WO2020189942A1 - Cellule immunitaire à capacité de destruction du cancer améliorée - Google Patents

Cellule immunitaire à capacité de destruction du cancer améliorée Download PDF

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WO2020189942A1
WO2020189942A1 PCT/KR2020/003321 KR2020003321W WO2020189942A1 WO 2020189942 A1 WO2020189942 A1 WO 2020189942A1 KR 2020003321 W KR2020003321 W KR 2020003321W WO 2020189942 A1 WO2020189942 A1 WO 2020189942A1
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cancer
cells
genetically modified
modified immune
cell
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PCT/KR2020/003321
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Korean (ko)
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장미희
전은성
주안나
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한국과학기술연구원
재단법인 아산사회복지재단
울산대학교 산학협력단
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Priority claimed from KR1020190120852A external-priority patent/KR102292657B1/ko
Application filed by 한국과학기술연구원, 재단법인 아산사회복지재단, 울산대학교 산학협력단 filed Critical 한국과학기술연구원
Priority to US16/771,918 priority Critical patent/US11649282B2/en
Publication of WO2020189942A1 publication Critical patent/WO2020189942A1/fr

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    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4613—Natural-killer cells [NK or NK-T]
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/54—Pancreas

Definitions

  • CAR chimeric antigen receptor
  • Immunotherapy which has recently emerged, is a treatment that uses the human body's own immune system to minimize damage to normal cells and removes cancer cells more specifically.It is in various fields (antibody therapy, immune cell therapy, Viral immunotherapy, nanotechnology immunotherapy, etc.) are being actively researched.
  • immune cell therapy includes lymphocytes obtained from the patient's blood, natural killer cells, natural killer T cells, T cells, B cells, and dendritic cells. It is a method of treating cancer by increasing the number of cells in the body, enhancing its function in vitro , and returning it back to the patient's body. Therapies using these immune cells show good effects in immune response control therapy, and are evaluated to be excellent in terms of toxicity and safety.
  • TIL Tumor Infiltrating Lymphocytes
  • CAR Chimeric Antigen Receptor
  • TCR T-Cell Receptor
  • the chimeric antigen receptor is an artificial receptor designed to transmit antigen specificity to T cells. They include antigen specific components, transmembrane components, and intracellular components selected to activate T cells and provide specific immunity. Chimeric antigen receptor expressing T cells can be used in a variety of therapies, including cancer therapy.
  • immune cell therapy using NK cells has the advantage of being the only cell therapy that can use other people's immune cells without side effects, and interest in it is increasing. Therefore, for the past 10 years, tumor immunity therapy using the patient's immune system has been steadily developed, and'cell therapy products' using this have also been commercialized. Therefore, in order to promote patient-tailored treatment, interest in cell therapy products that separate and cultivate immune cells (e.g., CAR-NK cells) introduced with chimeric antigen receptors from healthy healthy blood and inject them into cancer patients. The situation is rising.
  • CAR-NK cells e.g., CAR-NK cells
  • One aspect provides a genetically modified immune cell expressing a chimeric antigen receptor (CAR) and/or TRAIL comprising an antigen binding domain that specifically binds to cancer cells.
  • CAR chimeric antigen receptor
  • One aspect provides genetically modified immune cells that produce TRAIL proteins.
  • One aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the genetically modified immune cells as an active ingredient.
  • One aspect provides a cell therapy comprising the genetically modified immune cells as an active ingredient.
  • Another aspect provides a method of providing information for diagnosis of cancer, comprising the step of contacting the genetically modified immune cells with a sample isolated from an individual.
  • Another aspect comprises introducing a recombinant vector comprising i) an antigen-binding domain that specifically binds to cancer, ii) comprising a TRAIL gene, or iii) a combination thereof, into immune cells isolated from the human body It provides a method for producing genetically modified immune cells.
  • Another aspect provides a method of preventing or treating cancer comprising administering the genetically modified immune cells to an individual in need thereof.
  • a genetically modified immune cell expressing a chimeric antigen receptor (CAR) comprising an antigen-binding domain that specifically binds to cancer cells is provided.
  • CAR chimeric antigen receptor
  • compositions for preventing or treating cancer comprising the genetically modified immune cells as an active ingredient.
  • It provides a cell therapy comprising the genetically modified immune cells as an active ingredient.
  • It provides a method of providing information for diagnosis of cancer, comprising the step of contacting the genetically modified immune cells with a specimen isolated from an individual.
  • Genetically modified comprising the step of introducing a recombinant vector containing i) an antigen binding domain that specifically binds to FOLR1, ii) containing a TRAIL gene, or iii) a combination thereof into immune cells isolated from the human body It provides a method of manufacturing the immune cells.
