WO2022244876A1 - 抗腫瘍剤 - Google Patents

抗腫瘍剤 Download PDF

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WO2022244876A1
WO2022244876A1 PCT/JP2022/020990 JP2022020990W WO2022244876A1 WO 2022244876 A1 WO2022244876 A1 WO 2022244876A1 JP 2022020990 W JP2022020990 W JP 2022020990W WO 2022244876 A1 WO2022244876 A1 WO 2022244876A1
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peptide
cell receptor
cell
cxorf48
cells
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PCT/JP2022/020990
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English (en)
French (fr)
Japanese (ja)
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麻衣子 松下
豊 服部
裕 河上
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慶應義塾
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • A61K40/32—T-cell receptors [TCR]
    • 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
    • A61K40/4267—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor

Definitions

  • the present invention relates to antitumor agents.
  • T cell receptor (TCR) gene transfer T cell therapy (both TCR-T) has attracted attention as a treatment for tumors. It is a therapeutic method based on the principle that when T cells transfected with a TCR gene consisting of ⁇ and ⁇ chains recognize an antigen, the T cells are activated and exhibit an antitumor effect (Immunology. 2017, 152 (3) : 357-371.; Science. 2018, 359(6382): 1361-1365.).
  • CXorf48 is one of cancer testis (CT) antigens.
  • CT cancer testis
  • CXorf48 has been expressed in many tumor cells such as leukemia, multiple myeloma, prostate cancer, and pancreatic cancer, but it has been clarified that in normal cells, strong expression is observed only in spermatogonia.
  • CXorf48 an HLA-A*24:02-restricted CXorf48 epitope recognized by T cells has been identified (see Patent Document 1).
  • HLA-A24*02 is an HLA molecule possessed by 60 to 70% of Japanese, and CXorf48 is highly expressed in cancer stem cells (Non-Patent Document 3), and is expressed in various cancers. , are considered promising targets in the treatment of tumors.
  • An object of the present invention is to provide a novel antitumor agent.
  • One embodiment of the present invention is a first peptide comprising the following sequence.
  • This first peptide may have 10 or less amino acid mutations and may be a peptide that recognizes CXorf48 or a portion thereof by a T-cell receptor constituting the second peptide described below.
  • Another embodiment of the present invention is a second peptide comprising the following sequence.
  • This second peptide may have 10 or less amino acid mutations and may be a peptide that recognizes CXorf48 or a portion thereof by the T cell receptor constituting the first peptide.
  • a further embodiment of the invention is a T-cell receptor comprising a first peptide and a second peptide.
  • the first peptide and/or the second peptide may have up to 10 amino acid mutations and the T cell receptor may recognize CXorf48 or a portion thereof.
  • a further embodiment of the present invention is a cell expressing the above T cell receptor.
  • This cell may be a T cell.
  • a further embodiment of the present invention is a DNA encoding the first peptide and/or the second peptide.
  • a further embodiment of the present invention is an expression vector that expresses the peptide described in the first peptide and/or the second peptide.
  • a further embodiment of the present invention contains, as an active ingredient, at least one selected from the group consisting of any of the above peptides, any of the above T cell receptors, any of the above DNAs, and any of the above cells.
  • the composition may be a pharmaceutical composition or an antineoplastic agent.
  • the antineoplastic agent may be an antineoplastic agent for prostate cancer. It may be co-administered with a DNA demethylating agent.
  • the T cell receptor consisting of a peptide having 80% or more homology with SEQ ID NO: 1 and a peptide having 80% or more homology with SEQ ID NO:2 comprises HLA-A24*02 and CXorf48 or a portion thereof.
  • a further embodiment of the present invention is a T cell receptor consisting of a peptide having 80% or more homology with SEQ ID NO: 1 and a peptide having 80% or more homology with SEQ ID NO:2 pulsed CXorf48 or a portion thereof
  • a method for assaying a T-cell receptor comprising the step of determining whether it recognizes the cells that have been labeled.
  • FIG. 1 shows (A) the base sequence inserted into the EcoRI site of the expression vector pMIG and (B) the amino acid sequence encoded by this base sequence in the examples of the present invention.
