WO2019164230A1 - Nano-vésicules dérivées de bactéries de l'espèce cupriavidus et utilisation associée - Google Patents

Nano-vésicules dérivées de bactéries de l'espèce cupriavidus et utilisation associée Download PDF

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WO2019164230A1
WO2019164230A1 PCT/KR2019/002015 KR2019002015W WO2019164230A1 WO 2019164230 A1 WO2019164230 A1 WO 2019164230A1 KR 2019002015 W KR2019002015 W KR 2019002015W WO 2019164230 A1 WO2019164230 A1 WO 2019164230A1
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cancer
vesicles
derived
disease
bacteria
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PCT/KR2019/002015
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English (en)
Korean (ko)
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김윤근
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주식회사 엠디헬스케어
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Priority claimed from KR1020190018989A external-priority patent/KR102087105B1/ko
Application filed by 주식회사 엠디헬스케어 filed Critical 주식회사 엠디헬스케어
Priority to JP2019548319A priority Critical patent/JP6959664B2/ja
Priority to CN201980001793.XA priority patent/CN110462066A/zh
Priority to EP19745027.3A priority patent/EP3567125A4/fr
Publication of WO2019164230A1 publication Critical patent/WO2019164230A1/fr
Priority to US16/563,594 priority patent/US20190390284A1/en
Priority to US17/029,711 priority patent/US11771742B2/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6851—Quantitative amplification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria

Definitions

  • the present invention relates to nanovesicles derived from the genus Cupriavidus and its use, and more specifically, cancer, cardiovascular disease, lung disease, metabolic disease, neuro-psychiatric diseases, etc. It relates to a diagnostic method, and compositions for the prevention, improvement or treatment of the disease, including the vesicles.
  • microbiota is a microbial community including microbes, archaea and eukarya that exist in a given settlement.
  • Locally secreted bacteria-derived vesicles are absorbed through epithelial cells or keratinocytes of the mucosa to induce local inflammatory responses, as well as to regulate immune and inflammatory responses in the organs absorbed by the body and distributed to each organ. do.
  • Eshcherichia vesicles derived from pathogenic Gram-negative bacteria such as coli are inhaled through the airways to induce emphysema, which leads to chronic obstructive pulmonary disease (COPD), and when absorbed through the intestine, causes colitis locally, Through vascular endothelial inflammatory response, it promotes systemic inflammatory response and blood coagulation, and is also absorbed into the muscle cells in which insulin acts, causing insulin resistance and diabetes.
  • vesicles derived from beneficial bacteria can control disease by controlling immune function abnormalities caused by pathogenic vesicles.
  • Th17 immune response characterized by the secretion of Interleukin (IL) -17 cytokines, which secrete IL-6 upon exposure to bacterial vesicles, This induces a Th17 immune response.
  • IL Interleukin
  • Th17 immune response Inflammation by the Th17 immune response is characterized by neutrophil infiltration, and tumor necrosis factor-alpha (TNF- ⁇ ) is secreted from inflammatory cells such as macrophages and neutrophils during inflammation. Plays an important role in the occurrence of.
  • TNF- ⁇ tumor necrosis factor-alpha
  • Cupriavidus spp. Is an aerobic Gram-negative bacillus isolated from soil and clinical specimens. Among these, Cupriavidus metallidurans is characterized by resistance to toxic heavy metals, producing energy through phosphorylation through oxygen, and generally not pathogenic.
  • Cupriavidus species such as Cupriavidus necator and Cupriavidus taiwanensis, are known as bacteria that fix nitrogen in legumes.
  • refractory diseases such as cancer, cardiovascular disease, lung disease, metabolic disease and neuropsychiatric disease. It has not been done.
  • the present inventors earnestly researched to solve the above-mentioned conventional problems, and compared to the normal person through metagenomic analysis, stomach cancer, colon cancer, pancreatic cancer, bile duct cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, etc.
  • the contents of bacteria-derived vesicles from Cupri abidus were significantly increased in samples from patients with malignant diseases, cardiomyopathy, atrial fibrillation, heteroangular angina, chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression. It was confirmed that it is reduced.
  • vesicles were isolated from C.