  • Another aspect provides a method of preventing or treating cancer comprising administering the genetically modified immune cells to an individual in need thereof.
  • the genetically modified immune cells according to one aspect When the genetically modified immune cells according to one aspect are used, excellent cytotoxicity to cancer cells including FOLR1, DR4, DR5, or a combination thereof is recognized, and can be effectively used as an anticancer agent. Therefore, the genetically modified immune cells produced according to one aspect exhibits highly efficient anticancer effects, and thus can be usefully used in gene therapy.
  • FIG. 1 shows the results of a Western blotting experiment confirming the expression of FOLR1 identified in pancreatic cancer cell lines PNAC-1, Aspc1 and Miapaca2 and patient-derived cells (PDC) SNU213, 410, 2491 and 110621. It is a diagram shown.
  • FIG. 2 is a diagram showing the expression of FOLR1, DR4 and DR5 identified in cancer cell lines PNAC-1, Aspc1, Miapaca2, SNU213, 410, 2491 and 110621 through FACS analysis.
  • FIG. 3 is a diagram schematically showing a transformed NK cell and a vector introduced into the NK cell.
  • Figure 4a is a diagram showing the result of confirming the FACS analysis in the prepared CAR-NK cells.
  • Figure 4b is a diagram showing the results of confirming the Western blotting ( Figure 4B) confirmed through the primary antibody against ⁇ -CD3zeta.
  • 4C is a diagram showing the results of confirming the expression of CAR through a multifocal fluorescence microscope.
  • Figure 5a is a diagram showing the cell death effect by treating the prepared CAR-NK cells to the cancer cell line SNU2491.
  • 5B is a graph showing the cell-specific killing effect by treating the prepared CAR-NK cells with SNU2491 and SNU2469.
  • 6A is a diagram showing the results of confirming the ability to inhibit proliferation through the effect of reducing the volume of cancer cells appearing on day 18 after administration of the prepared CAR-NK cells to a cancer model mouse.
  • Figure 6b is a diagram showing the results showing the tumor volume measured 3, 6, 9, 12, 15, and 18 days after administration of CAR-NK cells.
  • Figure 6c is a diagram showing the results of apoptosis through Tunel staining of a group administered with GFP, Fra CAR, and TRAIL, respectively, and a group administered with Fra CAR and TRAIL in combination with SNU2491 cancer cells.
  • Figure 6d is a diagram showing the results of apoptosis through H&E staining of a group administered with GFP, Fra CAR, and TRAIL, respectively, and a group administered with Fra CAR and TRAIL in combination.
  • One aspect provides a genetically modified immune cell expressing a chimeric antigen receptor (CAR) and/or TRAIL comprising an antigen binding domain that specifically binds to cancer cells.
  • CAR chimeric antigen receptor
  • the immune cells may be any one selected from the group consisting of macrophages, B lymphocytes, T lymphocytes, mast cells, monocytes, dendritic cells, eosinophils, natural killer cells, basophils, and neutrophils.
  • NK cell is a type of white blood cell in the blood responsible for innate immunity, and is also called a “natural killer cell.”
  • the main function of the NK cells is to directly attack and destroy virus-infected cells or cancer cells.
  • NK cells attack cancer cells to prevent the occurrence, proliferation, and metastasis of cancer cells, and it is also known that it can effectively control cancer stem cells, which play the most important role in recurrence of cancer. Treatment continues to be studied, and the need for research on CAR-NK incorporating chimeric antigen receptors is emerging.
  • cancer-related antigens include folate receptor alpha (FOLR1), HER2, HER2/neu, NKG2D, PSMA, CEA, IL13Roc2, EphA2, BCMA, CSPG4, CD138, survivin, CD19, CD20, CD22, k light chain, CD30, CD33, CD123, CD38, ROR1, ErbB2,ErbB3/4, ErbB dimers, EGFr vIII, carcinoembryonic antigen, EGP2, EGP40, mesothelin, TAG72, PSMA, NKG2D ligands, B7- H6, IL-13 receptor a2, MUC 1, MUC 16, CA9, GD2, GD3, HMW-MAA, CD171, Lewis Y, G250/CAIX, HLA-AI MAGE Al, HLA-A2 NY- ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7/8, avb6 integrin
  • the chimeric antigen receptor may comprise an antigen binding domain that specifically binds to the above-mentioned antigen.
  • the chimeric antigen receptor may be an antigen binding domain that specifically binds to folate receptor alpha (FOLR1).
  • FOLR1 folate receptor alpha
  • the FOLR1 protein is encoded by the FOLR1 gene and is known as a member of the folate receptor (FOLR) family, and the protein has high affinity for folic acid and various folic acid derivatives, and 5-methyltetrahydrofolate (5 -methyltetrahydrofolate) is known to mediate delivery.
