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WO2019134213A1 - Récepteur antigénique chimérique comprenant un domaine intracellulaire c3ar, vecteur lentiviral, cellule d'expression et médicament - Google Patents

Récepteur antigénique chimérique comprenant un domaine intracellulaire c3ar, vecteur lentiviral, cellule d'expression et médicament Download PDF

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WO2019134213A1
WO2019134213A1 PCT/CN2018/075857 CN2018075857W WO2019134213A1 WO 2019134213 A1 WO2019134213 A1 WO 2019134213A1 CN 2018075857 W CN2018075857 W CN 2018075857W WO 2019134213 A1 WO2019134213 A1 WO 2019134213A1
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intracellular domain
cells
c3ar
chimeric antigen
antigen receptor
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Chinese (zh)
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杜欣
翁建宇
赖沛龙
陈晓梅
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Guangdong General Hospital Guangdong Academy of Medical Sciences
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Guangdong General Hospital Guangdong Academy of Medical Sciences
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    • 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
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A61K40/4211—CD19 or B4
    • 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 A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 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 A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 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 A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates to the field of cellular immunotherapy of tumors, and in particular to a chimeric antigen receptor comprising a C3aR intracellular domain, and to a nucleic acid comprising a chimeric antigen receptor encoding a C3aR intracellular domain and use thereof.
  • Chimeric Antigen Receptors is a milestone in the hope of curing tumors.
  • CAR-T technology is a genetic modification technique that uses a single chain fragment variable (scFv) to recognize tumor antigens.
  • the intracellular activation motif recombinant gene is transfected into T lymphocytes to achieve better recognition and killing of tumors.
  • CAR-T molecules typically include an extracellular hinge region, a transmembrane region, and an intracellular signaling region.
  • the extracellular hinge region is formed by the linkage of a heavy chain and a light chain variable region of a single-chain antibody through a peptide segment;
  • the transmembrane region is mainly derived from a transmembrane region of a molecule such as CD8, CD28 or 4-1BB;
  • the intracellular signal region is mainly derived from the intracellular chimera of T cell signaling molecules such as CD28, 4-1BB, CD3zeta, CD27 or OX-40.
  • High affinity, high specificity scFv determines that CAR-T targets an antigen. Once bound to the antigen, the intracellular segment of CAR transmits activation and co-stimulatory signals to T cells, activates T cells and effectively targets tumor cells.
  • T cells require two activation signals, that is, the TCR-CD3 on the surface of T cells binds to the MHC-I molecule as the first signal of activation, determines the killing activity of T cells on tumor cells; the costimulatory molecules on the surface of T cells and corresponding Ligand binding is the second signal of activation that determines T cell proliferation.
  • CAR-T cells recognize specific molecules on the surface of tumor cells through antigen-antibody recognition patterns, and then activate, proliferate and exert cell killing function through their intracellular signaling.
  • the structural design of CAR molecules has undergone multiple generations of research and development.
  • the structure of the first generation CAR molecule comprises an scFv that recognizes tumor cell surface antigens, a transmembrane domain, and an intracellular domain of the TCR complex CD3zeta that activates T cells. Since the signal domain of the first generation of CAR is a single signal molecule and lacks the costimulatory signal, the first generation of CAR-T cells have a short survival time in vivo, and have weak killing power against tumor cells, and the therapeutic effect is not satisfactory. In order to fully simulate the dual-signal model of T lymphocyte activation in human body, enhance the ability of first-generation CAR molecules to activate T cells, and start a second-generation CAR.
  • the second-generation CAR mainly adds a co-stimulation in the intracellular domain.
  • co-stimulatory ligands that have been reported so far are mainly concentrated on antigen-presenting cells that specifically bind to co-stimulatory molecules on T cells, including CD7, B7-1 (CD80), B7-2 (CD86), PD-L1.
  • One CAR signal domain has only a single signal molecule ⁇ chain (first generation CAR-T), and the other has been added at the same time.
  • the ⁇ chain and co-stimulatory molecule CD28 (second generation CAR-T) the in vitro culture and detection results showed that the second generation CAR-T cells containing CD28 signal chain showed significant advantages in terms of proliferation and cytokine secretion levels in vitro. .