  • the EcoRI recognition sequence used for insertion is shown in lower case, the nucleotide sequences encoding the ⁇ and ⁇ chains of the T-cell receptor are shown in bold, and the nucleotide sequence encoding the T2A sequence is underlined.
  • the amino acid sequences of the T-cell receptor ⁇ and ⁇ chains are shown in bold, and the amino acid sequence of the T2A sequence is underlined.
  • FIG. 1 shows (A) the base sequence inserted into the EcoRI site of the expression vector pMIG and (B) the amino acid sequence encoded by this base sequence in the examples of the present invention.
  • the EcoRI recognition sequence used for insertion is shown in lower case, the nucleotide sequences encoding the ⁇ and ⁇ chains of the T-cell receptor are shown in bold, and the nucleo
  • FIG. 2 is a schematic diagram of CXorf48-specific dextramers used in the examples of the present invention.
  • A Percentage of cells actually expressing the T cell receptor among the cells transfected with the T cell receptor expression vector obtained in the Examples of the present invention
  • B T cell receptor expression vector [Fig. 10] A diagram showing the ratio of cells to which CXorf48-specific dextramer bound among cells into which was introduced.
  • FIG. 10 shows the result that T cell receptor-expressing CD8 + Jurkat cells recognized CXorf48 peptide-pulsed B cells and IL-2 secreted into the supernatant was detected in Examples of the present invention.
  • FIG. 10 is a diagram showing the results of the experiment.
  • T cells expressing this T cell receptor can be used for T cell receptor gene transfer T cell therapy against tumors expressing CXorf48, and HLA-A * 2402-positive tumors expressing CXorf48. It is useful as an antitumor drug against cells.
  • the first peptide and the second peptide are, in addition to the peptides of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, extra amino acid sequences, as long as the T cell receptor constituted by them recognizes CXorf48 or a part thereof. may have Although the length of the extra amino acid sequence is not particularly limited, it is preferably 100 or less amino acid residues, more preferably 50 or less amino acid residues, and 20 or less amino acid residues.
  • the first peptide and the second peptide may have mutations in their sequences as long as the T cell receptor constituted by them recognizes CXorf48 or a portion thereof.
  • the number of mutated amino acids is not particularly limited, but is preferably 10 or less, more preferably 5 or less, even more preferably 4 or less, even more preferably 3 or less, and 2 It is more preferably less than or equal to 1, more preferably 1.
  • This mutation may be an insertion mutation, a deletion mutation, or a substitution mutation.
  • the partial sequence of CXorf48 is not particularly limited, but preferably contains or consists of DYGMIDESI (SEQ ID NO:5).
  • T cells expressing this T cell receptor can be produced by introducing into T cells DNAs that express the first peptide and the second peptide, respectively.
  • compositions, pharmaceutical compositions, or antineoplastic agents disclosed herein comprise a first peptide or a second peptide, DNA or RNA encoding the first peptide or the second peptide, the first peptide and T cells expressing a T cell receptor comprising the second peptide, or a T cell receptor comprising the first peptide and the second peptide, but comprising the first peptide and the second peptide It is preferred to contain T-cells expressing T-cell receptors comprising:
  • Tumors to be treated and prevented with this antitumor drug are not limited as long as they express CXorf48, and examples include hepatocellular carcinoma, colon cancer, gastric cancer, non-small cell lung cancer, and breast cancer. , malignant melanoma, glioblastoma, lung cancer, pancreatic cancer, bladder cancer, prostate cancer, leukemia, lymphoma, and multiple myeloma, with prostate cancer being particularly preferred.
  • the primary targets for treatment and prophylaxis are human patients with such tumors, but also non-human vertebrate animals with tumors.
  • CXorf48 In adult animals, the expression of CXorf48 is observed only in spermatogonia, so it is highly specific to tumor cells, and CXorf48 is very effective as a therapeutic target cancer antigen. Also, in myeloid leukemia and prostate cancer, it is known to be highly expressed in cancer stem cells, so this antitumor drug has a high ability to attack cancer stem cells.