  • FOLR folate receptor
  • the genetically modified immune cells include those introduced by a recombinant vector containing a sequence encoding a chimeric antigen receptor.
  • the term “vector” refers to a means for expressing a gene of interest in a host cell.
  • a viral vector selected from the group consisting of a plasmid vector, a cosmid vector, a bacteriophage vector, a herpes simplex virus, and a basinia virus, an adenovirus vector, a retroviral vector, a lentiviral expression vector and an adeno-associated virus vector Include.
  • Vectors that can be used as the recombinant vector are, for example, pSC101, pGV1106, pACYC177, ColE1, pKT230, pME290, pBR322, pUC8/9, pUC6, pBD9, pHC79, pIJ61, pLAFR1, pHV14, pGEX series, pET series and pUC19 Plasmids often used in the art, such as ⁇ gt4 ⁇ B, ⁇ -Charon, ⁇ z1, and phages such as M13, or viruses such as SV40 may be fabricated.
  • the polynucleotide sequence encoding the fusion protein is operably linked to a promoter.
  • operatively linked refers to a functional linkage between a nucleotide expression control sequence, such as a promoter sequence, and another nucleotide sequence, whereby the control sequence facilitates transcription and/or translation of the other nucleotide sequence. Will be adjusted.
  • the recombinant vector may be an expression vector capable of stably expressing the fusion protein in a host cell.
  • the expression vector may be a conventional one used in the art to express foreign proteins in plants, animals or microorganisms.
  • the recombinant vector can be constructed through various methods known in the art.
  • the recombinant vector can be constructed using prokaryotic or eukaryotic cells as a host.
  • a strong promoter capable of promoting transcription e.g., pL ⁇ promoter, trp promoter, lac promoter, tac promoter, T7 promoter, etc.
  • a ribosome binding site for initiation of translation and a transcription/translation termination sequence are generally included.
  • the origin of replication operating in eukaryotic cells included in the vector includes the f1 origin of replication, SV40 origin of replication, pMB1 origin of replication, adeno origin of replication, AAV origin of replication, BBV origin of replication, etc. It is not limited.
  • a promoter derived from the genome of a mammalian cell e.g., metallotionine promoter
  • a promoter derived from mammalian virus e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, The cytomegalovirus promoter and the tk promoter of HSV
  • a promoter derived from the genome of a mammalian cell e.g., metallotionine promoter
  • a promoter derived from mammalian virus e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, The cytomegalovirus promoter and the tk promoter of HSV
  • a polyadenylation sequence as a transcription termination sequence.
  • the cells are yeast, fungi, protozoa, plants, higher plants and insects, or cells of amphibians, or cells of mammals such as CHO, HeLa, HEK293, and COS-1.
  • yeast fungi, protozoa, plants, higher plants and insects, or cells of amphibians, or cells of mammals such as CHO, HeLa, HEK293, and COS-1.
  • the organism may be yeast, fungi, protozoa, plants, higher plants and insects, amphibians, or mammals.
  • CAR-NK or CAR-natural killer cells are cancer immunity using conventional CAR-T therapeutic agents.
  • CAR-NK cells can be allografted, high-efficiency cells can be premade compared to CAR-T, which uses the patient's own immune cells, thus shortening the time of administration of therapeutic agents to increase therapeutic efficacy, as well as development and treatment. It can be usefully used in the development of therapeutic agents for various diseases according to cost reduction.
  • antibody refers to a substance produced by stimulation of an antigen in the immune system, and the kind is not particularly limited.
  • the antibody includes, but is not limited to, fragments of an antibody having antigen-binding ability, such as Fab, Fab', F(ab')2 and Fv.
  • Chimeric antibody refers to an antibody originating in an animal whose variable region or complementarity determining region (CDR) thereof is different from the rest of the antibody.
  • the antibody variable region may be derived from an animal other than human (eg, mouse, rabbit, poultry, etc.), and the antibody constant region may be an antibody derived from human.
  • Such chimeric antibodies can be prepared by methods such as gene recombination known in the art.
  • the “heavy chain” is a variable region domain VH containing an amino acid sequence of a variable region sufficient to confer antigen specificity, and a full-length heavy chain including three constant region domains CH1, CH2 and CH3, and fragments thereof. It is called.
  • light chain refers to both a full-length light chain including a variable region domain VL and a constant region domain CL including an amino acid sequence of a variable region sufficient to confer antigen specificity and a fragment thereof.
  • the antigen-binding domain included in the chimeric antigen receptor is a site through which the main signal is transmitted and is outside the cell membrane and refers to a site that recognizes the cell membrane ligand (a substance that binds to and activates a receptor) of a target cell with a specific antigen.
