutic effect on non-alcoholic steatohepatitis, and its effect is significantly better than the single treatment group.
- 6-week-old male db/db mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
- the breeding environment is 22-24°C
- the relative humidity is 45-65%
- the lighting time is 12h/day.
- After feeding the D12450B feed to 14 weeks of age about 20 ⁇ l of whole blood was collected from the intraocular canthal venous plexus, and the glycosylated hemoglobin content was detected.
- db/db mice were randomly divided into vehicle control group, FP4I-5mg/kg group (referred to as FP4I group), and dulaglutide-1.5mg/kg group (referred to as dulaglutide group) , FP-B-1.5mg/kg group (abbreviated as FP-B group), FP-A-1.5mg/kg group (abbreviated as FP-A group), FP4I-5mg+duraglutide-1.5mg/kg group (abbreviated as FP4I+duraglutide group), FP4I-5mg/kg+FP-B-1.5mg/kg (referred to as FP4I+FP-B group) and FP4I-5mg+FP-A-1.5mg/kg group (referred to as FP4I+FP -Group A), db/m mice of the same age as the normal control group, 8 mice in each group.
- FP4I group FP4I-5mg/kg group
- dulaglutide group
- the control group and the single-agent treatment group were given the corresponding protein solution or buffer by subcutaneous injection on the back of the neck; the combined drug group was given FP4I by subcutaneous injection on the back of the neck, and duraglutide, FP-A or FP-B were given by subcutaneous injection on the abdomen. It is administered once every 3 days for a total of 12 administrations. After the last dosing cycle, the mice in each group fasted overnight. Whole blood was taken from the intraocular canthal venous plexus to detect the glycosylated hemoglobin content. After the blood was taken, the mice were sacrificed by removing the cervical vertebrae, and the mouse heart tissue was separated and called the whole heart mass.
- db/db is a spontaneous diabetic mouse, and its characteristics are highly similar to clinical symptoms, so it can more accurately reflect the therapeutic effect of hypoglycemic drugs.
- the study of this example shows that the combined medication can restore the blood sugar of db/db mice to normal, which is better than the single treatment group.
- Diabetic cardiomyopathy is one of the main complications of diabetes, and the main pathological feature is cardiac hypertrophy.
- the results are shown in Figure 9.
- the 20-week-old db/db mouse has a significantly higher whole heart mass than normal control mice, showing the characteristics of diabetic cardiomyopathy.
- the administration of FGF21 Fc fusion protein or GLP-1 Fc fusion protein alone had no significant effect on the heart quality of db/db mice. After combined medication, the whole heart mass of db/db mice was significantly reduced. The study in this example shows that the combined medication can prevent and treat the occurrence and development of diabetic cardiomyopathy.
Abstract
Description
Claims (10)
- FGF21 Fc融合蛋白,其氨基酸序列:(1)如SEQ ID NO:4所述;或(2)与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代)、缺失和/或添加的序列)。
- GLP-1 Fc融合蛋白,其氨基酸序列:(1)如SEQ ID NO:5、SEQ ID NO:6或SEQ ID NO:7所示;或(2)与上述序列中的任何基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高度相似的或具有一个或更多个氨基酸取代(例如保守性取代)、缺失和/或添加的序列)。
- 组合治疗剂,其特征在于,所述组合治疗剂由包含权利要求1所述的FGF21 Fc融合蛋白的第一药物组合物和包含权利要求2所述的GLP-1 Fc融合蛋白的第二药物组合物组成。
- 如权利要求3所述的组合治疗剂,其特征在于,所述FGF21 Fc融合蛋白和GLP-1 Fc融合蛋白可以预防有效量或治疗有效量包含于所述第一和第二药物组合物中。
- 如权利要求3所述的组合治疗剂,其特征在于,所述第一药物组合物还包含药学上可接受的载体、和/或赋形剂、和/或稳定剂。