  • the present invention is gastric cancer, colorectal cancer, pancreatic cancer, bile duct cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, dysplastic angina, chronic obstructive pulmonary disease, stroke, diabetes, kidney failure, dementia
  • gastric cancer colorectal cancer
  • pancreatic cancer pancreatic cancer
  • bile duct cancer breast cancer
  • ovarian cancer bladder cancer
  • prostate cancer head and neck cancer
  • lymphoma lymphoma
  • cardiomyopathy atrial fibrillation
  • dysplastic angina CAD
  • chronic obstructive pulmonary disease stroke
  • diabetes diabetes
  • kidney failure dementia
  • the present invention is a gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, heteroangular angina, Another object is to provide a composition for preventing, ameliorating or treating chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression.
  • the present invention includes the following steps, gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrium Provides information on the diagnosis of fibrillation, angina, chronic obstructive pulmonary disease, stroke, diabetes, kidney failure, dementia, Parkinson's disease, or depression:
  • the present invention includes the following steps, gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, dysplastic angina, chronic obstructive pulmonary disease, Provides diagnostic methods for stroke, diabetes, kidney failure, dementia, Parkinson's disease, or depression:
  • the sample in step (a) may be feces, blood, urine, or saliva.
  • the primer pair in step (b) may be a primer of SEQ ID NO: 1 and SEQ ID NO: 2.
  • the present invention includes a vesicle derived from the bacteria of the genus Cupriavidus as an active ingredient, gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, heterogeneity
  • a pharmaceutical composition for preventing or treating angina, chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression.
  • the present invention includes a vesicle derived from the bacteria of the genus Cupriavidus as an active ingredient, gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, heterogeneity
  • a food composition for preventing or ameliorating angina, chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression.
  • the present invention is a gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial chamber containing the cubic vesicles derived from the genus Cupriavidus as an active ingredient
  • an inhalant composition for the prevention or treatment of fibrillation, angina, chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease or depression.
  • the present invention comprises the step of administering to the subject a pharmaceutical composition
  • a pharmaceutical composition comprising the cubic vesicles bacteria-derived vesicles as an active ingredient, gastric cancer, colon cancer, pancreatic cancer, bile duct cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer,
  • the present invention is a vesicle derived from the genus Cupriavidus, stomach cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, dysplastic angina, chronic obstructive pulmonary Provided for the prophylaxis or treatment of a disease, stroke, diabetes, kidney failure, dementia, Parkinson's disease, or depression.
  • the vesicles may have an average diameter of 10 to 200 nm.
  • the vesicles may be secreted naturally or artificially from the bacteria of the genus cupriavidus.
  • the cupria-derived bacteria-derived vesicles may be cupria-derived metallidurance-derived vesicles.
  • the present inventors confirmed that intestinal bacteria are not absorbed into the body, but in the case of bacterial-derived vesicles, they are absorbed into the body through epithelial cells, distributed systemically, and excreted in vitro through the kidneys, liver, and lungs.
  • Stomach cancer, colorectal cancer, pancreatic cancer, bile duct cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation The presence of bacteria-derived vesicles in cupriavidus present in feces, blood, urine or saliva of patients with chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, and depression It was.
  • cuprous avidus metallidurans a species of the bacterium of the cupri avidus, was cultured in vitro to separate the vesicles, and when administered to inflammatory cells in vitro, it significantly inhibited the secretion of inflammatory mediators caused by pathogenic vesicles.
  • the bacterium-derived vesicles of the genus cupriavidus are gastric cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, heteroangular angina, chronic It is expected that the present invention can be usefully used in the diagnosis of obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression, and compositions for preventing, improving or treating such diseases.
  • Figure 1a is a picture of the distribution of bacteria and vesicles by time after oral administration of bacteria and bacteria-derived vesicles (EV) to the mouse
  • Figure 1b is 12 hours after oral administration, blood, kidney
  • the results of evaluating the distribution of bacteria and vesicles in the liver, liver, and various organs were evaluated.
  • Figures 2a to 2c is a result of comparing the distribution of bacteria-derived vesicles of Cupri avidus after the bacteria-derived vesicle metagenome analysis present in gastric cancer patients and normal people, Figure 2a is feces, Figure 2b is blood, Figure 2c is urine The result is a sample.
