WO2023063738A1 - Vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles un anticorps anti-ace2 est fixé, et leur utilisation - Google Patents

Vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles un anticorps anti-ace2 est fixé, et leur utilisation Download PDF

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WO2023063738A1
WO2023063738A1 PCT/KR2022/015482 KR2022015482W WO2023063738A1 WO 2023063738 A1 WO2023063738 A1 WO 2023063738A1 KR 2022015482 W KR2022015482 W KR 2022015482W WO 2023063738 A1 WO2023063738 A1 WO 2023063738A1
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extracellular vesicles
mesenchymal stem
antibody
coronavirus
present
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PCT/KR2022/015482
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English (en)
Korean (ko)
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백문창
예경무
박준국
허종익
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재단법인대구경북과학기술원
경북대학교 산학협력단
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Priority claimed from KR1020220130342A external-priority patent/KR20230054277A/ko
Application filed by 재단법인대구경북과학기술원, 경북대학교 산학협력단 filed Critical 재단법인대구경북과학기술원
Publication of WO2023063738A1 publication Critical patent/WO2023063738A1/fr

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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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues

Definitions

  • the present invention relates to mesenchymal stem cell-derived extracellular vesicles to which anti-ACE2 antibodies are attached and uses thereof.
  • Coronavirus is a virus composed of a single piece of the (+) strand RNA genome of about 27-32 kb, distributed in humans and other mammals. It is known that coronaviruses produce 6 to 8 subgenomic RNAs that have a common mRNA at the 3' end of genome-RNA through replication and transcription processes. In most people, coronavirus infection causes mild symptoms but is highly contagious, with SARS (Severe Respiratory Syndrome, 10% mortality rate) coronavirus and MERS (Middle East Respiratory Syndrome, 37% mortality) coronavirus affecting more than 10,000 people over the past 20 years. has been infected
  • COVID-19 a recently discovered new coronavirus (SARS-CoV-2, severe acute respiratory syndrome coronavirus 2) infection, was discovered in China on December 1, 2019 and first reported on December 12, 2019 as an acute respiratory syndrome. , symptoms include fever, cough, shortness of breath, and atypical pneumonia. Since January 2020, it has spread widely outside of China, and it is developing into a situation of concern, such as a rapid transmission around the Lunar New Year holiday in China, a rapid increase in the number of infected people, and the paralysis of the entire city of Wuhan.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • SARS-CoV2 binds to the angiotensin-converting enzyme 2 (hACE2) protein, which is mainly present in human lung epithelial cells, invades cells and reproduces the virus by replicating its genetic material inside human cells. Finding strategies to prevent the coronavirus from entering human cells is a fundamental way to treat the COVID-19 pandemic.
  • the spike protein S1-RBD (Receptor Binding Domain) present on the surface of the corona virus binds to the hACE2 protein, and the three-dimensional structure of the binding at this time has been revealed by recent studies.
  • An object of the present invention is to provide mesenchymal stem cell-derived extracellular vesicles (EV) expressing an anti-ACE2 antibody or an antigen-binding fragment thereof.
  • EV mesenchymal stem cell-derived extracellular vesicles
  • Another object of the present invention is an antiviral composition for coronavirus containing the extracellular vesicles as an active ingredient, a pharmaceutical composition for preventing or treating coronavirus infection, or for preventing or treating acute respiratory distress syndrome (ARDS) It is to provide a pharmaceutical composition.
  • ARDS acute respiratory distress syndrome
  • the present invention is a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 1; And mesenchymal stem cell-derived extracellular vesicles (EVs) expressing an anti-ACE2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 2 are provided.
  • EVs mesenchymal stem cell-derived extracellular vesicles
  • the present invention provides an antiviral composition for coronavirus comprising the extracellular vesicles as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating coronavirus infection comprising the extracellular vesicles as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating acute respiratory distress syndrome (ARDS) comprising the extracellular vesicles as an active ingredient.
  • ARDS acute respiratory distress syndrome
  • the present invention relates to an anti-ACE2 antibody-derived mesenchymal stem cell-derived extracellular vesicle and its use, and more specifically, to mesenchymal stem cell (MSC) expressing an anti-ACE2 antibody on its surface.
  • MSC mesenchymal stem cell
  • EVs extracellular vesicles
  • mesenchymal stem cell-derived extracellular vesicles attached with the anti-ACE2 antibody of the present invention Since it was confirmed that SARS-CoV2 infection can be prevented by blocking ACE2, it is expected to be useful as an infection blocker in the early stage of coronavirus infection.
  • Figure 1 shows the results of the virus infection blocking test analysis of extracellular vesicles (Extracellular vesicle; EV).
  • FIG 2 shows the results of regeneration analysis (MTS) of cells damaged by LPS.
  • Figure 3 shows the results of regeneration analysis (cell count) of cells damaged by LPS.
  • Figure 4 shows the results of regeneration analysis (Trans-well permeability assay) of cells damaged by LPS.
  • the present invention comprises a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 1; And mesenchymal stem cell-derived extracellular vesicles (EVs) expressing an anti-ACE2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence represented by SEQ ID NO: 2 are provided.
  • EVs mesenchymal stem cell-derived extracellular vesicles
  • the mesenchymal stem cells may express the anti-ACE2 antibody or antigen-binding fragment thereof on the surface through lentivirus infection, but is not limited thereto.
  • the "anti-ACE2 antibody” of the present invention is an antibody (C3 antibody) confirmed to bind to ACE2 in Korean Patent Application No. 10-2021-0130808 previously filed by the present inventors, and the amino acid sequence of the C3 antibody is shown in the table below. Same as 1.