  • an antigen-binding domain that specifically binds to FOLR1 was used, and an antibody or antibody fragment that specifically binds to FOLR1 was used as the antigen-binding domain.
  • the fragment of the antibody may be scFv, and the fragment of the antibody may be, for example, a nucleotide sequence represented by SEQ ID NO: 1, but is not limited thereto.
  • the chimeric antigen receptor may include an intracellular signal transduction domain.
  • the intracellular signal transduction domain which is a component of the chimeric antigen receptor, can be used without limitation in the intracellular signal transduction domain known in the art.
  • the intracellular signal transduction domain may be a costimulatory domain, CD3z, or a combination thereof, but is not limited thereto.
  • the co-stimulatory domain may be at least one selected from the group consisting of ICOS, CD27, CD28, 4-1BB, and OX40.
  • the chimeric antigen receptor may exhibit a killing effect on cancer cells with high activity of NK cells by using a costimulatory domain, CD3z, or a combination thereof as an intracellular signaling domain.
  • the CD3z (zeta) may function as an NK cell activation domain.
  • CD27 may be, for example, a nucleotide sequence represented by SEQ ID NO: 2
  • CD3z may be, for example, a nucleotide sequence represented by SEQ ID NO: 3, but is not limited thereto.
  • the chimeric antigen receptor may be, for example, a nucleotide sequence represented by SEQ ID NO: 6.
  • One aspect provides genetically modified immune cells that produce TRAIL proteins.
  • the recombinant vector according to an aspect may further include a TNF-related apoptosis-inducing ligand (TRAIL) gene to produce a TRAIL protein in cells into which the recombinant vector has been introduced.
  • TRAIL TNF-related apoptosis-inducing ligand
  • the genetically modified immune cells that produce the TRAIL protein for example, genetically modified natural killer cells, may be introduced by the introduction of a recombinant vector containing the TRAIL gene.
  • the TRAIL gene may be, for example, a nucleotide sequence represented by SEQ ID NO: 4, but is not limited thereto.
  • Genetically modified immune cells are i) cytotoxic against cancer cells expressing a cancer cell-specific antigen (eg, FOLR), ii) expressing DR4 or DR5, or iii) a combination thereof. It may be to represent.
  • a cancer cell-specific antigen eg, FOLR
  • FOLR cancer cell-specific antigen
  • immune cells genetically modified by the introduction of a recombinant vector comprising a single chain variable fragment of a FOLR1 antibody and TRAIL for example, a genetically modified natural killer cell
  • a recombinant vector including a showed an anticancer effect superior to that of various cancer cells (Example 3).
  • the NK cells expressing CAR according to one aspect have excellent cytotoxic effects on cancer cells expressing FOLR.
  • One aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the genetically modified immune cells as an active ingredient.
  • genetically modified immune cells such as genetically modified natural killer cells, that express chimeric antigen receptor (CAR) containing an antigen-binding domain that specifically binds to cancer cells or produce TRAIL protein.
  • CAR chimeric antigen receptor
  • the pharmaceutical composition can be used for the prevention and/or treatment of cancer.
  • prevention refers to any action that prevents the disease by eliminating the etiology or early detection of cancer.
  • treatment refers to any action in which symptoms caused by cancer are improved or beneficially altered.
  • the term'cancer' refers to a group of diseases characterized by excessive cell proliferation and invasion into surrounding tissues when the normal apoptosis balance is broken.
  • the cancer is, for example, lung cancer, laryngeal cancer, gastric cancer, colon / rectal cancer, liver cancer, gallbladder cancer, pancreatic cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, kidney cancer, carcinoma derived from epithelial cells such as skin cancer, Group consisting of sarcoma derived from connective tissue cells such as bone cancer, muscle cancer, fat cancer, fibroblast cancer, hematopoietic cells such as leukemia, lymphoma, and multiple myeloma, and tumors occurring in nerve tissue It may be one or more selected from, but is not limited thereto.
  • CAR chimeric antigen receptor
  • the pharmaceutical composition comprising i) exhibits excellent cancer cell killing effect against cancer cells expressing i) a cancer cell-specific antigen (eg, FOLR), ii) expressing DR4 or DR5, or iii) a combination thereof.
  • a cancer cell-specific antigen eg, FOLR
  • FOLR cancer cell-specific antigen
  • the pharmaceutical composition for preventing or treating cancer Acceptable carriers such as saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome, and one or more of these components can be mixed and used, and antioxidants as needed , May further include other conventional additives such as a buffer solution.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • it may be preferably formulated according to each component by an appropriate method in the art or by using a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.