  • Figure 3a and 3b is a result of comparing the distribution of bacteria-derived vesicles in cupri avidus after analyzing the bacteria-derived vesicle metagenome present in colorectal cancer patients and normal people, Figure 3a is a stool, Figure 3b is a urine sample The result is.
  • Figure 4 is a result of comparing the distribution of bacteria-derived vesicles of the genus Cupri avids after analyzing the bacteria-derived vesicles metagenome present in the pancreatic cancer patients and normal blood.
  • Figure 5 is a result of comparing the distribution of the bacteria-derived vesicles of the genus Cupri avids after analyzing the bacteria-derived vesicles metagenome present in patients with bile duct cancer.
  • Figure 6a and 6b is a result of comparing the distribution of bacteria-derived vesicles of Cupri Avidus after the bacteria-derived vesicle metagenome analysis present in breast cancer patients and normal people, Figure 6a is a blood, Figure 6b is a result of the sample as urine to be.
  • FIG. 7A and 7B show the distribution of bacteria-derived vesicles from cupriavidus after bacterial vesicle metagenome analysis in ovarian cancer patients and normal people.
  • FIG. 7A is blood and
  • FIG. 7B is urine as a sample. The result is.
  • Figures 8a and 8b is a result of comparing the distribution of bacteria-derived vesicles in cupri avids after analyzing the bacteria-derived vesicle metagenome analysis present in bladder cancer patients and normal people, Figure 8a is the blood, Figure 8b is the result of the sample as urine to be.
  • Figure 10 is a result of comparing the distribution of the bacteria-derived vesicles of the genus Cupriavidus after analyzing the bacteria-derived vesicles metagenome present in head and neck cancer patients and normal saliva.
  • 11 is a result of comparing the distribution of the bacteria-derived vesicles of Cupri avidus after analyzing the bacteria-derived vesicles metagenome present in lymphoma patients and normal blood.
  • FIG. 12a to 12c is a result of comparing the distribution of bacteria-derived vesicles derived from cupriavidus after bacterial-derived vesicle metagenome analysis present in patients with heart disease and normal blood,
  • Figure 12a is a cardiomyopathy,
  • Figure 12b is atrial fibrillation,
  • Figure 12c shows the case of heteroangular angina.
  • Fig. 13 shows the results of comparing the distribution of bacterial-derived vesicles of Cupri avidus after analyzing the bacterial-derived vesicles metagenome that are present in stroke patients and normal blood.
  • COPD chronic obstructive pulmonary disease
  • Figure 15a to 15c is a result of comparing the distribution of bacteria-derived vesicles in cupri avidus after analyzing the bacteria-derived vesicle metagenome analysis present in diabetic patients and normal people, Figure 15a is blood, Figure 15b is urine, Figure 15c is saliva The result is a sample.
  • Fig. 16 shows the results of comparison of distribution of bacteria-derived vesicles belonging to Cupriaviders after analysis of bacterial-derived vesicles metagenome present in renal failure patients and normal blood.
  • Fig. 17 shows the results of comparing the distribution of bacterial-derived vesicles of Cupri avidus after the analysis of bacterial-derived vesicles metagenome present in dementia patients and normal blood.
  • Fig. 18 shows the results of comparing the distribution of bacterial-derived vesicles belonging to Cupriaviders after the bacterial-derived vesicle metagenome analysis present in Parkinson's disease patients and normal urine.
  • 20 is a result of evaluating the degree of apoptosis by administering the vesicles to macrophages (Raw264.7) in order to evaluate the apoptosis effect of cupri avidus metallidurans-derived vesicles.
  • Figure 21 is a pre-treatment of the cuprividus bacteria-derived vesicles before the treatment of E. coli EV, a pathogenic vesicle (E. coli EV) in order to evaluate the anti-inflammatory and immunomodulatory effect of the cupri-aviders metallidurans-derived vesicles, Is a result of evaluating the effect on the secretion of IL-6 and TNF- ⁇ .
  • E. coli EV a pathogenic vesicle
  • FIG. 22 is a protocol in which cupriavidose metallidurans-derived vesicles were administered to mice in order to evaluate the anticancer efficacy of cupriavidus metallidurans-derived vesicles.
  • the present invention relates to vesicles derived from the genus Cupriavidus and their use.