  • the two kinds of cells were simultaneously input into the patient, and the number of cells was periodically detected. The results showed that the proliferation rate and survival time of the second generation CAR-T cells were superior to those of the first generation CAR-T cells (SavoldoB, RamosCA, LiuE, eta1.CD28 costimulation).
  • the third generation of CAR-T integrates two or more costimulatory molecules on the first generation. Different combinations of costimulatory signals may affect the function and efficacy of CAR-T cells. Studies have shown that not all The third generation of CAR-T is better than the second generation. The third generation of CAR-T has been used in clinical trials of mantle cell lymphoma (MCL) and follicular non-Hodgkin's lymphoma (NHL), but it has not shown superior clinical outcomes than the second generation. At present, the second-generation CAR-T technology is more successful in the clinical application of acute leukemia.
  • MCL mantle cell lymphoma
  • NHS follicular non-Hodgkin's lymphoma
  • the second-generation CAR-T technology is more successful in the clinical application of acute leukemia.
  • One co-stimulatory molecule is mainly CD28 or CD137 (4-1BB), and the other costimulatory molecule is CD3zeta. It can be seen that the structure design
  • the complement system has important biological effects in the innate immune response and adaptive humoral immune response.
  • the intrinsic component of complement in the body exists in the form of a precursor enzyme in physiological conditions, and when activated, it can produce active molecular fragments, such as C3a, C4a, and C5a, thereby exerting a biological immunological effect.
  • the attacking membrane complex is finally synthesized, attacking microorganisms or other target cells, thereby causing dissolution and rupture of the target cells.
  • These complement lysates exert immunological functions primarily by binding to the complement receptor (CR): C3aR, C5aR. There is a close mutual regulation relationship between complement and CD4+ T cells.
  • the C3aR complement pathway promotes Th17 differentiation and inhibits the production of regulatory T cells.
  • the use of C3aR in combination with other costimulatory molecules for the construction of chimeric antigen receptors is even less predictive of the effect of the chimeric antigen receptor after construction.
  • one of the objects of the present invention is to provide a chimeric antigen receptor comprising a C3aR intracellular domain cell
  • a second object of the present invention is to provide a lentiviral vector comprising a chimeric antigen receptor of a C3aR intracellular domain
  • a third aspect of the present invention provides a use of the chimeric antigen receptor comprising a C3aR intracellular domain cell or the lentiviral vector in the preparation of an immune cell comprising a chimeric antigen receptor of a C3aR intracellular domain cell;
  • a fourth object of the present invention is to provide an immune cell which expresses a chimeric antigen receptor comprising a C3aR intracellular domain cell, which is prepared by using the chimeric antigen receptor comprising a C3aR intracellular domain cell or the lentiviral vector. ;
  • a fifth object of the present invention is to provide a chimeric antigen receptor comprising a C3aR intracellular domain or a lentiviral vector for the preparation of a chimeric antigen receptor comprising a C3aR intracellular domain for targeting tumor cells Application in .
  • the present invention achieves the above object by the following technical means:
  • the present invention provides a chimeric antigen receptor comprising an extracellular domain capable of binding an antigen, a transmembrane domain and at least one intracellular domain,
  • the intracellular domain is selected from the intracellular domain of the C3aR intracellular domain or the signal transduction domain in tandem with the C3aR intracellular domain.
  • intracellular domain refers to any oligopeptide or polypeptide known to function in a cell as a transmitting signal to cause activation or inhibition of a biological process.
  • the at least one intracellular domain refers to a C3aR intracellular domain, or an intracellular domain of other signaling regions such as CD3 ⁇ , CD28, 4-1BB, etc. in tandem with the C3aR intracellular domain.
  • the antigen may be a tumor antigen
  • the tumor antigen includes, for example, 5T4, ⁇ 5 ⁇ 1-integrin, 707-AP, AFP, ART-4, B7H4, BAGE, ⁇ -catenin/ m, Bcr-abl, MN/C IX antibody, CA125, CAMEL, CAP-1, CASP-8, CD4, CD19, CD20, CD22, CD25, CDC27/m, CD30, CD33, CD52, CD56, CD80, CDK4/ m, CEA, CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnTV, Gp100, HAGE, HER-2/new, HLA-A*0201-R170I, HPV-E7, HSP70-2M, HST-2, hTERT (or hTRT), iCE, IGF
  • the extracellular domain capable of binding an antigen refers to a single-chain variable fragment that binds to an antibody that targets the antigen.
