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WO2023013965A1 - Composition comprenant un miarn dérivé de vésicules extracellulaires de lymphocytes t activés en tant que principe actif, et ses utilisations - Google Patents

Composition comprenant un miarn dérivé de vésicules extracellulaires de lymphocytes t activés en tant que principe actif, et ses utilisations Download PDF

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Publication number
WO2023013965A1
WO2023013965A1 PCT/KR2022/011068 KR2022011068W WO2023013965A1 WO 2023013965 A1 WO2023013965 A1 WO 2023013965A1 KR 2022011068 W KR2022011068 W KR 2022011068W WO 2023013965 A1 WO2023013965 A1 WO 2023013965A1
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mir
seq
nucleotide sequence
cancer
sequence represented
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Korean (ko)
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백문창
예경무
신상희
정인성
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Daegu Gyeongbuk Institute of Science and Technology
Industry Academic Cooperation Foundation of KNU
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Daegu Gyeongbuk Institute of Science and Technology
Industry Academic Cooperation Foundation of KNU
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Priority claimed from KR1020220092891A external-priority patent/KR20230022800A/ko
Publication of WO2023013965A1 publication Critical patent/WO2023013965A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a composition comprising miRNA derived from extracellular endoplasmic reticulum of activated T cells as an active ingredient and a use thereof.
  • Cancer is a product of uncontrolled and disorderly cell proliferation caused by an excess of abnormal cells, and can be said to be a disease caused by genetic mutations from a molecular biological point of view.
  • small extracellular vesicles are membrane-structured small vesicles secreted from most cells.
  • the diameter of sEVs is approximately 30-100 nm, and sEVs contain various types of proteins, genetic materials (DNA, RNA, miRNA), lipids, etc. derived from the cell.
  • sEVs are not directly released from the plasma membrane, but originate from specific intracellular compartments called multivesicular bodies (MVBs) and are released and secreted outside the cell. That is, when the fusion of the polycystic body and the plasma membrane occurs, the vesicles are released into the extracellular environment, which is called sEV.
  • MVBs multivesicular bodies
  • MicroRNA one of the substances derived from extracellular endoplasmic reticulum, is a non-coding RNA with 22 base sequences or less, which degrades target mRNA or inhibits the transcription of target mRNA. to regulate gene expression. Its gene expression regulation is related to cell differentiation and cell proliferation. In particular, during embryogenesis, miRNAs are expressed at elusive times, which play an important role in each stage of embryonic development. However, although the important function of regulating miRNA differentiation continues to be discovered, the precise mechanism regulating miRNA expression remains unknown. Recently, the possibility of epigenetic expression of miRNAs with anticancer functions in human cancer cells has been suggested, and various evidences for the epigenetic regulation of miRNA clusters have been reported.
  • the anticancer miRNA encoding various DNA regions is abnormally hypermethylated in human breast cancer cell lines, so the gene is not activated, and DNMT (DNA methylatransferase) 5-Asa in AGS gastric cancer cell lines.
  • DNMT DNA methylatransferase 5-Asa in AGS gastric cancer cell lines.
  • An object of the present invention is to provide a composition for enhancing immunity comprising, as an active ingredient, miRNAs that enhance the activity of immune cells among miRNAs derived from extracellular endoplasmic reticulum of activated T cells.
