WO2023090976A1 - Vésicules de membrane externe et composition de traitement ou de prévention de cancer les comprenant - Google Patents

Vésicules de membrane externe et composition de traitement ou de prévention de cancer les comprenant Download PDF

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WO2023090976A1
WO2023090976A1 PCT/KR2022/018479 KR2022018479W WO2023090976A1 WO 2023090976 A1 WO2023090976 A1 WO 2023090976A1 KR 2022018479 W KR2022018479 W KR 2022018479W WO 2023090976 A1 WO2023090976 A1 WO 2023090976A1
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cancer
genus
extracellular vesicles
bacterial
outer membrane
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PCT/KR2022/018479
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English (en)
Korean (ko)
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이태룡
이창진
송성현
이재욱
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(주)로제타엑소좀
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/02—Separating microorganisms from their culture media
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to bacterial extracellular vesicles having a homogeneous size and composition, and to a composition for treating or preventing cancer comprising the same. Specifically, the present invention provides bacterial extracellular vesicles with higher anticancer activity and properties more suitable for commercial development as pharmaceuticals.
  • Bacterial extracellular vesicles are double-lipid membrane structured nanoparticles naturally secreted by bacteria to communicate with the host or other bacteria.
  • extracellular vesicles secreted by Gram-negative bacteria are also called OMVs (outer membrane vesicles), and are known to have an average diameter of about 20 nm to 200 nm [JH Kim, et al., "Gram-negative and Gram-positive bacterial extracellular vesicles", Semin. Cell. Dev. Biol. 40, 97-104, (2015)].
  • various bacterial extracellular vesicles not only have direct therapeutic efficacy for various diseases including cancer, but can also be used as drug delivery systems for treating these diseases. And it is being used or developed clinically as a vaccine delivery system to prevent or treat various diseases such as meningitis.
  • Bacterial extracellular vesicles contain various immune-inducing substances that can activate the host immune system when injected into an animal host having an immune system, including humans.
  • the extracellular endoplasmic reticulum which is a double lipid membrane structure, has various components such as proteins, lipids, and nucleic acids in the double lipid membrane and lumen. It was presumed to trigger an anti-cancer effect, and this was first revealed in a previous study by the present research team.
  • bacterial extracellular vesicles are specifically accumulated in cancer tissues with enhanced permeability and retention effect (EPR effect) due to their nano-sized characteristics, and anticancer cytokines from natural killer cells and T lymphocytes. It induces a strong anticancer immune response through a mechanism of action that promotes the secretion of IFN- ⁇ (Ibid.).
  • EPR effect enhanced permeability and retention effect
  • the particle size of Escherichia coli extracellular vesicles measured by DLS (dynamic light scattering) corresponds to about 20-200 nm, and the mixture nature of particles having various sizes within this range is mixed.
  • Bacterial extracellular vesicles vary greatly in composition as well as in size, and this diversity is particularly prominent in extracellular vesicles derived from Gram-negative bacteria composed of outer and inner membranes.
  • the extracellular vesicles naturally secreted by Gram-negative bacteria contain a mixture of inner membrane-derived extracellular vesicles and nucleic acid particles in addition to the cell outer membrane-derived extracellular vesicles.
  • the cell membrane-derived extracellular vesicles have lipopolysaccharides (LPS) in the outer cell membrane on the membrane surface, and contain the cell membrane proteins and periplasm proteins.
  • LPS lipopolysaccharides
  • intracellular membrane-derived extracellular vesicles contain intracellular membranes, intracellular proteins, and cytoplasmic proteins.
  • the outer and inner membrane-derived extracellular vesicles are secreted out of the cells and mixed in the culture medium. It is very difficult to separate and purify the outer membrane-derived extracellular vesicles from the inner membrane-derived extracellular vesicles, so the purified Gram-negative bacteria used in previous studies
  • the extracellular cell body included extracellular vesicles derived from the outer and inner membranes of the cell.
  • extracellular vesicles have various sizes as well as components, even if they are derived from a single cell. Therefore, it has been accepted as a natural phenomenon that extracellular vesicles purified by conventional separation or purification methods of naturally secreted extracellular vesicles have various components and size distributions.
  • the present inventors confirmed that they are clearly distinguished from each other in terms of spectroscopic characteristics and constituent proteins as well as size through identification work on each of P1 and P2.
  • P1 is relatively large in size and heterogeneous, and has spectroscopic characteristics with an absorbance value at 280 nm smaller than that at 260 nm (A 280 /A 260 ⁇ 1), and is derived from endomembrane-derived proteins and cytoplasm. Contains a lot of protein.
  • P2 was shown to have a relatively small and homogeneous size, spectroscopic characteristics with an absorbance value at 280 nm greater than that at 260 nm (A 280 /A 260 >1), and a large amount of cell membrane-derived proteins. included.
  • the average particle size of P2 is in the range of about 20-30 nm, and the polydispersity index is about 0.35 or less, or about 0.3 or less, or about 0.25 or less. It has very homogeneous properties.
  • P2 is 90% or more, preferably 95% or more, more preferably 97% or more of the total particles of extracellular vesicles in the above range.
  • Their zeta potential value is about -14 ( ⁇ 3) mV, and they are negatively charged.
  • the bacterial extracellular vesicles according to the present invention are superior in the treatment or prevention of cancer compared to extracellular vesicles naturally secreted and purified from bacteria and having heterogeneous characteristics.
