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WO2020180065A1 - Procédé de préparation de cellule tueuse naturelle dans un monocyte de sang de cordon ombilical - Google Patents

Procédé de préparation de cellule tueuse naturelle dans un monocyte de sang de cordon ombilical Download PDF

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WO2020180065A1
WO2020180065A1 PCT/KR2020/002943 KR2020002943W WO2020180065A1 WO 2020180065 A1 WO2020180065 A1 WO 2020180065A1 KR 2020002943 W KR2020002943 W KR 2020002943W WO 2020180065 A1 WO2020180065 A1 WO 2020180065A1
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cells
natural killer
differentiation
cluster
positive
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Korean (ko)
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안용운
나득채
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Oncoinsight Co Ltd
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    • 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
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0646—Natural killers cells [NK], NKT cells
    • 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
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/125—Stem cell factor [SCF], c-kit ligand [KL]
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]
    • C12N2501/2303—Interleukin-3 (IL-3)
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]
    • C12N2501/2315—Interleukin-15 (IL-15)
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/26—Flt-3 ligand (CD135L, flk-2 ligand)
    • 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
    • C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/02—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from embryonic cells
    • C12N2506/025—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from embryonic cells from extra-embryonic cells, e.g. trophoblast, placenta

Definitions

  • the present invention relates to a method for producing natural killer cells, and more particularly, to a method for producing natural killer cells with increased surface antigen expression in the body using CD117-positive cells isolated from cord blood.
  • NK cells natural killer cells
  • T cells with similar functions can attack cancer cells only by recognizing both the major histocompatibility complex (MHC) and tumor antigens expressed in the target cells. It is not easy to prepare T cells having various antigen specificities targeting various carcinomas because they are different depending on the type.
  • MHC major histocompatibility complex
  • T cells when the T cell receptor is different from the main histocompatibility complex of a cancer patient, it has a limitation that T cells must be produced from the patient's own blood because it can attack normal cells. Therefore, natural killer cells that can selectively attack only cancer cells, even if they are not cells derived from the patient themselves, are cell therapeutics that can be effectively used for various diseases.
  • natural killer cells with increased expression of surface antigens such as natural killer cells in peripheral blood from umbilical cord blood
  • natural killer cells with increased therapeutic efficiency can be easily manufactured in large quantities and thus cells of various diseases. It is expected to be widely used as a therapeutic agent.
  • the present invention was devised to solve the problems of the prior art as described above, a method of producing a natural killer cell with increased expression of a surface antigen using CD117-positive cells contained in umbilical cord blood, prepared by the above method It is intended to provide a natural killer cell, the use of the natural killer cell, and the like.
  • the present invention provides a method for separating cells for differentiation of natural killer cells, including the step of separating cells positive for CD117 (Cluster of Differentiation 117; SCF receptor (stem cell factor receptor); c-kit) from umbilical cord blood.
  • CD117 Cluster of Differentiation 117; SCF receptor (stem cell factor receptor); c-kit
  • the present invention provides a method for producing natural killer cells using the isolated cells for differentiation of natural killer cells.
  • the manufacturing method is preferably (a) separating CD117 (Cluster of Differentiation 117) positive cells from umbilical cord blood; And (b) treating the isolated cells with cytokines to differentiate into natural killer cells, but is not limited thereto, as long as it is generally differentiated into natural killer cells.
  • the present invention provides a natural killer cell prepared by the above method.
  • the present invention provides a cell therapy comprising natural killer cells prepared by the above method.
  • the CD117-positive cells may preferably be CD34 (Cluster of Differentiation 34) negative cells, may be CD56 (Cluster of Differentiation 56) positive cells, or CD34 negative and CD56 positive cells