  • the present invention relates to any one or more selected from the group consisting of miR-10a-5p, miR-25-3p, miR-215-5p, miR-155-5p, miR-375, miR-148a-3p and miR-374b-5p.
  • a composition for enhancing immunity comprising miRNA as an active ingredient.
  • the present invention comprises the steps of treating IL-2 to T cells; Separating extracellular vesicles from the T cells; Collecting miRNA from the extracellular vesicles; and selecting miRNAs that enhance the expression of IFN- ⁇ and Granzyme B genes in T cells from among the collected miRNAs.
  • miR-10a-5p, miR-25-3p, miR-215-5p, miR-155-5p, miR-375, miR contained in IL-2-activated T cell-derived extracellular vesicles -148a-3p and miR-374b-5p confirm that they exhibit an immune-enhancing effect by increasing the expression levels of IFN- ⁇ and Granzyme B genes in T cells, so that the composition containing the miRNAs can be provided as an immune-enhancing composition.
  • 1 is a result of selecting miRNAs with high expression in T cell-derived extracellular vesicles through data analysis.
  • Figure 2 shows the results of evaluating the effects of 27 miRNAs, which are abundant in T cell-derived extracellular vesicles, on IFN- ⁇ and Granzyme B expression in primary CD8+ T cells.
  • 3 shows the results of evaluating the effects of 7 miRNAs with excellent activity among miRNAs abundant in T cell-derived extracellular vesicles on IFN- ⁇ and Granzyme B expression in primary CD8+ T cells.
  • the present invention relates to any one or more selected from the group consisting of miR-10a-5p, miR-25-3p, miR-215-5p, miR-155-5p, miR-375, miR-148a-3p and miR-374b-5p.
  • a composition for enhancing immunity comprising miRNA as an active ingredient.
  • the miR-10a-5p consists of the nucleotide sequence represented by SEQ ID NO: 5
  • the miR-25-3p consists of the nucleotide sequence represented by SEQ ID NO: 7
  • the miR-215-5p is represented by SEQ ID NO: 11
  • the miR-155-5p consists of the nucleotide sequence represented by SEQ ID NO: 12
  • the miR-375 consists of the nucleotide sequence represented by SEQ ID NO: 15
  • the miR-148a-3p consists of the nucleotide sequence represented by SEQ ID NO: 15 It consists of the nucleotide sequence represented by SEQ ID NO: 18, and the miR-374b-5p may consist of the nucleotide sequence represented by SEQ ID NO: 25.
  • composition for enhancing immunity is let-7a-5p, let-7f-5p, miR-148b-3p, miR-92a-3p, miR-320b, miR-4443, miR-24-3p, miR-191-5p, miR-200b-3p, miR-10b-5p, miR-221-3p, miR-199a-3p, miR-484, miR-197-3p, miR-340-5p, miR-374c-3p, miR-130b- It may further include any one or more miRNAs selected from the group consisting of 5p, miR-19b-3p, miR-185-5p, and let-7g-5p.
  • the let-7a-5p consists of the nucleotide sequence represented by SEQ ID NO: 1
  • the let-7f-5p consists of the nucleotide sequence represented by SEQ ID NO: 2
  • the miR-148b-3p is represented by SEQ ID NO: 3
  • the miR-92a-3p consists of the nucleotide sequence represented by SEQ ID NO: 4
  • the miR-320b consists of the nucleotide sequence represented by SEQ ID NO: 6
  • the miR-4443 consists of the nucleotide sequence represented by SEQ ID NO: 6
  • the miR-24-3p consists of the nucleotide sequence represented by SEQ ID NO: 9
  • the miR-191-5p consists of the nucleotide sequence represented by SEQ ID NO: 10
  • the miR-191-5p consists of the nucleotide sequence represented by SEQ ID NO: 10.
  • the miR-10b-5p consists of the nucleotide sequence represented by SEQ ID NO: 14
  • the miR-221-3p consists of the nucleotide sequence represented by SEQ ID NO: 16
  • the miR-199a-3p consists of the nucleotide sequence represented by SEQ ID NO: 17
  • the miR-484 consists of the nucleotide sequence represented by SEQ ID NO: 19
  • the miR-197-3p consists of the nucleotide sequence represented by SEQ ID NO: 19
  • the miR-340-5p consists of the nucleotide sequence represented by SEQ ID NO: 21
  • the miR-374c-3p consists of the nucleotide sequence represented by SEQ ID NO: 22