  • the above CAR molecule may have only the C3aR intracellular domain as its intracellular domain, and may also comprise one or more (eg, 2 or 3) other cells than the C3aR intracellular domain.
  • Internal domain in addition to the C3aR intracellular domain, the intracellular domain further comprises a 4-1BB, CD3 sputum intracellular domain; further preferably, the C3aR intracellular domain is configurable at CD3 ⁇ The C-terminal side of the intracellular domain.
  • the intracellular domain is a 4-1BB intracellular domain, a CD3 intracellular domain, and a C3aR intracellular domain joined in sequence from the N-terminal side.
  • the chimeric antigen receptors of the invention also encompass the case where the intracellular domain comprises two or more intracellular domains joined in tandem; and, alternatively, the C3aR intracellular domain can be Configured on the N-terminal side of the intracellular domain of the chimeric antigen receptor.
  • the chimeric antigen receptor comprises, in sequence from the N-terminal side, a single-chain variable region of an anti-tumor antigen antibody as an extracellular domain, a transmembrane domain of CD28 molecule and a 4-1BB cell. Internal domain, CD3 intracellular domain, C3aR intracellular domain.
  • the C3aR intracellular domain contains a nucleotide sequence as shown in Sequence Listing 1.
  • the coding nucleic acid of the chimeric antigen receptor contains the sequence as described in Sequence Listing 1, but is not limited to this series, and should also include other C3aR encoding nucleic acids.
  • the intracellular domain of the signaling region in series with the C3aR intracellular domain is selected from one or more of CD3, CD28, 4-1BB.
  • the invention provides a lentiviral vector expressing a chimeric antigen receptor as described above.
  • the present invention provides a chimeric antigen receptor-expressing cell, wherein the chimeric antigen receptor according to the first aspect is introduced; preferably, the cell is a T cell or a cell population containing T cells .
  • the present invention provides a method of producing a chimeric antigen receptor-expressing cell according to the third aspect, which comprises the step of introducing a chimeric antigen receptor according to the first aspect into a cell; preferably, the cell It is a T cell or a cell population containing T cells.
  • the invention provides a chimeric antigen receptor according to the first aspect, or a lentiviral vector according to the second aspect, or a chimeric antigen receptor expressing cell according to the third aspect Use in the preparation of a medicament for treating tumors.
  • the tumor is a solid tumor or a hematoma.
  • the tumor is B-ALL.
  • the CAR of the present invention is characterized in that it comprises a C3aR intracellular domain as its intracellular domain.
  • the C3aR intracellular domain includes variants thereof having the same function.
  • variant refers to any variant comprising a substitution, deletion or addition of one or several to more amino acids, provided that the variant substantially retains the same function as the original sequence.
  • the chimeric antigen receptor of the invention can enhance the subpopulation of T17 cells, eliminate the immunosuppressive effect of regulating T cells, can significantly improve the in vitro killing efficiency of tumor target cells, and can significantly improve the killing effect of the second generation CAR T cells on tumors. Provide a new idea and choice for the field of CAR-T cell therapy.
  • Figure 1a is a schematic representation of a viral vector containing a combination of C3aR intracellular domains.
  • Figure 1b is a schematic representation of a viral vector that does not contain a combination of C3aR intracellular domains.
  • Figure 2 is a graph showing the in vitro killing effect of GFP T, CAR19 T and CAR19C3aR T cells on CD19-expressing NALM6-GL cells. The results showed that CAR19C3aR T is superior to GFP T and CAR19 T, and NALM6 indicates NALM6-GL cells.
  • Figure 3 is a graph showing the in vitro killing effect of GFP T, CAR19 T and CAR19C3aR T cells on Raji cells expressing CD19. The results show that CAR19C3aR T is superior to GFP T and CAR19 T.