  • the cells may be, preferably, hematopoietic stem cells, natural killer cell progenitor cells, undifferentiated natural killer cells, and the like, more preferably CD34 positive, CD56 negative, and CD117 positive hematopoietic stem cells.
  • Hematopoietic progenitor cells CD34 negative, CD56 positive, and CD117 positive immature natural killer cells; It may be a CD34-negative, CD56-negative, and CD117-positive natural killer cell progenitor cell, but is not limited thereto as long as it is a CD117-positive cell isolated from cord blood.
  • the natural killer cell is characterized in that the surface antigen (receptor) is increased to increase the activity of the cell, preferably CD2 (Cluster of Differentiation 2), CD16 (Cluster of Differentiation 16). ), and KIR (Killer Cell Immunoglobulin-like Receptors), but may have one or more surface antigens selected from the group consisting of, but not limited thereto, if it is a surface antigen related to the activity of natural killer cells.
  • CD2 Cluster of Differentiation 2
  • CD16 Cluster of Differentiation 16
  • KIR iller Cell Immunoglobulin-like Receptors
  • the cytokine is IL-3 (Interleukin-3), IL-15 (Interleukin-15), SCF (Stem Cell Factor), FLT3L (Fms-related tyrosine kinase 3 ligand), etc.
  • the cytokine treatment is (a) IL-3 (Interleukin-3), IL-15 (Interleukin-15), SCF (Stem Cell Factor), and FLT3L (Fms-related tyrosine kinase 3 ligand) treatment.
  • Step to do (b) treating FLT3L and IL-15; And (c) treating IL-15, wherein IL-3 is treated at a concentration of 2 to 8 ng/mL, and IL-15 is treated at a concentration of 5 to 15 ng/mL, and , The SCF is treated at a concentration of 10 to 30 ng/mL, and the FLT3L can be treated at a concentration of 5 to 15 ng/mL.
  • the manufacturing method can be cultured with feeder cells, and the culture auxiliary cells are generally treated with mitomycin C or X-ray ) Cells that inhibit division and proliferation through irradiation, and produce various metabolites to help the proliferation of target cells.
  • the kind of the culture aid cell is not limited as long as it is a cell that is generally used, and is preferably a cell that overexpresses human delta-like 4 protein (Delta-Like 4; DDL-4).
  • the present invention provides a method for preventing recurrence of cancer, or preventing or treating cancer, comprising the step of administering to an individual the natural killer cells prepared by the above method.
  • the present invention provides a use for preventing recurrence of cancer of natural killer cells prepared by the above method, or for preventing or treating cancer.
  • the cancer may be leukemia, breast cancer, ovarian cancer, brain cancer, melanoma cancer, gastric cancer, liver cancer, colon cancer, lung cancer, etc., but limited to cancer that can be treated using natural killer cells. It doesn't work.
  • the CD117 marker according to the present invention When the CD117 marker according to the present invention is used, cells isolated from umbilical cord blood can be used to increase the differentiation efficiency and differentiation speed into natural killer cells, and differentiated natural killer cells can attack cancer cells. And the expression of surface antigens (receptors) such as CD16 is remarkably high. Therefore, the natural killer cells of the present invention can be produced not only to increase the productivity of natural killer cells, but also to produce natural killer cells with improved therapeutic effects in various diseases by the method for producing natural killer cells provided in the present invention. It is expected that it can be widely applied to the treatment of various diseases such as cancer.
  • FIG. 1 is a schematic diagram schematically showing a method of separating CD117 positive cells from umbilical cord blood.
  • FIG. 2 is a view showing a result of confirming the composition of CD117-positive cells isolated from umbilical cord blood according to an embodiment of the present invention using a flow cytometer.
  • FIG. 3 is a schematic diagram schematically showing a method of differentiating CD117-positive cells into natural killer cells according to an embodiment of the present invention.
  • FIG. 4 is a result of confirming the phenotype of CD117-positive cells-derived natural killer cells according to an embodiment of the present invention by flow cytometry, (a) is a result of confirming the phenotype of natural killer cells when cultured together with a culture auxiliary cell , (b) is a diagram showing the result of confirming the phenotype of natural killer cells when cultured alone or together with culture aid cells.
  • FIG. 5 is a view showing the result of differentiating CD34-negative, CD56-positive, and CD117-positive cells into natural killer cells according to an embodiment of the present invention, and confirming the degree of differentiation into KIR-positive natural killer cells.