  • the miR-374c-3p consists of the nucleotide sequence represented by SEQ ID NO: 22.
  • let-7g-5p may consist of the nucleotide sequence represented by SEQ ID NO: 27.
  • the miRNA can increase the expression levels of IFN- ⁇ and Granzyme B genes in T cells.
  • the miRNA may be derived from extracellular vesicles of T cells activated by IL-2.
  • the extracellular vesicles are small extracellular vesicles (sEVs) having a diameter of 30 to 100 nm, and may include exosomes, microvesicles, and the like.
  • the composition for enhancing immunity is melanoma, colon cancer, lung cancer, skin cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, proximal anal cancer, breast cancer, fallopian tube carcinoma, uterus Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hawkins' disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte Prevention or treatment of any one or more cancer diseases selected from the group consisting of lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. It can be used as
  • the pharmaceutical composition of the present invention is prepared in unit dosage form or multi-dose by formulating using a pharmaceutically acceptable carrier according to a method that can be easily performed by those skilled in the art. It can be prepared by incorporating into a container.
  • the pharmaceutically acceptable carrier is one commonly used in formulation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • the pharmaceutical composition 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.
  • the content of the additives included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the range of content used in conventional formulations.
  • the pharmaceutical composition is an aqueous solution, suspension, emulsion, etc. for injection, pills, capsules, granules, tablets, creams, gels, patches, sprays, ointments, warning agents, lotions, liniment agents, pasta agents, and cataplasma agents. It may be formulated in the form of one or more external preparations selected from the group consisting of agents.
  • the pharmaceutical composition of the present invention may further contain pharmaceutically acceptable carriers and diluents for formulation.
  • pharmaceutically acceptable carriers and diluents include excipients such as starch, sugar and mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethylcellulose and hydroxypropylcellulose, gelatin, alginates, and polyvinyl fibres.
  • binders such as rolidone, etc., lubricants such as talc, calcium stearate, hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone, crospovidone, surfactants such as polysorbates, cetyl alcohol, and glycerol; don't
  • the pharmaceutically acceptable carrier and diluent may be biologically and physiologically compatible with the subject.
  • diluents include, but are not limited to, saline, aqueous buffers, solvents and/or dispersion media.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenous, subcutaneous, intraperitoneal or topical application) depending on the desired method.
  • parenterally eg, intravenous, subcutaneous, intraperitoneal or topical application
  • it may be formulated into tablets, troches, lozenges, aqueous suspensions, oily suspensions, powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs.
  • parenteral administration it may be formulated as an injection solution, suppository, powder for respiratory inhalation, aerosol for spray, ointment, powder for application, oil, cream, etc.
  • the dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, age, sex, health condition, dietary constitution specificity, the nature of the preparation, the severity of the disease, the administration time of the composition, the administration method, the administration period or interval, and the excretion rate. , And the range may vary depending on the type of drug, and may be appropriately selected by a person skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg/kg, but is not limited thereto, and may be divided and administered once or several times a day.