  • extracellular vesicle (EV) refers to nano-sized vesicles derived from cells, and depending on the secretion type and size, exosomes, microvesicles, and ectosomes ), microparticles, membrane vesicles, nanovesicles, and outer membrane vesicles.
  • Extracellular endoplasmic reticulum is a major means of communication between cells, including nucleic acids and proteins, which are the main components of cells.
  • antibody refers to a protein molecule that acts as a receptor that specifically recognizes an antigen, including an immunoglobulin molecule that is immunologically reactive with a specific antigen, and includes, for example, monoclonal antibodies, Clonal antibodies, full-length antibodies and antibody fragments may all be included. Also, the term “antibody” may include bivalent or bispecific molecules (eg, bispecific antibodies), diabodies, triabodies or tetrabodies.
  • the term “heavy chain” refers to a full-length heavy chain and fragments thereof comprising a variable region VH and three constant regions CH1, CH2 and CH3 comprising an amino acid sequence having sufficient variable region sequence to impart specificity to an antigen. can include all.
  • the term “light chain” may include both a full-length light chain and fragments thereof including a variable region VL and a constant region CL, which include an amino acid sequence having sufficient variable region sequence to impart specificity to an antigen. there is.
  • fragment In the present invention, the terms “fragment”, “antibody fragment” and “antigen-binding fragment” are used interchangeably to refer to any fragment of an antibody of the present invention that retains the antigen-binding function of the antibody.
  • exemplary antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv, and the like.
  • the present invention provides an antiviral composition for coronavirus comprising the extracellular vesicles as an active ingredient.
  • the coronavirus may be SARS-CoV2, but is not limited thereto.
  • the present invention provides a pharmaceutical composition for preventing or treating coronavirus infection comprising the extracellular vesicles as an active ingredient.
  • the coronavirus infection may be COVID-19, but is not limited thereto.
  • COVID-19 refers to a novel coronavirus infection, and represents variants of SARS and MERS as RNA viruses. COVID-19 shares about 77.5% sequence identity with SARS and about 50% with MERS. However, in contrast to SARS and MERS, the spike glycoprotein of COVID-19 forms a structure in which one RBD domain protrudes upward, which causes the target receptor ACE2 (angiotensin) and It shows 100 to 1,000 times stronger binding force. This strong binding force makes it easier to penetrate into cells, thereby increasing the infectivity.
  • ACE2 angiotensin
  • the present invention provides a pharmaceutical composition for preventing or treating acute respiratory distress syndrome (ARDS) comprising the extracellular vesicles as an active ingredient.
  • ARDS acute respiratory distress syndrome
  • the ARDS may be due to a coronavirus infection, but is not limited thereto.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier is one commonly used in formulation, including lactose, dextrose, sucrose, sorbitol, mannitol, and starch. , acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, stear including, but not limited to, acid magnesium and mineral oil, and the like.
  • the pharmaceutically acceptable carrier is one commonly used in formulation, including lactose, dextrose, sucrose, sorbitol, mannitol, and starch.
  • acacia gum calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenz
  • composition for preventing or treating cancer metastasis of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
  • composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, etc. can be administered with
  • parenteral administration intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, etc.
  • oral compositions can be formulated to coat the active agent or protect it from degradation in the stomach, and the composition of the present invention can be used in any device through which the active agent can move to target cells. can be administered by
  • a suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, morbid condition, food, administration time, administration route, excretion rate and reaction sensitivity, usually This allows the skilled physician to readily determine and prescribe dosages effective for the desired treatment or prophylaxis.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by those skilled in the art, or Or it can be prepared by incorporating into a multi-dose container.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, suppository, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.
  • Example 1 extracellular endoplasmic reticulum ( Extracellular vesicle; EV) viral infection blocking test analysis
  • a lentivirus was prepared by transferring the Sc-Fv DNA sequence of an antibody (C3 antibody) confirmed to bind to ACE2 in Korean Patent Application No. 10-2021-0130808 previously filed by the present inventors into a lentivirus vector.
  • This lentivius was infected with mesenchymal stem cells (MSC), and as a result, C3 antibody was expressed on its surface.
  • MSC mesenchymal stem cells
  • EVs were extracted from the antibody-expressed mesenchymal stem cells.
  • HEK-293T-hACE2 cells (NR-52511, BEI resources) were treated with various concentrations of EV (0ng/ml, 0.5ng/ml, 5ug/ml). .
  • SARS-Related Coronavirus 2 Wuhan-Hu-1 Spike-Pseudotyped Lentiviral Kit (NR-52948, BEI resources) were infected. Cells were lysed at 48 hpi and Luciferase activity was measured with Bright-GloTM (E2610, Promega, Madison, WI, USA) according to the manufacturer's instructions. Quantification of Luciferase activity was performed using a Perkinelmer EnVision microplate reader. The protocol of the experiment is described in Crawford, KHD, et al.
  • MSC-EVs Cell experiments using MTS were conducted to confirm that the efficacy of MSC-EVs to regenerate cells damaged by LPS due to cell engineering was not impaired.
  • Cells used for the assay were Human Bronchial Epithelial Cell Line (16HBE14o-, Sigma. SSC150), seeded in a 96 well plate, and cultured for 24 h. Thereafter, LPS (Sigma, #L2880) was pretreated with 1 ug/ml for 1 hour, and EVs were treated with 5 ng/ml concentration.
  • FITC-Dextran (Sigma, #53379) was treated and reacted (15 min, RT), and then the basal media of the bottom plate was measured at (em/ex 485 nm/530 nm) wavelengths did As a result, it was confirmed that the group treated with the EV of the present invention restored the cells to a similar degree to the control EV and reduced the permeability of the cell layer (FIG. 4).