  • the pharmaceutical composition of the present invention is not particularly limited in its formulation, but is preferably formulated as an injection or inhalant.
  • the method of administering the pharmaceutical composition according to an aspect is not particularly limited, but may be administered parenterally or orally, such as intravenous, subcutaneous, intraperitoneal, inhalation or topical application, depending on the intended method.
  • the dosage range varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease.
  • the daily dosage refers to an amount of a therapeutic substance according to an aspect sufficient to treat a disease state alleviated by being administered to an individual in need of treatment.
  • the effective amount of a therapeutic substance depends on the particular compound, the disease state and its severity, the individual in need of treatment, which can be determined routinely by a person skilled in the art.
  • the dosage of the composition according to one aspect to the human body may vary depending on the age, weight, sex, dosage form, health condition, and degree of disease of the patient. Based on an adult patient weighing 70 kg, for example, about 1,000-10,000 cells/time, 1,000-100,000 cells/time, 1,000-1000,000 cells/time, 1,000-10,000,000, 1,000-100,000,000 cells/time, 1,000 to 1,000,000,000 cells/time, 1,000 to 10,000,000,000 cells/cycle, may be dividedly administered once or several times a day at regular time intervals, or may be administered several times at regular time intervals.
  • the term'individual' refers to an object in need of treatment for cancer, vascular disease, or inflammatory disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, and It means mammals such as cattle.
  • the pharmaceutical composition comprises a pharmaceutical composition comprising a genetically modified immune cell that expresses a chimeric antigen receptor (CAR) containing an antigen-binding domain that specifically binds to cancer cells or produces a TRAIL protein. to provide.
  • a pharmaceutical composition comprising a genetically modified immune cell that expresses a chimeric antigen receptor (CAR) containing an antigen-binding domain that specifically binds to cancer cells or produces a TRAIL protein.
  • CAR chimeric antigen receptor
  • the pharmaceutical composition or cell therapy may be used for the prevention and/or treatment of cancer.
  • One aspect provides a cell therapy comprising the genetically modified immune cells as an active ingredient.
  • cell therapy refers to a therapeutic agent using autologous, allogenic, and xenogenic cells to restore tissue functions, and refers to a therapeutic agent used to suppress cancer.
  • Including the immune cells, for example, genetically modified natural killer cells as an active ingredient, can be used as a cell therapy for the treatment and prevention of cancer.
  • the cell therapy agent may further include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be used by mixing, for example, saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, human serum albumin (HSA), and one or more of these components.
  • HSA human serum albumin
  • other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as needed.
  • the cell therapy agent if necessary, depending on the formulation, suspending agent, solubilizing aid, stabilizer, isotonic agent, preservative, adsorption inhibitor, surfactant, diluent, excipient, pH adjuster, painless agent, buffer, sulfur-containing reducing agent, antioxidant Etc.
  • suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragant mal, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate, and the like.
  • solution adjuvant examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester and the like.
  • dextran 40 methylcellulose, gelatin, sodium sulfite, sodium metasulfate, etc. are mentioned.
  • Examples of the tonicity agent include D-mannitol and sorbitol.
  • preservative examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
  • adsorption inhibitor examples include human serum albumin, lecithin, dextran, ethylene oxide propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, polyoxyethylene hydrogenated castor oil, polyethylene glycol, and the like.
  • sulfur-containing reducing agent examples include N-acetylcysteine, N-acetylhomocysteine, thioctoic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, carbon atom number. And those having a sulfhydryl group such as 1 to 7 thioalkanoic acid.
  • antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, ⁇ -tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid.
  • chelating agents such as stearate, sodium hydrogen sulfite, sodium sulfite, triamyl gallic acid, propyl gallic acid or sodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.
  • the cell therapy product when the cell therapy product is based on an adult patient weighing 70 kg, for example, about 1,000 to 10,000 cells/time, 1,000 to 100,000 cells/time, 1,000 to 100,000 cells/time, 1,000 to 10,000,000, 1,000 ⁇ 100,000,000 cells/time, 1,000 ⁇ 1,000,000,000 cells/time, 1,000 ⁇ 10,000,000,000 cells/time, may be dividedly administered once or several times a day at regular time intervals, or several times at regular time intervals.
  • the injection product according to the present invention may be prepared in the form of a filled injection by taking an amount commonly known in the art according to the constitution of the patient and the type of defect.
  • therapeutic agent or “pharmaceutical composition” refers to a molecule or compound that imparts several beneficial effects upon administration to a subject.
  • the beneficial effect is to enable diagnostic decisions; Improvement of a disease, symptom, disorder or condition; Reducing or preventing the onset of a disease, symptom, disorder or condition; And the response of a disease, symptom, disorder or condition in general.