  • the pharmaceutical composition may be administered orally or parenterally (eg, intravenous, subcutaneous, intraperitoneal or topical application) depending on the desired method.
  • the pharmaceutically effective amount and effective dose of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time and/or administration route of the pharmaceutical composition, and those skilled in the art can use the purpose Dosages effective for treatment can be easily determined and prescribed. Administration of the pharmaceutical composition of the present invention may be administered once a day, or may be divided into several administrations.
  • the present invention comprises the steps of treating IL-2 to T cells; Separating extracellular vesicles from the T cells; Collecting miRNA from the extracellular vesicles; and selecting miRNAs that enhance the expression of IFN- ⁇ and Granzyme B genes in T cells from among the collected miRNAs.
  • Primary CD4+ T cells (human CD4+ T cells) and primary CD8+ T cells (human CD8+ T cells) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin and streptomycin (Hyclone).
  • FBS fetal bovine serum
  • Hyclone penicillin and streptomycin
  • PBMC Human peripheral blood In mononuclear cells
  • 50ml of blood was collected using a 50ml syringe, transferred to a vacuum containing heparin (BD Vacutainer), and then centrifuged at 550xg for 10 minutes to remove the supernatant. Then, it was mixed with PBS in a ratio of 1:1. Thereafter, 5 ml of ficoll (GE Healthcare) per 8 ml of blood mixed with PBS was added and centrifuged at 550xg for 30 minutes. Then, the supernatant was removed and the buffy coat layer was transferred to a new 50ml conical tube. After adding PBS up to 30ml, centrifugation was performed at 550xg for 10 minutes. Then, the pellet was mixed with RPMI 1640 medium supplemented with 10% FBS, 1% penicillin and streptomycin, and cultured for 16 hours in a 10 cm plate (Cat, 430167; Corning).
  • the number of cells of human peripheral blood mononuclear cells cultured in a 10 cm plate (Cat, 430167; Corning) was counted by trypan blue staining, and then centrifuged at 550xg for 10 minutes. Then, 40 ⁇ l of Macs buffer was added per 10 7 . Thereafter, 10 ⁇ l of Biotin-Ab cocktail was added per 10 7 , mixed, and incubated at 4° C. for 5 minutes. Thereafter, 20 ⁇ l of microbead cocktail was added per 10 7 , mixed, and incubated at 4° C. for 10 minutes. Then, the LS column was placed in the magnetic field of the MACS separator. After that, the column was washed 3 times with 1 ml of Macs buffer.
  • the cell supernatant cultured for 10 minutes was put into the column and flow-through was received in a 5ml tube.
  • the above process was repeated three times to receive a total of 3 ml of cell supernatant and centrifuged at 550xg for 10 minutes.
  • the pellet was mixed with RPMI 1640 medium supplemented with 10% FBS, 1% penicillin and streptomycin, and cultured on a 10 cm plate (Cat, 430167; Corning).
  • Example 3 Isolation of extracellular vesicles (sEVs) derived from primary CD4+ T cells
  • CD4+ T cells were added at a density of 2 ⁇ 10 6 per 10 cm plate (Cat. 430167; Corning), divided into plates treated with IL-2 at a concentration of 500 IU/ml and untreated plates, and cultured for 48 hours. Thereafter, in order to collect the extracellular vesicles, the medium was replaced with a medium without FBS and further cultured for 24 hours. After collecting the cell culture supernatant, cells and debris were removed by centrifugation.
  • each supernatant obtained from each cell was 300xg, 2500xg, and 10,000xg was continuously centrifuged. The supernatant was then filtered through a 0.2 ⁇ m syringe filter and centrifuged at 120,000 ⁇ g. The extracellular endoplasmic reticulum pellet was resuspended in PBS and centrifuged again at 120,000xg. The purified pellet was resuspended in PBS or 1X cell lysis buffer for the next experiment.