  • the bacterial extracellular vesicles according to the present invention have relatively homogeneous physicochemical properties, so quality control (QC) is easy in terms of drug development, which is more advantageous for the development of anticancer drugs based on bacterial extracellular vesicles.
  • FIG. 1 is an absorption chromatogram according to elution time obtained by fractionating extracellular vesicles purified by a conventional method using size-exclusion chromatography (SEC, size-exclusion chromatography) (FIG. 1a) and the SEC elution time (retention time) It is the transmission electron microscope observation result of each fraction (FIG. 1b).
  • Figure 2 is a result of separating the extracellular vesicles purified by a conventional method into P1 and P2 through centrifugation, and performing proteomics analysis for each.
  • the content of proteins identified in P1 and P2 (Fig. 2a), the top 5% proteins in the content ranking (Fig. 2b), the number of proteins according to subcellular localizations (Fig. 2c) and the content (Fig. 2d) is the result showing
  • Figure 3 is an animal experiment method and design for comparing the anticancer activity of P1 and P2 according to the dose.
  • Figure 4 shows the results of animal experiments comparing the anticancer activity of P1 (a) and P2 (b) according to the dose.
  • the term "about” means to include a commonly accepted error range (standard deviation) depending on a device, instrument, or method used to measure or determine a numerical value defined by the term.
  • the size of extracellular vesicles measured by dynamic light scattering (DLS) may have an error range of ⁇ 5 nm.
  • size means “average diameter” unless otherwise indicated.
  • the terms “separation” or “purification” are used interchangeably without any significant difference in meaning.
  • the term is not limited to the act of fractionating only the desired component excluding other components, but may mean any action for selectively enriching the content of the desired component.
  • extracellular vesicles purified by a conventional method or “extracellular vesicles purified using a conventional separation or purification method” refers to components other than extracellular vesicles obtained from bacterial cell culture prior to the present invention. It refers to extracellular vesicles obtained after a series of processes to remove various biologically active substances derived from bacteria, such as phosphoproteins, lipids, genetic materials (DNA, RNA), and virulence factors. Therefore, it should be understood that the extracellular endoplasmic reticulum has not been subjected to a special separation, purification or concentration process for P1 or P2 discovered in the present invention.
  • P2 or "extracellular vesicles that are relatively small and homogeneous in size” has an average particle size in the range of about 20-30 nm and is less than or equal to about 0.35, or less than or equal to about 0.3, as identified herein. , or polydispersity of about 0.25 or less, meaning extracellular vesicles with highly homogeneous properties.
  • the present invention has revealed that extracellular vesicles (P2) having a very homogeneous size distribution exist among the population of naturally secreted extracellular vesicles or extracellular vesicles purified therefrom by conventional methods.
  • the present invention provides extracellular vesicles having a relatively small size and a high content of homogeneous extracellular vesicles (P2) compared to naturally secreted extracellular vesicles.
  • the content of P2 in the extracellular vesicles according to the present invention is 90% or more, preferably 95% or more, more preferably 97% or more of the total particles.
  • the extracellular vesicles (P2) according to the present invention are cultured with bacteria, removed by centrifugation, and then used in addition to chromatographic methods such as size exclusion chromatography and ion exchange chromatography. It can be separated by various methods known in the art, such as centrifugation, filtration, dialysis, ultrafiltration, immunoaffinity separation, microfluidic separation, aqueous two-phase system, and polymer-based precipitation. Specific conditions and experimental protocols according to each method for selectively purifying the extracellular vesicles (P2) according to the present invention are appropriately selected by those skilled in the art who understand the composition and characteristics of the extracellular vesicles disclosed in the present invention can be used
  • the bacteria include, but are not limited to, Gram-negative bacteria.
  • the gram-negative bacteria are Escherichia genus, Helicobacter genus, Hemophilus genus, Neisseria genus, Cyanobacterium genus, Klebsiella genus, Aceto Genus Acetobacter , Genus Acinetobacter , Genus Enterobacter , Genus Chlamydia , Genus Vibrio , Genus Pseudomonas , Genus Salmonella , Genus Thiobacter Genus , Borrelia , Burkholderia , Serratia, Treponema , Rikenella , Alistipes , Marinillabili Sub ( Marinilabilia ), Proteus ( Proteus ), Enhydrobacter ( Enhydrobacter ) genus, Methylobacterium ( Methylobacterium ) genus, Morganella ( Morganella ) genus, Cupriavidus ( Cupriavidus ) genus, Yersinia ( Yersin
  • centrifugation In the centrifugation method mainly used in the step of treating a substance inducing precipitation of extracellular vesicles and recovering the precipitated extracellular vesicles, centrifugation must be performed for a longer period of time than is sufficient to separate normal extracellular vesicles.
  • P2 can be easily isolated or purified from the naturally secreted extracellular vesicle population or extracellular vesicles purified therefrom by conventional methods.
  • the extracellular vesicles (P2) according to the present invention are subjected to centrifugation for a longer period of time than sufficient to separate normal extracellular vesicles, or in the size-specific fractionation method through size exclusion chromatography, the P2 particles disclosed herein It can be separated with reference to size and elution time, or purified through a filter method and ultrafiltration method having a pore size of 0.1 ⁇ m to 0.05 ⁇ m.