  • treatment or “treating” or “relaxing” or “improving” are used interchangeably. These terms refer to methods of obtaining beneficial or desired results, including but not limited to therapeutic benefits and/or prophylactic benefits.
  • a therapeutic benefit refers to any therapeutically significant improvement or effect thereon of one or more diseases, disorders or symptoms under treatment.
  • the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more physiological symptoms of the disease, even if the disease, condition, or symptom is not yet present.
  • an effective amount refers to an amount of an agent sufficient to produce an advantageous or desired result.
  • the therapeutically effective amount may vary according to one or more of the subject and condition to be treated, the weight and age of the subject, the severity of the condition, the mode of administration, and the like, which can be easily determined by those skilled in the art. Further, the term applies to the capacity to provide an image for detection by any of the imaging methods described herein.
  • the specific dosage may vary depending on one or more of the particular agent selected, the dosage regimen that follows, whether it is administered in combination with other compounds, the timing of administration, the tissue being imaged, and the body delivery system carrying it.
  • the genetically modified immune cells expressing CAR-NK have a synergistic effect when administered in combination with TRAIL.
  • Another aspect provides a method of providing information for diagnosis of cancer, comprising the step of contacting the genetically modified immune cells with a sample isolated from an individual.
  • a chimeric antigen receptor (CAR) containing an antigen-binding domain that specifically binds to folate receptor alpha (FOLR1) is expressed or genetically produced by a TRAIL protein.
  • a composition for diagnosis of cancer and a kit for diagnosis of cancer including modified immune cells, immune cells, for example, genetically modified natural killer cells.
  • Another aspect of the present invention is a gene that expresses a chimeric antigen receptor (CAR) or produces a TRAIL protein comprising an antigen-binding domain that specifically binds to one aspect of folate receptor alpha (FOLR1).
  • a method of providing information for diagnosis of cancer comprising contacting a composition comprising entirely modified immune cells with a sample isolated from an individual.
  • diagnosis refers to determining an object's susceptibility to a particular disease or condition, determining whether an object currently has a particular disease or condition, or the prognosis of an object suffering from a particular disease or condition. determining prognosis, or therametrics (eg, monitoring the condition of an object to provide information about treatment efficacy).
  • Another aspect is the step of introducing a recombinant vector comprising i) an antigen-binding domain that specifically binds to cancer cells, ii) including a TRAIL gene, or iii) a combination thereof, into immune cells isolated from the human body. It provides a method for producing a genetically modified immune cell comprising, for example, a genetically modified natural killer cell.
  • Another aspect provides a method of preventing or treating cancer comprising administering the genetically modified immune cells to an individual in need thereof.
  • the method may further include the step of administering TRAIL in combination, and the TRAIL may be administered simultaneously, separately or sequentially in combination with the immune cells.
  • the genetically modified immune cells and TRAIL are administered in combination with two active ingredients, the therapeutic effect on cancer may be additional or synergistic.
  • the genetically modified immune cells can be administered to individuals in need thereof by various routes. All modes of administration can be expected and can be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injection.
  • Redundant content is omitted in consideration of the complexity of the present specification, and terms not otherwise defined herein have meanings commonly used in the technical field to which the present invention belongs.
  • pancreatic cancer cell lines PNAC-1, Aspc1 and Miapaca2 and patient-derived cancer cell lines PDC
  • PDC patient-derived cancer cell lines
  • SNU213, 410, 2491 and 110621 SNU213, 410, 2491 and 110621 to select target antigens commonly expressed in various types of cancer cells
  • FACS fluorescence activated cell sorter
  • the stained cells were collected using a Guava easyCyte flow cytometer (Merck Millipore) and analyzed with FlowJo version 10.2 (TreeStar).
  • FOLR1, DR4 and DR5 were detected by APC-conjugated anti-human FOLR1, APC-conjugated anti-human DR4, and PE-conjugated anti-human DR5 antibodies, respectively, and FACS analysis was performed and the results are shown in FIG. Indicated.
  • pancreatic cancer cell line PNAC-1, Aspc1, and PDC SNU410 and 110621 hardly showed FOLR1.
  • ⁇ -FOLR1 was shown to be weak, but in cancer cell lines SNU2491 and SNU213 derived from patients, ⁇ -FOLR1 was found to be at a strong level.
  • TRAIL receptors DR4 and DR5 are the seven cancer cell lines. It was confirmed that all were expressed in large amounts.
  • FOLR1 was expressed only in some pancreatic cancer cell lines, but it was confirmed that TRAIL receptors DR4 and DR5 appeared in various types of cancer cell lines. Accordingly, it was confirmed that FOLR1 can be used for specific targeting of pancreatic cancer cell lines, and it was confirmed that DR4 and DR5 can be used as cancer cell-specific target antigen markers for targeting more various types of cancer cells.