  • the present inventors have found that, through metagenome analysis, the vesicle-derived vesicles of Cupri avidus are significantly reduced in clinical samples of patients with cancer, cardiovascular disease, lung disease, metabolic disease, and neuro-psychiatric disease compared to normal people. It was confirmed that can be diagnosed. In addition, the first separation and characterization of the vesicles from C. metallidurans strains, it was confirmed that the strain-derived vesicles can control immune function abnormalities, inflammation and cancer caused by pathogenic vesicles. .
  • the present invention includes the following steps, gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, dysplastic angina, chronic obstructive pulmonary disease, Provides information on how to diagnose stroke, diabetes, kidney failure, dementia, Parkinson's disease, or depression:
  • the term "diagnosis" in the broad sense means to determine the actual condition of the patient's disease in all aspects.
  • the content of the judgment is the name of the disease, the etiology, the type of disease, the seriousness, the detailed mode of the condition, the presence or absence of complications, and the prognosis.
  • the diagnosis is gastric cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, dysplastic angina, chronic obstructive pulmonary disease, stroke, diabetes, kidney failure, dementia , Parkinson's disease, and / or depression, and the level of disease.
  • the sample may be feces, blood, urine, or saliva, but is not limited thereto.
  • the term "metagenome” used in the present invention also referred to as "gunoelectric”, refers to the sum total of the genome including all viruses, bacteria, fungi, etc. in an isolated area such as soil, animal intestine, mainly culture It is used as a concept of genome explaining the identification of many microorganisms at once using sequencer to analyze microorganisms that are not.
  • the metagenome does not refer to one genome or genome, but to a kind of mixed dielectric as the genome of all species of one environmental unit. This is a term from the point of view of defining a species in the course of the evolution of biology in terms of functional species as well as various species that interact with each other to create a complete species.
  • rapid sequencing is used to analyze all DNA and RNA, regardless of species, to identify all species in one environment, and to identify interactions and metabolism.
  • the present invention comprises a stomach-derived bacterium-derived vesicles, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy It provides a composition for the prevention, treatment or amelioration of atrial fibrillation, heteroangular angina, chronic obstructive pulmonary disease, stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression.
  • the composition includes a food composition, an inhalant composition, and a pharmaceutical composition, in which the food composition comprises a nutraceutical composition.
  • the composition of the present invention may also be a formulation of an oral spray, nasal spray or inhalant.
  • prevention means any action that inhibits or retards the disease by administration of a composition according to the present invention.
  • treatment means any action that improves or advantageously changes the condition for the disease by administration of the composition according to the present invention.
  • the term “improvement” means any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
  • the term "nanovesicle” or “vesicle” refers to a structure of nanoscale membranes secreted by various bacteria.
  • Vesicles or outer membrane vesicles (OMVs) derived from gram-negative bacteria have proteins, low molecular weight compounds, and bacterial DNA and RNA as well as lipopolysaccharides, and gram-positive bacteria.
  • the vesicles also contain peptidoglycan and lipoteichoic acid.
  • the nano-vesicles or vesicles are naturally secreted or artificially produced by the bacteria of the cupri avidus, and has an average diameter of 10 to 200 nm.
  • the vesicle is centrifuged, ultra-fast centrifugation, high pressure treatment, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical degradation, chemical treatment, filter
  • the separation can be carried out using one or more methods selected from the group consisting of filtration, gel filtration chromatography, pre-flow electrophoresis, and capillary electrophoresis. In addition, it may further include a process for washing to remove impurities, concentration of the obtained vesicles and the like.
  • the bacteria and bacterial-derived vesicles were orally administered to mice to observe the absorption, distribution, and excretion of the bacteria and vesicles in the body. It was confirmed that it was absorbed within 5 minutes of administration and distributed systemically and excreted through the kidneys, liver, and the like (see Example 1).
  • gastric cancer gastric cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, angina, chronic obstructive pulmonary disease, stroke, diabetes
  • Bacterial metagenomic analysis was performed using vesicles isolated from feces, blood, urine, or saliva of normal persons with age and gender matching to patients with renal failure, dementia, Parkinson's disease, and depression.
  • the cupri avids metalliduran strains were cultured to evaluate whether the vesicles secreted therefrom have anti-cancer therapeutic effects.