  • differential centrifugation is used to first remove large particles at a low centrifugation speed, and then the supernatant can be separated by centrifugation at high speed for a long time.
  • the extracellular vesicles (P2) according to the present invention have a size range of about 20-30 nm, which is smaller than the size range of about 20-200 nm of the extracellular vesicles separated by conventional methods and is homogeneous.
  • P2 has a relatively large number of outer membrane-derived factors that have been shown to have anticancer effects through stimulation of the immune system, and is small in size, so it is internal (luminal) compared to large extracellular vesicles. ) is expected to be because it is unlikely to contain various substances that do not specifically contribute to immune activation.
  • the present invention provides a pharmaceutical composition comprising the extracellular vesicles (P2) according to the present invention as an active ingredient.
  • the pharmaceutical composition according to the present invention can be used for the treatment and prevention of cancer.
  • the cancer is liver cancer, thyroid cancer, testicular cancer, bone cancer, glioblastoma, oral cancer, ovarian cancer, brain tumor, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, head and neck cancer, lymphoma, bladder cancer, leukemia, esophageal cancer, kidney cancer, and stomach cancer.
  • breast cancer, cervical cancer, prostate cancer, rectal cancer, spinal cord tumor, pancreatic cancer, salivary gland cancer, lung cancer, skin cancer, laryngeal cancer, melanoma, etc. but may be selected from the group, but is not limited thereto.
  • the administration route of the pharmaceutical composition according to the present invention may be administered through any general route as long as it can reach the target tissue.
  • Parenteral administration for example, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, or intradermal administration may be administered, but is not limited thereto.
  • the pharmaceutical composition according to the present invention may be formulated in a suitable form together with a pharmaceutically acceptable carrier commonly used for anticancer treatment.
  • a pharmaceutically acceptable carrier commonly used for anticancer treatment.
  • Pharmaceutically acceptable carriers include, for example, parenteral administration carriers such as sterile water, physiological saline, suitable oil, aqueous glucose and glycol, and the like, and may further contain a stabilizer and a preservative.
  • Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, sucrose, albumin, and the like.
  • Suitable preservatives include dimethylsulfoxide (DMSO), glycerol, ethylene glycol, sucrose, trehalose, dextrose, polyvinylpyrrolidone, etc. there is
  • a cancer prevention or treatment method comprising the step of administering to a subject the cell therapy composition for anticancer comprising the extracellular vesicles according to the present invention.
  • the subject means a mammal, preferably a human.
  • a culture solution from which cells were removed was prepared by centrifugation at 6,000 ⁇ g for 20 minutes. After filtering the culture solution with a 0.2 ⁇ m pore-sized filter, a 10-fold concentrated culture solution was produced through tangential flow filtration (TFF) using a 100 kDa molecular weight cut-off (MWCO) membrane filter.
  • FFF tangential flow filtration
  • MWCO molecular weight cut-off
  • a buffer solution pH 7.2
  • 25 mM CaCl 2 25 mM CaCl 2 was added to the concentrated culture medium, and the reaction was refrigerated and shaken for 1 hour to precipitate the extracellular vesicles selectively. After recovering the precipitate by centrifugation, it was dissolved in a buffer solution, and 1 mM MgSO 4 and Benzonase (2.5 U/mL) were added, followed by shaking at room temperature for 1 hour to remove nucleic acid impurities.
  • the sample was placed in a 100 kDa MWCO dialysis membrane, and the dialysis solution was changed 5 times for a total of 18 hours at 4° C. to purify the bacterial extracellular vesicles.
  • the extracellular vesicles purified by the method in 1 above were injected into a column (10 x 200 mm) filled with S500, developed with HEPES buffer at a flow rate of 1.0 mL/min, and the absorbance at 260 nm, 280 nm, and 450 nm was measured. measured.
  • Specific SEC fractionation conditions are as follows:
  • the extracellular vesicles purified by the method of Example 1-1 were centrifuged at 13,000 ⁇ g for 40 minutes. After centrifugation, the pellet was referred to as P1 and the supernatant as P2. After extracting proteins from P1 and P2, they were digested into peptides by treatment with trypsin, and proteomics analysis was performed by LC-ESI-MS/MS (Fig. 2 and Table 1).
  • Figure 2b shows the protein types belonging to the top 5% of the content ranking among the proteins of P1 and P2.
  • both the number and content of cytoplasmic proteins were higher than those of P2.
  • both the number and content of outer membrane proteins were higher than those of P1, and the number of periplasmic proteins was higher than that of P1 (FIGS. 2c and 2d).
  • P2 can be said to be closer to the extracellular vesicles of Gram-negative bacteria.
  • the fraction (P1 - pellet, large extracellular vesicles; P2 - supernatants, small extracellular vesicles) were compared according to the dose.
  • the animal experiment method and design were performed as shown in FIG. 3 .
  • the mouse colorectal cancer cell line CT26 (1 ⁇ 10 6 cells/head) was injected into the right dorsal side of BALB/c female mice, and after 1 week, cancer tissues were identified and the experimental groups were divided. A buffer solution was injected into the control group, and 2, 5, or 10 ⁇ g/head of P1 and P2 were injected into the cancer tissues at 8, 11, 14, and 17 days after colon cancer cell line injection, depending on the experimental group. Direct injection (intratumoral administration) was performed. In addition, the size of cancer tissue was measured up to 22 days after colon cancer cell line injection.
  • extracellular vesicles of Gram-negative bacteria separated by a conventional method could be further purified to obtain extracellular vesicles that were relatively small and homogeneous in size and had improved anticancer efficacy.