  • a T cell expressing a T cell receptor containing the first peptide and the second peptide introduces DNA or RNA encoding the first peptide and the second peptide into the T cell, and intracellularly produces the first peptide. It can be produced by expressing a peptide and a second peptide. These peptides may be encoded by one DNA or RNA, or may be encoded by separate DNAs or RNAs. DNA or RNA sequences encoding the first and second peptides can be designed by conventional methods.
  • a vector for expressing the first peptide and the second peptide in cells is not particularly limited, and can be selected by those skilled in the art using well-known techniques.
  • Construction of the first peptide and the second peptide can also be performed using well-known gene recombination techniques.
  • one expression vector may be used to express the first peptide and the second peptide, or each expression vector may be used to express the first peptide and the second peptide.
  • the T2A sequence may be used, for example, as shown in FIG. 1A.
  • the DNA encoding the first peptide and the DNA encoding the second peptide may have the following sequences, but the bases encoding the amino acid sequence of the first peptide and the amino acid sequence of the second peptide, respectively It is not limited to these as long as it is an array.
  • the T cells into which DNA or RNA is introduced are not particularly limited, but are preferably cells of the patient himself/herself.
  • mature T cells blood stem cells, or pluripotent stem cells may be used.
  • DNA or RNA may be introduced to express the T cell receptor. is preferably differentiated into mature T cells.
  • Mature T cells may be CD8 positive cytotoxic T cells (CTL) or CD4 positive helper T cells and the like.
  • intradermal administration subcutaneous administration, intravenous administration, lymph node administration, intraperitoneal administration, etc. are possible, and although not particularly limited, intravenous administration is preferable.
  • intratumoral administration is preferred as it can directly attack cells expressing the antigen.
  • the T cells obtained in this manner may be used as they are after isolation, or may be further cultured in the presence of an interleukin such as IL-2, an antigen-presenting cell, and a peptide consisting of sequence 1. may be used. This manipulation can enhance T cell cytotoxicity.
  • an interleukin such as IL-2
  • an antigen-presenting cell such as IL-2
  • a peptide consisting of sequence 1. may be used. This manipulation can enhance T cell cytotoxicity.
  • a DNA demethylating agent When administering this antitumor drug to cancer patients, a DNA demethylating agent may be co-administered.
  • a DNA demethylating agent enhances the expression level of CXorf48 in tumor cells, but does not affect the expression level of CXorf48 in normal cells. Conceivable.
  • DNA demethylating agents include, but are not limited to, 5-azacytidine and 5-aza-2'-deoxycytidine.
  • co-administration refers to administering the other while one effect is occurring, and may be a combination drug, but may be administered independently, or , administration may be simultaneous, but may be administered at different times.
  • DNAs are introduced into cells to express the first mutant peptide and the second mutant peptide in the same cell to form a mutant T cell receptor in the cell. At this time, one of them may be the original first peptide or the second peptide that has not been mutated.
  • the method of examination is not particularly limited, but any method that allows a person skilled in the art to see the results and determine whether it can be used for the production of an antitumor agent. For example, determine whether the mutant T-cell receptor binds to a complex of HLA-A24*02 and CXorf48 or a portion thereof, or whether it recognizes cells pulsed with CXorf48 or a portion thereof. By doing so, we can know whether it can be used for T cell receptor gene transfer T cell therapy.
  • Mutant T-cell receptors determined to be useful for T-cell receptor gene-transferred T-cell therapy can then be transferred to the next stage, such as clinical trials.
  • the partial sequence of CXorf48 is not particularly limited, but preferably contains or consists of DYGMIDESI (SEQ ID NO:5).
  • T-cell receptors for use in T-cell receptor gene transfer T-cell therapy it is also possible to screen T-cell receptors for use in T-cell receptor gene transfer T-cell therapy. That is, in a T-cell receptor library containing a plurality of mutant T-cell receptors, each mutant T-cell receptor is assayed for its applicability to T-cell receptor transgenic T-cell therapy as described herein. Mutant T-cell receptors for use in T-cell receptor transgenic T-cell therapy can be identified from among T-cell receptor libraries.
  • T cell receptor expression vector The base sequence shown in Fig. 1A was inserted into the EcoRI site of the expression vector pMIG to prepare a T cell receptor expression vector.