  • a cancer model was made by subcutaneously injecting a cancer cell line, and the size of the cancer tissue was measured for 20 days after oral or intraperitoneal administration of the cupriavidus metallidurans-derived vesicles to the mouse 4 days prior to treatment with the cancer cell line.
  • the size of the cancer tissues was reduced compared to the control group, and particularly, when the vesicles were administered orally (see Example 23).
  • the pharmaceutical composition according to the invention may comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are conventionally used in the preparation, and include, but are not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • Suitable pharmaceutically acceptable carriers and formulations can be preferably formulated according to the individual components using methods disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, external preparation for skin, oral ingestion, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, skin, nasal, airways) according to the desired method, and the dosage is determined by the condition and weight of the patient, disease Depending on the degree, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug and the drug. Sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
  • the composition according to the present invention may be administered as a separate therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg daily or every other day, per kg of body weight Or divided into 1 to 3 times a day.
  • the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the inhalant composition of the present invention may be added to the inhalant as it is, or used in combination with other ingredients, and may be suitably used according to conventional methods.
  • the amount of the active ingredient to be mixed may be suitably determined depending on the purpose of use (prophylactic or therapeutic).
  • the food composition of the present invention includes a nutraceutical composition.
  • the food composition according to the present invention may be used as it is, or may be used in combination with other foods or food ingredients, or may be appropriately used according to conventional methods.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the compositions of the invention are added in amounts of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the amount may be below the above range.
  • the food composition of the present invention in addition to containing the active ingredient as an essential ingredient in the indicated ratio, there are no particular restrictions on other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract, for example, rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • these components can be used independently or in combination.
  • the proportion of such additives may also be appropriately selected by those skilled in the art.
  • Example 1 Analysis of absorption, distribution, and excretion of intestinal bacteria and bacterial-derived vesicles
  • the intestinal bacteria and enteric bacteria-derived vesicles are absorbed systemically, 50 ⁇ g of fluorescently labeled bacteria and bacteria-derived vesicles are administered in the same manner as described above to evaluate the infiltration into various organs.
  • 50 ⁇ g of fluorescently labeled bacteria and bacteria-derived vesicles are administered in the same manner as described above to evaluate the infiltration into various organs.
  • blood, heart, lungs, liver, kidneys, spleen, fat and muscle were collected.
  • the bacteria-derived vesicles were distributed in the blood, heart, lung, liver, spleen, fat, muscle, kidney, it can be seen that the bacteria are not absorbed.
  • DNA extracted by the above method was amplified using the above 16S rDNA primers, followed by sequencing (Illumina MiSeq sequencer), and the result was outputted as a Standard Flowgram Format (SFF) file, using GS FLX software (v2.9).
  • SFF Standard Flowgram Format
  • OTU operational taxonomy unit
  • clustering is performed according to sequence similarity using UCLUST and USEARCH, genus 94%, family 90%, order 85%, strong ( class is 80%, phylum is clustered based on 75% sequence similarity, and the phylum, class, order, family, and genus levels of each OTU are clustered. Sorting was performed and bacteria with greater than 97% sequence similarity at the genus level were profiled (QIIME) using BLASTN and GreenGenes' 16S RNA sequence database (108,453 sequences).
  • Example 2 the genes were extracted from the vesicles in the stool and 63 stools of gastric cancer patients and 126 normal controls matched with sex and age. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the Cupri avidus bacteria significantly reduced in the stool of gastric cancer patients compared to the normal stool (see Table 2 and Figure 2a).
  • Example 2 the blood of 67 gastric cancer patients and 198 blood of the normal control group matched with sex and age were extracted from the vesicles present in the blood and subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the blood of gastric cancer patients compared to normal blood (see Table 3 and FIG. 2B).
  • the genes were extracted from the vesicles present in the urine in the urine of 61 gastric cancer patients and 120 urine control groups matched with sex and age, followed by metagenomic analysis.
  • the distribution of vesicles derived from bacteria in Biders was evaluated.
  • the vesicle-derived bacteria of Cupriaviders significantly decreased in the urine of gastric cancer patients compared to normal urine (see Table 4 and FIG. 2C).