  • FIG 4a and Figure 4b show the effect of GFP T, CAR19 T and CAR19C3aR T cells on T17 cell subsets (CD4+IL17A+) and regulatory T cell subsets (CD4+CD25+FoxP3+).
  • the results show that CAR19C3aR T can be significant Increase the subpopulation of T17 cells and eliminate immunosuppression of regulatory T cells. * P ⁇ 0.05.
  • Figure 5 is a graph showing the load of GFP T, CAR19 T and CAR19C3aR T cells on NALM6 tumor cells (CD19+) in NCG mice. The results show that CAR19C3aR T is superior to GFP T and CAR19 T. * P ⁇ 0.05.
  • Figure 6 is a BLI image showing the load and location of NALM6 cells in NCG mice.
  • Figure 7 is a graph showing the effect of GFP T, CAR19 T and CAR19C3aR T cells on the growth phase of NCG mice. The results showed that CAR19C3aR T significantly prolonged the growth phase of NCG mice compared with GFP T and CAR19 T. * P ⁇ 0.05.
  • the plasmid carrying the chimeric antigen receptor gene containing the C3aR intracellular domain of the present invention was prepared as follows:
  • Plasmid pUC57-CAR19 containing anti-CD19ScFv-4-1BB-CD3 ⁇ (CAR19) by gene synthesis, molecular cloning, etc. contains anti-CD19 monoclonal antibody ScFV, CD28 transmembrane region and 4-1BB, CD3 intracellular region , that is, CD19 ScFv-4-1BB-CD3 ⁇ .
  • lentiviruses expressing GFP (blank control), CAR19-GFP (control), CAR19C3aR-GFP, respectively, were obtained by using the CAR plasmid of the present invention prepared in Example 1 and the relevant control plasmid by lentiviral packaging.
  • the CAR-containing plasmid was uniformly described as a pWPXLd-CAR-GFP plasmid
  • the lentivirus overexpressing CAR was uniformly described as a CAR lentivirus.
  • the pWPXLd-CAR-GFP plasmids ie, CAR19, CAR19C3aR, respectively
  • the blank control plasmid pWPXLd-GFP were separately ligated with the lentiviral packaging helper plasmid pMD2.
  • G and psPAX2 were jointly transferred into 293T cells, and the reagents and dosages were as follows:
  • the collected virus is dispensed into a cryotube and stored frozen at -80 ° C until use.
  • T cells mononuclear cells in the blood were separated by Ficoll density gradient method, and red blood cells were lysed by erythrocyte lysate, and then T cells were sorted by MACS Pan-T magnetic beads;
  • the sorted T cells were diluted with medium (AIM-V medium + 5% FBS + penicillin 100 U / ml + streptomycin 0.1 mg / ml) to a cell concentration of 2.5 ⁇ 10 6 / ml for use;
  • T cells Stimulate T cells by magnetic beads coated with CD2, CD3, and CD28 antibodies (product source: German scorpio), that is, coated magnetic beads and T cells are mixed at a ratio of 1:2, and the final density of T cells should be 5. ⁇ 10 6 /ml/cm2. After mixing, the cells were incubated at 37 ° C in a 5% CO 2 incubator for 48 hours.
  • CAR T cell expansion The CAR T cell density was maintained at about 1 ⁇ 10 6 /ml, and a half-quantity change was performed every 2-3 days. After two weeks, the number of CAR T cells can be amplified by a factor of 100. GFP-positive cells were successfully transfected cells, and the proportion of GFP-positive cells was detected by flow cytometry, ie, the ratio of two CAR T cells (CAR19-GFP, CAR19C3aR-GFP, respectively) or blank control T cells (GFP-T) was obtained. . The effect on the subpopulation of Th17 cells (CD4+IL17A+) and the regulation of T cell subsets (CD4+CD25+FoxP3+) was examined.