  • CD117-positive cells are isolated from umbilical cord blood using CD117 as a marker, and the CD117-positive cells are used to differentiate into natural killer cells in the presence of human DLL4 overexpressing culture aid cells.
  • the natural killer cells prepared by the method of the present invention had remarkably high expression of surface antigens (receptors) such as KIR, CD2, and CD16 that can attack cancer cells. Therefore, it can be confirmed that the natural killer cells prepared using the markers of the present invention can significantly increase the treatment efficiency of diseases such as cancer compared to the natural killer cells prepared using cells isolated from the existing cord blood. Therefore, it is expected to be effectively used in the treatment of various cancers.
  • natural killer cells refers to a broad concept that collectively refers to cytotoxic large granular lymphocytes (CLGL). These natural killer cells mature in the liver or bone marrow and attack and destroy cancer cells and virus-infected cells in the body.
  • cancer treatment that is, hematopoietic It can be used in combination as an immunotherapy during hair cell transplantation, surgery, or chemotherapy, or it can be used for the purpose of preventing recurrence of cancer after treatment.
  • co-administration of monoclonal antibodies such as Rituximab and cytokines such as IL-2 and IL-15 is also under clinical trials and can be applied for various purposes in the treatment of cancer.
  • cell therapy refers to a drug (US FDA regulation) used for treatment, diagnosis, and prevention of cells and tissues manufactured through isolation, culture, and special manipulation from humans. It refers to a drug used for treatment, diagnosis, and prevention through a series of actions such as proliferating or selecting allogeneic or xenogeneic cells in vitro to restore tissue function, or changing the biological properties of cells in other ways. .
  • Cell therapy is largely classified into somatic cell therapy and stem cell therapy according to the degree of differentiation of cells, and the present invention specifically refers to a therapy including natural killer cells differentiated from cells isolated from umbilical cord blood.
  • the cell therapeutic agent of the present invention may contain one or more active ingredients exhibiting the same or similar functions in addition to natural killer cells.
  • compositions may be prepared by including one or more additional pharmaceutically acceptable carriers for administration.
  • Pharmaceutically acceptable carriers can be used as binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc. for oral administration, and buffering agents, preservatives, painlessness, etc. for injections.
  • Agents, solubilizers, isotonic agents, stabilizers, and the like can be mixed and used, and in the case of topical administration, a base agent, excipient, lubricant, preservative, etc. can be used.
  • the formulation of the cell therapeutic agent of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration it can be prepared in the form of tablets, troches, capsules, elixir, suspension, syrup, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms.
  • Others, solutions, suspensions, tablets, capsules, can be formulated as sustained-release preparations.
  • the route of administration of the cell therapy according to the present invention is not limited to these, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Includes sublingual or rectal.
  • the cell therapy products of the present invention vary according to a number of factors, including the activity of the cell therapy used, age, weight, general health, sex, formulation, time of administration, route of administration, excretion rate, drug formulation and the severity of the specific disease to be prevented or treated. And can be appropriately selected by a person skilled in the art. For example, it may be administered at a dose of 1 ⁇ 10 6 to 1 ⁇ 10 9 cells/kg, preferably 1 ⁇ 10 7 to 1 ⁇ 10 9 cells/kg. The administration may be administered once or several times a day. In addition, when formulated as a liquid unit formulation such as a solution, suspension, or emulsion, it may be administered to a patient at the cell concentration.
  • a liquid unit formulation such as a solution, suspension, or emulsion
  • prevention refers to any action that suppresses or delays onset of diseases such as cancer by administration of natural killer cells according to the present invention.
  • treatment refers to any action in which symptoms such as cancer are improved or beneficially changed by the administration of natural killer cells according to the present invention.
  • “individual” refers to a subject to which the natural killer cells of the present invention can be administered, and the subject is not limited.