  • Example 2 the gene was extracted from the vesicles in the stool and subjected to metagenomic analysis of the feces of 52 colon cancer patients and 83 of the normal control group matched with sex and age, and then cupri-aviders. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of cupriavidus significantly decreased in the stool of colorectal cancer patients compared to the normal stool (see Table 5 and FIG. 3A).
  • Example 2 the urine of 38 patients with colorectal cancer and the urine of 38 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenomic analysis. The distribution of vesicles derived from the genus Priaviders was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders significantly decreased in urine of colorectal cancer patients compared to normal urine (see Table 6 and FIG. 3B).
  • Example 2 the genes were extracted from the vesicles in the blood of 96 breast cancer patients and 192 blood of the normal control group matched with sex and age, and then subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders were significantly reduced in the blood of breast cancer patients compared to normal blood (see Table 9 and FIG. 6A).
  • Example 2 the genes were extracted from the vesicles in the urine of 127 breast cancer patients and 220 urine in the normal control group matched with sex and age. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the urine of breast cancer patients compared to normal urine (see Table 10 and FIG. 6B).
  • Example 2 136 blood of ovarian cancer patients and 136 blood of a normal control group matched with sex and age were extracted from vesicles present in the blood and subjected to metagenomic analysis, followed by cupri avids. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders were significantly reduced in blood of ovarian cancer patients compared to normal blood (see Table 11 and FIG. 7A).
  • Example 2 the genes were extracted from the vesicles in the urine of 136 ovarian cancer patients and 136 urine control groups matched with sex and age, and then subjected to metagenomic analysis. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders significantly decreased in urine of ovarian cancer patients compared to normal urine (see Table 12 and FIG. 7B).
  • Example 2 the urine of 95 patients with bladder cancer and the urine of 157 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenomic analysis. The distribution of vesicles derived from bacteria in Biders was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders significantly decreased in urine of bladder cancer patients compared to normal urine (see Table 14 and FIG. 8B).
  • Example 2 In the method of Example 2, the urine of 53 patients with prostate cancer and the urine of 159 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenomic analysis. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the urine of prostate cancer patients compared to normal urine (see Table 15 and FIG. 9).
  • Example 2 the saliva of 57 head and neck cancer patients and 277 saliva of the normal control group were extracted from the vesicles present in the saliva, and the metagenome analysis was performed. Was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the saliva of head and neck cancer patients compared to normal saliva (see Table 16 and FIG. 10).
  • Example 2 blood was collected from 57 patients with lymphoma and 163 blood of a normal control group matched with sex and age, and a gene was extracted from vesicles present in blood and subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders was significantly reduced in the blood of lymphoma patients compared to normal blood (see Table 17 and FIG. 11).
  • Example 2 the blood of 80 patients with heterozygous angina, and the blood of 80 normal controls matched with sex and age were extracted from vesicles present in the blood, and then subjected to metagenomic analysis. The distribution of vesicles derived from the genus bacteria was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the blood of patients with heterophagy compared to normal blood (see Table 20 and FIG. 12C).
  • Example 2 the genes were extracted from the vesicles in the blood of 115 patients with stroke and 109 normal controls matched with sex and age, and then subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the blood of stroke patients compared to normal blood (see Table 21 and FIG. 13).
  • Example 15 Patients with Chronic Obstructive Pulmonary Disease (COPD) Blood Bacteria-Derived Vesicles Metagenome analysis
  • Example 2 In the method of Example 2, 205 blood of COPD patients and 231 blood of normal control group matched with sex and age were extracted from vesicles present in the blood, and then subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders were significantly reduced in blood of COPD patients compared to normal blood (see Table 22 and FIG. 14).
  • Example 2 the blood of 61 diabetic patients and 122 blood of the normal control group matched with sex and age were extracted from the vesicles present in the blood and subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders were significantly reduced in blood of diabetic patients compared to normal blood (see Table 23 and FIG. 15A).
  • Example 2 In the method of Example 2, the urine of 60 diabetic patients and the urine of 134 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders significantly decreased in urine of diabetic patients compared to normal urine (see Table 24 and FIG. 15B).
  • Example 2 the salivary saline of 37 diabetic patients and salivary salivary control group of 277 age-matched normal control groups were extracted from the vesicles present in the saliva, and then subjected to metagenomic analysis. The distribution of was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders were significantly reduced in the saliva of diabetic patients compared to normal saliva (see Table 25 and FIG. 15C).