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Abstract

La présente invention concerne des vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles un anticorps anti-ACE2 est fixé, et leur utilisation. Plus précisément, il a été identifié, à partir des résultats de l'extraction de vésicules extracellulaires (EV) à partir de cellules souches mésenchymateuses (MSC) dans lesquelles un anticorps anti-ACE2 est exprimé sur la surface de celles-ci et de l'étude de l'efficacité des vésicules extracellulaires contre l'entrée de pseudo-virions, que les vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles l'anticorps anti-ACE2 est fixé selon la présente invention peuvent empêcher l'infection par le SARS-CoV2 par blocage de l'ACE2, et pourraient être utilisées efficacement comme agent pour bloquer une infection COVID-19 à un stade précoce.
PCT/KR2022/015482 2021-10-14 2022-10-13 Vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles un anticorps anti-ace2 est fixé, et leur utilisation WO2023063738A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2021-0136301 2021-10-14
KR20210136301 2021-10-14
KR10-2022-0130342 2022-10-12
KR1020220130342A KR20230054277A (ko) 2021-10-14 2022-10-12 항-ace2 항체가 부착된 중간엽 줄기세포 유래 세포외소포체 및 이의 용도

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112430581A (zh) * 2020-11-09 2021-03-02 苏州大学 一种表达ace2蛋白的外泌体的制备方法及应用
US20210260201A1 (en) * 2020-02-21 2021-08-26 Physis Biotechnologies, Llc Extracellular vesicles for the treatment and prevention of infections and other diseases
WO2021177473A1 (fr) * 2020-03-05 2021-09-10 Mvex Japan, Inc. Compositions de vésicules extracellulaires et leur utilisation dans le traitement d'affections cutanées et dans la modulation immunitaire
WO2021181399A1 (fr) * 2020-03-12 2021-09-16 Exostem Biotec Ltd. Cellules stromales mésenchymateuses et vésicules extracellulaires pour le traitement d'infections virales, d'inflammation et de fibrose tissulaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210260201A1 (en) * 2020-02-21 2021-08-26 Physis Biotechnologies, Llc Extracellular vesicles for the treatment and prevention of infections and other diseases
WO2021177473A1 (fr) * 2020-03-05 2021-09-10 Mvex Japan, Inc. Compositions de vésicules extracellulaires et leur utilisation dans le traitement d'affections cutanées et dans la modulation immunitaire
WO2021181399A1 (fr) * 2020-03-12 2021-09-16 Exostem Biotec Ltd. Cellules stromales mésenchymateuses et vésicules extracellulaires pour le traitement d'infections virales, d'inflammation et de fibrose tissulaire
CN112430581A (zh) * 2020-11-09 2021-03-02 苏州大学 一种表达ace2蛋白的外泌体的制备方法及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG JUNSONG, HUANG FENG, XIA BAIJIN, YUAN YAOCHANG, YU FEI, WANG GUANWEN, CHEN QIANYU, WANG QIAN, LI YUZHUANG, LI RONG, SONG ZHE: "The interferon-stimulated exosomal hACE2 potently inhibits SARS-CoV-2 replication through competitively blocking the virus entry", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 6, no. 1, XP093058752, DOI: 10.1038/s41392-021-00604-5 *

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