  • RNA libraries were generated by the Next Seq 500 system using single-end 75 sequencing (Illumina, San Diego, CA., USA).
  • Sequence reads were mapped with the bowtie2 software tool to obtain bam files (alignment files). Mature miRNA sequences were used as references for mapping. The number of reads mapped to mature miRNA sequences were extracted from alignment files using bedtools (v2.25.0) and Bioconductor (R development Core Team, 2011) using the R (version 3.2.2) statistical programming language. Read counts were used to determine the expression levels of miRNAs. Quantile normalization method was used for comparison between samples.
  • RNA-seq data as shown in Figure 1, through differentially expressed genes analysis, extracellular vesicles (CE) derived from CD4+ T cells and extracellular vesicles (IL) derived from T cells activated by IL-2 -2E), miRNAs with significantly higher expression were selected, and among those miRNAs, a miRNA candidate list with higher expression in IL-2E compared to CE was selected.
  • the 27 miRNA candidates selected in this experiment are shown in Table 1 below.
  • miRNAs base sequence sequence number hsa-let-7a-5p UGAGGUUAGUAGGUUGUAUAGUU One hsa-let-7f-5p UGAGGUAGAUAGAUUGUAUAGUU 2 hsa-miR-148b-3p UCAGUGCACUACAGAACUUUGU 3 hsa-miR-92a-3p UAUUGCACUUGUCCCGGCCUGU 4 hsa-miR-10a-5p UACCCUGUAGAUCCGAAUUUGUG 5 hsa-miR-320b AAAAGCUGGGUUGAGAGGGCAA 6 hsa-miR-25-3p CAUUGCACUUGUCUCGGUCUGA 7 hsa-miR-4443 UUGGAGGCGUGGGUUUU 8 hsa-miR-24-3p UGGCUCAGUUCAGCAGGAACAG 9 hsa-miR-191-5p CAACGGAAUCCCAAAAGCAGCUG 10 h
  • Example 5 In isolated primary CD8+ T cells microRNA mimic oligo transfection
  • each hsa-microRNA mimic oligo was added to a 100 ⁇ l Nucleocuvette Vessel (Cat; PCK-2005, Lonza), and 4D Nucleofector Core unit (Serial no 510B0263, Lonza) and 4D Nucleofector X unit (Serial no: 510 X 0441, Lonza) and transfection was performed.
  • 500 ⁇ l of RPMI 1640 medium supplemented with 10% FBS was added to the Nucleocuvette, sucked up with single use pipettes, and then 12 well plate (REF; 3513, Corning ) and cultured for 24 hours in a 37°C, 5% CO 2 incubator.
  • Example 6 hsa - miRNAs mimic oligos Evaluation of cytotoxic ability of primary CD8+ T cells after transfection
  • mRNA (Cat; R2062, ZYMO RESEARCH) was extracted from the cells, and then using nanodrop (DS-11 Series Spectrophotometer; DeNovix) The concentration of mRNA was measured.
  • synthesizing cDNA (PrimeScriptTM 1st strand cDNA Synthesis Kit, # 6110A; TaKaRa) with 100ng of mRNA, gene expression was detected using TB GreenTM Premix Ex TaqTM (Tli RNaseH Plus) kit (# RR420A; TaKaRa). Primers used in this experiment are shown in Table 2 below.
  • Real-time polymerase chain reaction was performed using the Step One Plus Real-Time PCR System (Applied Biosystems).
  • the relative mRNA level of the sample was calculated by Ct (comparative threshold cycle) analysis after normalization for the amount of beta-actin in the same sample, and was expressed as a modified 2 - ⁇ Ct value from the initial Ct value.
  • hsa-miRNA mimic oligos seven hsa-miRNA mimic oligos (hsa-miR-10a-5p, hsa-miR-25-3p, hsa-miR-215-5p, hsa-miR-155-5p, hsa-miR-155- 5p, hsa-miR-375, hsa-miR-148a-3p and hsa-miR-374b-5p) enhanced the anticancer effect of primary CD8+ T cells by flow cytometry.
  • reaction was performed at 4°C for 1 hour with 0.1% PBST (Tween (Product No; 0777-1L, VWR LIFE SCIENCE)) containing 5% Goat serum (REF; S-1000, Vector Laboratories) and 1% BSA.
  • PBST Tetrachloride
  • the sample was reacted with primary antibody for 1 hour at 4°C, washed with PBS, reacted with secondary antibody (1:2000 dilution) for 1 hour at 4°C, washed with PBS, and analyzed by flow cytometry (FACSAria III; Becton Dickinson ) was performed. Data were analyzed with FlowJo software (Flowjo, Ashland, OR, USA).
  • the primary antibodies used in this experiment were: GZMB (ab4059, 1:100; Abcam), IFNG (ab9657, 1:500; Abcam).