  • Example 2 the blood of 32 renal convertors and the blood of the normal control group matched with sex and age were extracted from the vesicles present in the blood and subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in the blood of the renal converter compared to the normal blood (see Table 26 and FIG. 16).
  • Example 2 blood was collected from 67 blood of dementia patients and 70 blood of the normal control group which matched gender and age, and the genes were extracted from the vesicles present in the blood, followed by metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupri avidus significantly decreased in blood of dementia patients compared to normal blood (see Table 27 and FIG. 17).
  • the urine of 39 patients with Parkinson's disease and the urine of 76 normal controls matched with sex and age were extracted by extracting genes from the vesicles present in the urine, followed by metagenomic analysis.
  • the distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders was significantly reduced in the urine of Parkinson's disease patients compared to normal urine (see Table 28 and FIG. 18).
  • Example 2 In the method of Example 2, the urine of 20 depressive patients and the urine of 21 normal controls matched with sex and age were extracted from the vesicles present in the urine, followed by metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicle-derived bacteria of Cupriaviders was significantly reduced in the urine of depressed patients compared to normal urine (see Table 29 and FIG. 19).
  • C. metallidurans strains were cultured and their vesicles were isolated and characterized.
  • the cupriavidus metalliduran strain was incubated in TSB (Tryptic soy broth) medium until absorbance (OD 600 ) was 1.0 to 1.5 in an aerobic chamber at 28 ° C. and then subcultured to Luria Bertani broth (LB) medium. -culture). Then, the culture medium supernatant containing the strain was recovered and centrifuged at 10,000 g, 4 ° C. for 20 minutes, and the strain was removed and filtered through a 0.22 ⁇ m filter.
  • TSB Traptic soy broth
  • LB Luria Bertani broth
  • the filtered supernatant was concentrated to a volume of 50 ml by microfiltration using a MasterFlex pumpsystem (Cole-Parmer, US) with a 100 kDa Pellicon 2 Cassette filter membrane (Merck Millipore, US). The concentrated supernatant was once again filtered through a 0.22 ⁇ m filter. Then, the protein was quantified using BCA (Bicinchoninic acid) assay, and the following experiment was performed on the obtained vesicles.
  • BCA Boroninic acid
  • Example 22 Anti-inflammatory Effects of Cupria Avids Metallidurans-derived Vesicles
  • C. metallidurans EV C. metallidurans EV
  • DMEM Dulbeco's Modified Eagle's Medium
  • the cells were then treated with EZ-CYTOX (Dogen, Korea) for 4 hours, and then absorbance was measured at 450 nm using a SpectraMax M3 microplate reader (Molecular Devies, USA).
  • EZ-CYTOX Dogen, Korea
  • absorbance was measured at 450 nm using a SpectraMax M3 microplate reader (Molecular Devies, USA).
  • cupriavidose metallidurans-derived vesicles of various concentrations 0.1, 1, 10 ⁇ g / ml
  • the capture antibody was diluted in phosphate buffered saline (PBS), and 50 ⁇ l was dispensed into 96 well polystyrene plates according to the working concentration, followed by reaction at 4 ° C. overnight. I was.
  • PBS phosphate buffered saline
  • PBST phosphate buffered saline solution containing 0.05% tween-20
  • RD phosphate buffered saline solution containing 1% BSA
  • Blocking for a time (blocking) and the sample and standard (50 ⁇ l) was dispensed in accordance with the concentration and reacted for 2 hours at room temperature.
  • the detection antibody was diluted in RD and 50 ⁇ l was dispensed according to the working concentration for 2 hours at room temperature, and washed three times with 100 ⁇ l of PBST.
  • Streptavidin-HRP R & D system, USA
  • 50 ⁇ l was dispensed for 20 minutes at room temperature.
  • TMB substrate (SurModics, USA) was dispensed, and when the color development progressed after 5 to 20 minutes, 50 ⁇ l of 1 M sulfuric acid solution was stopped to stop the reaction. Absorbance was measured at 450 nm using a SpectraMax M3 microplate reader (Molecular Devices, USA).