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Abstract

La présente invention concerne des vésicules de membrane externe bactérienne qui sont homogènes en taille et en composants, et une composition de traitement ou de prévention de cancer les comprenant. Plus particulièrement, la présente invention concerne des vésicules de membrane externe bactérienne ayant une activité anticancéreuse plus élevée et des propriétés plus appropriées pour le développement commercial en tant que produits pharmaceutiques.
PCT/KR2022/018479 2021-11-22 2022-11-22 Vésicules de membrane externe et composition de traitement ou de prévention de cancer les comprenant WO2023090976A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190003359A (ko) * 2017-06-30 2019-01-09 주식회사 엠디헬스케어 프로테우스 속 세균 유래 나노소포 및 이의 용도
KR20190086351A (ko) * 2018-01-12 2019-07-22 주식회사 엠디헬스케어 모르가넬라 속 세균 유래 나노소포 및 이의 용도
KR20190110942A (ko) * 2018-03-21 2019-10-01 ㈜로제타엑소좀 독성이 약화된 박테리아 세포밖 소포체 및 이의 용도

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KR20190003359A (ko) * 2017-06-30 2019-01-09 주식회사 엠디헬스케어 프로테우스 속 세균 유래 나노소포 및 이의 용도
KR20190086351A (ko) * 2018-01-12 2019-07-22 주식회사 엠디헬스케어 모르가넬라 속 세균 유래 나노소포 및 이의 용도
KR20190110942A (ko) * 2018-03-21 2019-10-01 ㈜로제타엑소좀 독성이 약화된 박테리아 세포밖 소포체 및 이의 용도

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MEHANNY MINA, KOCH MARCUS, LEHR CLAUS-MICHAEL, FUHRMANN GREGOR: "Streptococcal Extracellular Membrane Vesicles Are Rapidly Internalized by Immune Cells and Alter Their Cytokine Release", FRONTIERS IN IMMUNOLOGY, vol. 11, 1 January 2020 (2020-01-01), pages 80, XP055856175, DOI: 10.3389/fimmu.2020.00080 *

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