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Abstract

La présente invention concerne une composition comprenant un miARN dérivé de vésicules extracellulaires de lymphocytes T activés en tant que principe actif, et ses utilisations. Comme il a été confirmé que miR-10a-5p, miR-25-3p, miR-215-5p, miR-155-5p, miR-375, miR-148a-3p et miR-374b-5p contenus dans des vésicules extracellulaires dérivées de lymphocytes T activés avec IL-2 présentent un effet d'amélioration immunitaire en augmentant les niveaux d'expression des gènes IFN-γ et Granzyme B dans les lymphocytes T, la composition comprenant les miARN peut être fournie en tant que composition d'amélioration immunitaire.
PCT/KR2022/011068 2021-08-05 2022-07-27 Composition comprenant un miarn dérivé de vésicules extracellulaires de lymphocytes t activés en tant que principe actif, et ses utilisations Ceased WO2023013965A1 (fr)

Applications Claiming Priority (4)

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KR20210102881 2021-08-05
KR10-2021-0102881 2021-08-05
KR10-2022-0092891 2022-07-27
KR1020220092891A KR20230022800A (ko) 2021-08-05 2022-07-27 활성화 T 세포의 세포외 소포체 유래 miRNA를 유효성분으로 포함하는 조성물 및 이의 용도

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4471143A1 (fr) * 2023-05-30 2024-12-04 Universidad Autónoma de Madrid Mir-148a pour utilisation dans la stimulation de la réponse antitumorale des lymphocytes t

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WO2014059248A1 (fr) * 2012-10-12 2014-04-17 Philadelphia Health & Education Corporation D/B/A/ Drexel Amélioration de l'immunité des lymphocytes t cd8+ grâce au mir-155
US20190307786A1 (en) * 2016-10-27 2019-10-10 The Regents Of The University Of California Microrna in t cell activation
WO2020157288A1 (fr) * 2019-02-01 2020-08-06 Universität Basel Cellules immunitaires résistantes aux inhibiteurs de la calcineurine destinées à être utilisées dans une thérapie par transfert cellulaire adoptive
KR20210027080A (ko) * 2019-09-02 2021-03-10 경북대학교 산학협력단 Il-2 표면 발현 세포외 소포체를 유효성분으로 포함하는 암 질환 예방 또는 치료용 조성물

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WO2014059248A1 (fr) * 2012-10-12 2014-04-17 Philadelphia Health & Education Corporation D/B/A/ Drexel Amélioration de l'immunité des lymphocytes t cd8+ grâce au mir-155
US20190307786A1 (en) * 2016-10-27 2019-10-10 The Regents Of The University Of California Microrna in t cell activation
WO2020157288A1 (fr) * 2019-02-01 2020-08-06 Universität Basel Cellules immunitaires résistantes aux inhibiteurs de la calcineurine destinées à être utilisées dans une thérapie par transfert cellulaire adoptive
KR20210027080A (ko) * 2019-09-02 2021-03-10 경북대학교 산학협력단 Il-2 표면 발현 세포외 소포체를 유효성분으로 포함하는 암 질환 예방 또는 치료용 조성물

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Title
DIAZ-SALAZAR CARLOS, SUN JOSEPH C.: "Coordinated Viral Control by Cytotoxic Lymphocytes Ensures Optimal Adaptive NK Cell Responses", CELL REPORTS, ELSEVIER INC, US, vol. 32, no. 12, 1 September 2020 (2020-09-01), US , pages 108186, XP093032581, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2020.108186 *
RODRÍGUEZ-GALÁN ANA, FERNÁNDEZ-MESSINA LOLA, SÁNCHEZ-MADRID FRANCISCO: "Control of Immunoregulatory Molecules by miRNAs in T Cell Activation", FRONTIERS IN IMMUNOLOGY, vol. 9, 25 September 2018 (2018-09-25), XP093032579, DOI: 10.3389/fimmu.2018.02148 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4471143A1 (fr) * 2023-05-30 2024-12-04 Universidad Autónoma de Madrid Mir-148a pour utilisation dans la stimulation de la réponse antitumorale des lymphocytes t
WO2024246201A1 (fr) * 2023-05-30 2024-12-05 Universidad Autónoma de Madrid Mir-148a destiné à être utilisé dans la stimulation d'une réponse anti-tumorale de lymphocytes t

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