  • Example 23 Anticancer Effect of Cupria Aviders Metallidurans-derived Vesicles
  • the anti-cancer effect of cupria vidders metallidurans-derived vesicles was to be examined.
  • the vesicles derived from Cuprividus metalliduran strain (CMT101) is administered intraperitoneally or orally to 6-week-old C57BL / 6 male mice, the cancer cell line (CT26 cell) on day 4 was injected subcutaneously to make a cancer model.
  • the cancer cell line C57BL / 6 male mice
  • the cancer cell line C57BL / 6 male mice
  • the cancer cell line C57BL / 6 male mice
  • CT26 cell cancer cell line
  • the vesicles derived from cupriavidus metallidurans strain were administered daily by intraperitoneal injection or orally and the size of the cancer tissue was measured until the 24th day.
  • the size of the cancer tissue was reduced in the size of the cancer tissue in mice orally administered mice and the oral administration of the vesicles compared to the physiological saline oral administration group as a control group, in particular, orally When administered, the size was further reduced.
  • the results indicate that the administration of cupriavidus metallidurance-derived vesicles can effectively inhibit the growth of cancer tissues.
  • the vesicle-derived vesicles of the genus Cupriavides are gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, head and neck cancer, lymphoma, cardiomyopathy, atrial fibrillation, dysplastic angina pectoris, chronic obstructive pulmonary disease,
  • As a diagnostic method for stroke, diabetes, renal failure, dementia, Parkinson's disease, or depression it can be used as a composition for preventing, ameliorating or treating the disease, and is expected to be useful in related medical and food industries. do.

Abstract

La présente invention concerne des nano-vésicules dérivées de bactéries de l'espèce Cupriavidus et une utilisation associée. Les présents inventeurs ont découvert expérimentalement des teneurs significativement réduites des vésicules dans des échantillons de patients atteints de maladies malignes, telles que le cancer de l'estomac, le cancer colorectal, le cancer du pancréas, le cholangiocarcinome, le cancer du sein, le cancer de l'ovaire, le cancer de la vessie, le cancer de la prostate, le cancer de la tête et du cou, le lymphome, etc., de maladies cardiaques, telles que la cardiomyopathie, la fibrillation auriculaire, l'angine de Prinzmetal, etc., la broncho-pneumopathie chronique obstructive, l'accident vasculaire cérébral, le diabète sucré, l'insuffisance rénale, la démence, la maladie de Parkinson et la dépression par comparaison à des personnes normales, et les vésicules inhibent significativement la sécrétion de médiateurs inflammatoires induite par des vésicules pathogènes ainsi que la suppression de l'oncogenèse. Les nano-vésicules dérivées de bactéries de l'espèce Cupriavidus selon la présente invention peuvent être utilisées efficacement pour développer une méthode de diagnostic de maladies malignes, telles que le cancer de l'estomac, le cancer colorectal, le cancer du pancréas, le cholangiocarcinome, le cancer du sein, le cancer de l'ovaire, le cancer de la vessie, le cancer de la prostate, le cancer de la tête et du cou, le lymphome, etc., de maladies cardiaques, telles que la cardiomyopathie, la fibrillation auriculaire, l'angine de Prinzmetal, etc., la broncho-pneumopathie chronique obstructive, l'accident vasculaire cérébral, le diabète sucré, l'insuffisance rénale, la démence, la maladie de Parkinson, ou la dépression, et une composition pour la prévention ou le traitement des maladies.
PCT/KR2019/002015 2018-02-21 2019-02-20 Nano-vésicules dérivées de bactéries de l'espèce cupriavidus et utilisation associée WO2019164230A1 (fr)

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JP2019548319A JP6959664B2 (ja) 2018-02-21 2019-02-20 クプリアウィドゥス属細菌由来のナノ小胞及びその使用
CN201980001793.XA CN110462066A (zh) 2018-02-21 2019-02-20 源自贪铜菌属细菌的纳米囊泡及其用途
EP19745027.3A EP3567125A4 (fr) 2018-02-21 2019-02-20 Nano-vésicules dérivées de bactéries de l'espèce cupriavidus et utilisation associée
US16/563,594 US20190390284A1 (en) 2018-02-21 2019-09-06 Nano-vesicles derived from genus cupriavidus bacteria and use thereof
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