  • Th17 cell subset detection method 1. Prepare effector cells (GFP-T, CAR19-GFP or CAR19C3aR-GFP T cells), add surface antibody 5ul CD4-PERCP, mix, protect from light, incubate for 30min. 2. Add 100 ul of Breaker A and incubate for 15 min at room temperature. 3. Add 3 ml PBS + 0.1% NaN3 + 5% FBS.4.300 g, centrifuge for 5 min, remove the supernatant, add buffer B, mix, add 5ul IL-17A APC-Cy7, incubate for 20min. 5. Add 3 ml PBS + 0.1% NaN3 + 5% FBS. 300 g, centrifuge for 5 min, remove the supernatant, and resuspend 400-500 ul PBE on the machine.
  • the GFP T (blank control), CAR19-GFP T (control), CAR19C3aR-GFP T cells prepared in Example 3 were mixed with 5 ⁇ 10 4 tumor cells in different proportions, and added to 96-well U-shaped plates, each set Three duplicate wells were set up and the tumor cells were added as the positive control. After centrifugation at 250g for 5min, they were placed in a 37°C 5% CO2 incubator for 24h. The GFP T, CAR19-GFP T and CAR19C3aR-GFP T cells were compared in vitro. When the blood tumor recognizes the killing function, the tumor cells use NALM6-GL, Raji two leukemia or lymphoma cell lines.
  • CFSE/PI double staining cytotoxicity assay method to evaluate the quantitative evaluation of killing efficiency: 1. Prepare effector cells (GFP T (blank control), CAR19-GFP T (control), CAR19C3aR-GFP T cells) and target cells, count, put CAR GFP% of T cells were calibrated with the same batch of WT cells, and the GFP% of each group was similar in size; T cells were diluted 8 ⁇ 10 6 /ml with 1640+10% FBS+1% P/S medium. 2.
  • target cells Nam6 cells, Raji cells
  • resuspend in 1ml of 1640 medium add 5umol CSFE, incubate in the dark at 37 °C for 20min, add 10ml medium to terminate for 5min, centrifuge, remove the supernatant, target cells Dilute to 5x10 5 /ml. 3.
  • D-dilutes the T cells and pre-adds 100 ul of fresh medium to the V-bottom 96-well plate with a lance. The first row is not added, then the first row is added with 100 ul of T cells, and the second row is added with 100 ul of T cells.
  • Example 5 CAR19C3aR T cells recognize killing tumors in vivo
  • mice were passed through the tail vein with 7 NCG (NOD/SCID IL2rg -/- ) immunodeficiency In mice; on day 2 and day 8 after NALM6 cell transplantation (day 0 of tumor cell transplantation), 5 ⁇ 10 6 T cells (four groups: GFP T, CAR19 T, CAR19C3aR T, injection in each group) Six mice were injected intravenously into NSI immunodeficient mice that had been transplanted with NALM6 cells.
  • C3aR second-generation CAR T cells

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Abstract

L'invention concerne un récepteur antigénique chimérique comprenant un domaine intracellulaire C3aR, un vecteur lentiviral, une cellule d'expression et un médicament. Le récepteur antigénique chimérique comprend un domaine extracellulaire capable de se lier à un antigène, un domaine transmembranaire et au moins un domaine intracellulaire. Le domaine intracellulaire est choisi parmi un domaine intracellulaire C3aR et un domaine intracellulaire d'un domaine de signalisation en série avec le domaine intracellulaire C3aR. Le récepteur antigénique chimérique peut augmenter le sous-ensemble cellulaire T17, peut éliminer l'immunosuppression de lymphocytes T régulateurs, et peut augmenter l'efficacité de destruction de cellules cibles tumorales in vitro.
PCT/CN2018/075857 2018-01-02 2018-02-08 Récepteur antigénique chimérique comprenant un domaine intracellulaire c3ar, vecteur lentiviral, cellule d'expression et médicament Ceased WO2019134213A1 (fr)

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CN201810001909.7A CN107903326B (zh) 2018-01-02 2018-01-02 包含C3aR胞内结构域的嵌合抗原受体、慢病毒载体、表达细胞及药物

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CN110358793A (zh) * 2019-05-30 2019-10-22 南京艾德免疫治疗研究院有限公司 一种用于car-t制备的慢病毒载体制备方法
EP4574838A1 (fr) 2023-12-21 2025-06-25 Vilnius University Récepteur antigénique chimérique (car) à recrutement amélioré de partenaires de signalisation

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