  • CAR-NK cells expressing the chimeric antigen receptor specific to FOLR1 identified in Example 1
  • an experiment was designed to confirm whether a cancer cell-specific killing effect could be exhibited.
  • DR4 and DR5 which are identified as markers in various cancer cells, are known as TRAIL receptors.
  • TRAIL When TRAIL is expressed in NK cells, which can exhibit anticancer effects by exhibiting cytotoxicity against cancer cells, expression of FOLR1-specific chimeric antigen receptor
  • an experiment for producing CAR-NK was designed.
  • a second-generation CAR vector expressing a fusion protein composed of a single chain variable fragment (scFv) of the FOLR1 antibody and a signal transduction region composed of CD27 and CD3z was constructed.
  • FOLR1-CAR DNA including scFv, CD27 and CD3z of FOLR1, was purchased from Creative biolabs (USA).
  • Lentiviral expression vectors containing pLVXPuro (Cat. #632164) were obtained from Addgene.
  • a CAR vector sequence was prepared by inserting a DNA fragment containing GFP below the P2A sequence.
  • a vector was prepared in which the TRAIL gene was further introduced into the vector into which the single-chain variable fragment for FOLR1 was introduced, and a vector to express only the TRAIL gene was prepared and inserted into GFP-expressing CAR-NK or NK cells.
  • the transformed NK cells and the vectors introduced into the NK cells are shown in Fig. 3, respectively.
  • the experimental method is specifically as follows: Invitrogen Lipofectamin 3000 reagent (Invitrogen, L3000-015) 293T cells through a lentivirus-expression vector and viral power lentiviral packaging MIX (Invitrogen, 44)-mediated transformation method -2050) was used to transform. After 48 hours, the culture medium was harvested and centrifuged for 5 minutes at 1300 rpm.
  • FACS fluorescence activated cell sorter
  • NK cell lines transfected with CAR was evaluated using a Guava easyCyte Flow cytometer (Merck Millipore), and analyzed with FlowJo version 10.2 (TreeStar). 2 x 10 5 cells were analyzed and GFP expressing cells were counted into the FL1 channel. In addition, 3 x 10 4 NK cells transduced with CAR were inoculated into an IVID dish, and expression was confirmed with a multifocal fluorescence microscope (Carl-zeiss, Germany). The CAR-transduced 3 ⁇ 10 4 NK cells were lysed using RIPA lysis buffer (Sigma) supplemented with a protease inhibitor (Thermo Scientific).
  • NK cells into which the chimeric antigen receptor was introduced express the chimeric antigen receptor of the present invention, and NK cells into which TRAIL was introduced also secrete the substance.
  • the vector prepared according to this example can effectively genetically modify CAR-NK cells.
  • CAR-transduced NK-92 cells were added to target cancer cells (2 x 10 5 cells), which are cancer cell lines SNU2491 and SNU2469 derived from patients, at a ratio of 2.5:1 and 5:1, and co-cultured in culture medium for 4 hours. I did. SNU2491 cells are cancer cell lines with high expression of FOLR1. Then, in order to visualize the NK cells, FITC was labeled with conjugated CD56 (Biolegend).
  • target cells were isolated and stained with 7-aminoactinomycin D (7-AAD), a red fluorescent probe that labels dead cells and necrotic target cells in cytotoxicity analysis, and Analysis was performed using FACS.
  • FITC-CD556-labeled cells were measured in the FL1 channel and 7-AAD stained cells were measured in the FL3 channel, and the results are shown in FIG. 5A.
  • the SNU2491 cancer cell line with high expression of FOLR1 and DR4/5 induces a higher degree of cytotoxicity than when co-cultured with NK cells expressing Fra GFP CAR and TRAIL compared to a control expressing only GFP.
  • the group containing the single-chain variable fragment of the FOLR1 antibody (NK-Fra CAR) and the group expressing TRAIL (NK-TRAIL) exhibited better apoptosis effect.
  • NK cells (NK-Combi) expressing a combination of Fra and TRAIL exhibit an improved synergistic effect, which is more than twice as excellent as the apoptosis effect of the FRa GFP group.
  • CAR-NK cells CAR-NK cells into which the Fra GFP vector was introduced, CAR-NK cells into which the TRAIL-GFP vector was introduced, and NK cells expressing a combination of Fra and TRAIL (FRa-TRAIL-GFP) in order.
  • FRa-TRAIL-GFP a combination of Fra and TRAIL
  • the CAR-NK cells were injected into a cancer disease model mouse and the volume of cancer cells of the disease model mouse was determined. An experiment to measure was performed.