  • Example 1 Isolation of CD117 positive cells from cord blood
  • CD117-positive cells CD117+ cells
  • PBS phosphate buffered saline
  • CD117-positive cells present in cord blood were 73% of CD34-positive hematopoietic stem cells (HSC), 9.4% of CD56-positive natural killer cells (NK cells), and NKG2A positive cells. It was confirmed that it was composed of NK progenitor cells, CD161 positive NK progenitor cells, etc., and it was confirmed that markers of T cells (CD3+), B cells (CD19+), and monocytes (CD14+) were not expressed in these cells.
  • CD117-positive cells were inoculated in DMEM:HAM'S F12 (2:1) medium to which 10% human serum was added. , 5 ng/mL of interleukin-3 (IL-3), 10 ng/mL of Fms-related tyrosine kinase 3 ligand (FLT3L), 20 ng/mL of stem A stem cell factor (SCF) and 10 ng/mL of interleukin-15 (IL-15) were added and incubated for 5 days.
  • IL-3 interleukin-3
  • FLT3L Fms-related tyrosine kinase 3 ligand
  • SCF stem A stem cell factor
  • IL-15 interleukin-15
  • the floating cells were collected and centrifuged at 800 rpm, and then the precipitated cells were replaced with a new medium to which 10 ng/mL of FLT3L and 10 ng/mL of IL-15 were added. After incubation for one day, the medium was replaced with a new medium to which 10 ng/mL of IL-15 was added, and further cultured for 6 days.
  • As feeder cells EL08.1D2 cells, a murine embryonic liver stromal cell line, or EL08.1D2 (human delta-like 4; hDDL4) overexpressing the human delta-like 4 protein (hDDL4) are overexpressed. EL-DLL4) cells were used. The overall differentiation method is briefly shown in FIG. 3.
  • CD16-positive natural killer cells showed 6% differentiation and maturity of KIR-positive natural killer cells.
  • CD117-positive cells it was confirmed that the differentiation and maturity of CD16-positive natural killer cells increased to 22% and KIR-positive natural killer cells 20%.
  • EL-DDL4 cells 60% of CD16-positive natural killer cells and 51% of KIR-positive natural killer cells were found to significantly increase differentiation and maturity.
  • CD2-positive natural killer cells when differentiated from CD34-positive cells, it was only 1.7%, but when differentiated from CD117-positive cells, the differentiation and maturity increased by more than 17 times to 29.5%.
  • the degree of differentiation into natural killer cells is about 30. %, but when differentiated from CD117-positive cells, the degree of differentiation was approximately 80%, confirming that the differentiation efficiency was increased by 2.5 times or more.
  • the degree of differentiation of CD2-positive natural killer cells and CD16-positive natural killer cells was significantly higher than that of CD34-positive natural killer cells.
  • Example 4 Differentiation from CD34 negative, CD56 positive and CD117 positive cells to natural killer cells
  • CD34-negative, CD56-positive, and CD117-positive cells were additionally isolated using a flow cytometer (BD FACS LSR II). And it was differentiated into natural killer cells in the same manner as in Example 3, and CD34 positive cells were used as a control. The results are shown in FIG. 5.
  • the CD117 marker of the present invention can also separate the CD34-CD117+ cell population compared to CD34, which was used as a separation marker for cells for differentiation of natural killer cells, the degree of differentiation into natural killer cells significantly increases.
  • the production method of natural killer cells using the CD117 marker according to the present invention can significantly increase the productivity of natural killer cells with improved therapeutic effects, it can be widely and effectively applied to the treatment of various diseases using natural killer cells.

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Abstract

La présente invention concerne un nouveau marqueur d'isolation des cellules pour une différenciation en cellules tueuses naturelles à partir du sang d'un cordon ombilical. Les cellules CD117 positives isolées à partir du sang du cordon ont un degré élevé de différenciation et peuvent être utilisées efficacement pour préparer des cellules tueuses naturelles ayant une activité améliorée, par comparaison avec des marqueurs classiques. Ainsi, les cellules tueuses naturelles (ou cellules NK de l'anglais « natural killer ») préparées à l'aide de la présente invention sont supposées trouver diverses applications.
PCT/KR2020/002943 2019-03-05 2020-03-02 Procédé de préparation de cellule tueuse naturelle dans un monocyte de sang de cordon ombilical Ceased WO2020180065A1 (fr)

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KR20150063374A (ko) * 2012-08-13 2015-06-09 안트로제네시스 코포레이션 자연 살해 세포 및 그의 용도
KR102032384B1 (ko) * 2019-03-05 2019-11-08 주식회사 온코인사이트 제대혈 단핵세포에서의 자연살해세포의 제조 방법

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