- 如权利要求3所述的组合治疗剂,其特征在于,所述第二药物组合物还包含药学上可接受的载体、和/或赋形剂、和/或稳定剂。
- 如权利要求3-6任一项所述的组合治疗剂,其中,所述第一和第二药物组合物被配制成适于经口服或注射给药的剂型。
- 如权利要求3-6任一项所述的组合治疗剂,其中,所述第一和第二药物组合物被分别配制成适于经口服或注射给药的剂型。
- 权利要求1所述的FGF21 Fc融合蛋白和/或权利要求2所述的GLP-1 Fc融合蛋白在制备用于预防或治疗心血管和/或代谢类疾病的药剂(优选是权利要求3-8任一项所述的组合治疗剂)中的用途。
- 如权利要求9所述的用途,其特征在于,所述心血管和/或代谢类疾病包含但不限于肥胖、高脂血症、动脉粥样硬化、非酒精性脂肪性肝病、糖尿病、糖尿病性心肌病、冠状动脉粥样硬化性心脏病以及其它与胰岛素抵抗相关的疾病。
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JP2022505283A JP7360751B2 (ja) | 2019-07-25 | 2020-07-08 | FGF21 Fc融合タンパク質、GLP-1 Fc融合タンパク質、それらの併用治療剤および使用 |
MX2022000984A MX2022000984A (es) | 2019-07-25 | 2020-07-08 | Proteina de fusion fgf21 fc, proteina de fusion glp-1 fc, y agente terapeutico de combinacion que comprende el mismo y su uso. |
BR112022001295A BR112022001295A2 (pt) | 2019-07-25 | 2020-07-08 | Proteína de fusão fgf21 fc, proteína de fusão glp-1 fc e agente terapêutico de combinação compreendendo as mesmas e uso dos mesmos |
AU2020317780A AU2020317780A1 (en) | 2019-07-25 | 2020-07-08 | FGF21 Fc fusion protein, GLP-1 Fc fusion protein, and combination therapeutic agent comprising same and use thereof |
EP20844267.3A EP4006058A4 (en) | 2019-07-25 | 2020-07-08 | FC FUSION PROTEIN FGF21, FC FUSION PROTEIN GLP-1, COMBINATION THERAPEUTIC AGENT COMPRISING THE SAME AND USE THEREOF |
CA3145475A CA3145475A1 (en) | 2019-07-25 | 2020-07-08 | Fgf21 fc fusion protein, glp-1 fc fusion protein, and combination therapeutic agent comprising same and use thereof |
KR1020227006670A KR20220039790A (ko) | 2019-07-25 | 2020-07-08 | FGF21 Fc 융합 단백질, GLP-1 Fc 융합 단백질 및 이들의 조합 치료제와 용도 |
US17/629,277 US20220242926A1 (en) | 2019-07-25 | 2020-07-08 | Fgf21 fc fusion protein, glp-1 fc fusion protein, and combination therapeutic agent comprising same and use thereof |
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CN201910675288.5A CN112279920B (zh) | 2019-07-25 | 2019-07-25 | FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 |
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EP (1) | EP4006058A4 (zh) |
JP (1) | JP7360751B2 (zh) |
KR (1) | KR20220039790A (zh) |
CN (1) | CN112279920B (zh) |
AU (1) | AU2020317780A1 (zh) |
BR (1) | BR112022001295A2 (zh) |
CA (1) | CA3145475A1 (zh) |
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- 2019-07-25 CN CN201910675288.5A patent/CN112279920B/zh active Active
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2020
- 2020-07-08 EP EP20844267.3A patent/EP4006058A4/en active Pending
- 2020-07-08 WO PCT/CN2020/100774 patent/WO2021012947A1/zh unknown
- 2020-07-08 US US17/629,277 patent/US20220242926A1/en active Pending
- 2020-07-08 MX MX2022000984A patent/MX2022000984A/es unknown
- 2020-07-08 AU AU2020317780A patent/AU2020317780A1/en active Pending
- 2020-07-08 KR KR1020227006670A patent/KR20220039790A/ko unknown
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- 2020-07-08 JP JP2022505283A patent/JP7360751B2/ja active Active
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Publication number | Publication date |
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US20220242926A1 (en) | 2022-08-04 |
BR112022001295A2 (pt) | 2022-03-22 |
CN112279920B (zh) | 2024-01-16 |
AU2020317780A1 (en) | 2022-02-24 |
MX2022000984A (es) | 2022-03-02 |
CN112279920A (zh) | 2021-01-29 |
KR20220039790A (ko) | 2022-03-29 |
JP7360751B2 (ja) | 2023-10-13 |
JP2022542151A (ja) | 2022-09-29 |
EP4006058A1 (en) | 2022-06-01 |
EP4006058A4 (en) | 2023-11-01 |
CA3145475A1 (en) | 2021-01-28 |
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