  • A is the largest diameter in the tumor and B is the shortest diameter in the tumor.
  • B is the shortest diameter in the tumor.
  • the mice were sacrificed, and the mice were dissected to further investigate the tumor, and the results of confirming the volume of cancer cells in the group to which the CAR-NK cells were administered are shown in FIG. 6A, wherein the CAR-NK cells were administered.
  • the results showing the tumor volume measured after 3, 6, 9, 12, 15 and 18 days are shown in Fig. 6B.
  • Mock relates to a group in which NK cells were not treated as a negative control group.
  • FIG. 6A it was confirmed that the volume of cancer cells was reduced in the group to which NK cells into which GFP and TRAIL were introduced compared to the control Mock. It was confirmed that the volume of cancer cells in the group administered with the Fra GFP CAR and the group expressing Fra GFP + TRAIL was significantly smaller than that of the control Mock.
  • FIG. 6B when the NK cell group into which GFP, TRAIL, and Fra GFP CAR was introduced was introduced was introduced, it was confirmed that the volume of the first cancer cell decreased by about 20% when 18 days elapsed after the administration of NK cells. .
  • the volume of cancer cells significantly decreased from the beginning of transduction, and when 18 days had elapsed after administration, the volume of cancer cells decreased by about 60%.
  • Example 2 In order to confirm whether the CAR-NK cells transfected with the CAR prepared in Example 2 can effectively inhibit the proliferation of cancer cells, the extent of cancer cell tissue cell death or necrosis through the administration of CAR-NK cells in an animal model TUNEL staining and hematoxylin-eosin (H&E) staining were performed to confirm.
  • TUNEL staining and hematoxylin-eosin (H&E) staining were performed to confirm.
  • Example 4.1 In order to evaluate the cell death of cancer tissues in vivo, in the animal model prepared in Example 4.1, when the tumor size of the mouse reaches 0.1 cm 3 , the cultured NK cells prepared in Example 2 were converted to 5 ⁇ 10 6 cells. It was administered intravenously 3 times at 3 days intervals at a density of. On the 28th day after NK cell administration, the mice were sacrificed, and the mice were dissected to further investigate the tumor, and TUNEL staining was performed using an in situ cell death detection kit (Roche) according to the manufacturer's instructions. Tumor tissue sections were fixed with 4% paraformaldehyde and permeabilized with 0.1% Triton X-100 and 0.1% sodium citrate.
  • H&E staining was also performed on the 28th day after administration of NK cells.
  • the tumor was fixed in 4% paraformaldehyde overnight, embedded in paraffin, and then sliced so that the tumor section had a 6 ⁇ m cross section using a microtome (Leica).
  • the prepared sections were de-paraffinized with xylene and the sections were rehydrated using a graded ethanol wash.
  • Tumor sections were stained with hematoxylin and eosin (H&E) and observed under an optical microscope (Olympus), and the results are shown in FIG. 6D.
  • Mock relates to a group in which NK cells were not treated as a negative control group.

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Abstract

La présente invention concerne une cellule immunitaire génétiquement modifiée exprimant un récepteur d'antigène chimérique (CAR) comprenant un domaine de liaison à l'antigène se liant spécifiquement à des cellules cancéreuses et/ou exprimant TRAIL, une composition comprenant la cellule immunitaire pour la prévention ou le traitement du cancer, un produit de thérapie cellulaire, un procédé pour fournir des informations sur le diagnostic du cancer, et un procédé de préparation d'une cellule immunitaire génétiquement modifiée.
PCT/KR2020/003321 2019-03-15 2020-03-10 Cellule immunitaire à capacité de destruction du cancer améliorée WO2020189942A1 (fr)

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Citations (3)

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KR20180028530A (ko) * 2015-07-29 2018-03-16 온키뮨 리미티드 증가된 세포독성을 갖는 변형된 자연 살해 세포 및 자연 살해 세포주
US20180161371A1 (en) * 2016-12-09 2018-06-14 Onkimmune Limited Engineered natural killer cells and uses thereof
WO2018104554A1 (fr) * 2016-12-09 2018-06-14 Onkimmune Limited Thérapie cellulaire améliorée reposant sur des lymphocytes nk

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KR20180028530A (ko) * 2015-07-29 2018-03-16 온키뮨 리미티드 증가된 세포독성을 갖는 변형된 자연 살해 세포 및 자연 살해 세포주
US20180161371A1 (en) * 2016-12-09 2018-06-14 Onkimmune Limited Engineered natural killer cells and uses thereof
WO2018104554A1 (fr) * 2016-12-09 2018-06-14 Onkimmune Limited Thérapie cellulaire améliorée reposant sur des lymphocytes nk

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