  • This nucleotide sequence encodes the peptide shown in FIG. 1B, and consists of ⁇ chain, T2A sequence, and ⁇ chain linked from the N-terminal side.
  • the T2A sequence is cleaved, resulting in ⁇ and ⁇ chains that combine to form the T cell receptor.
  • This T-cell receptor expression vector is introduced into PLAT-A cells and packaged into retroviruses, and the cell supernatant containing the retroviruses is transferred to Jurkat 76.7 cells (from Osaka University, Dr. Fumihiro Fujiki and Dr. Soyoko Morimoto).
  • the retrovirus was added to the culture medium of the donor), and the retrovirus was introduced into Jurkat 76.7 cells to obtain T cell receptor-expressing CD8 + Jurkat cells.
  • the Jurkat 76.7 cell is a Jurkat cell line lacking the expression of the endogenous T-cell receptor ⁇ -chain and highly expressing CD8.
  • a CXorf48-specific dextramer was allowed to bind to the T cell receptor-expressing CD8 + Jurkat cells prepared in (1) and analyzed by a flow cytometer (FACS). Specifically, T cell receptor-expressing CD8 + Jurkat cells were suspended in 5% FBS-containing PBS, and phycoerythrin (PE)-labeled CXorf48-specific dextramer or HIV-specific dextramer was added for 15 minutes at room temperature. reacted.
  • FACS flow cytometer
  • allophycocyanin (APC)-labeled anti-CD8 antibody was added and allowed to react on ice for 20 minutes, then the cells were washed with 5% FBS-containing PBS, resuspended in 5% FBS-containing PBS, and subjected to FACS. Fluorescence intensity from PE and APC was measured.
  • T cell receptor expression was observed in about 16.7% of the cells (Figure 3A), and CXorf48-specific dextramer bound to about 6.61% of the cells ( Figure 3A). 3B). No binding was detected when an HIV-specific dextramer was used as a control.
  • the T cell receptor of the present disclosure can specifically bind to CXorf48 on cells.
  • T-cell receptor-expressing CD8 + Jurkat cells recognized cells pulsed with a CXorf48 peptide (DYGMIDESI: SEQ ID NO: 5) consisting of a portion of CXorf48. and release IL-2, an inflammatory cytokine.
  • CXorf48 peptide DYGMIDESI: SEQ ID NO: 5
  • CXorf48 peptide 4 ⁇ g/mL was added to HLA-A*2402-positive human B cell line C1R-A24 and left at 37° C. for 1 hour to pulse the cells with CXorf48 peptide. After incubating these cells with Phorbol-12-myristate-13-acetate (PMA)-supplemented T-cell receptor-expressing CD8 + Jurkat cells (denoted as J767-TCR1 in FIG.
  • PMA Phorbol-12-myristate-13-acetate
  • the T-cell receptor The amount of IL-2 in the culture supernatant secreted by the expressing CD8 + Jurkat cells upon recognition of C1R-A24 was measured by ELISA using an anti-IL-2 antibody (denoted as C1R-A24+CXorf48peptide in FIG. 4). ).
  • experiments were performed using DMSO or HIV peptide (RYLRDQQLL: SEQ ID NO: 6) instead of CXorf48 peptide (denoted as C1R-A24+DMSO and C1R-A24+HIVpeptide in FIG. 4).
  • CD8 + Jurkat cells transfected with a GFP expression vector without the TCR gene (denoted as J767empty in FIG. 4) were used.
  • IL-2 was detected in the supernatant only when T cell receptor-expressing CD8 + Jurkat cells and CXorf48 peptide-pulsed C1R-A24 were combined, as shown in FIG. It was confirmed that expressing CD8 + Jurkat cells recognize CXorf48 peptide-bound B cells.
  • T-cell receptor-expressing CD8 + Jurkat cells express the T-cell receptor of the present disclosure, thereby enabling them to recognize CXorf48 peptide-binding B cells. Accordingly, T-cell receptor-expressing T-cells that express the T-cell receptors of the present disclosure are useful for T-cell receptor-expressing T-cell therapy.
  • DAC 5-aza-2'-deoxycytidine
  • DAC 5-aza-2'-deoxycytidine
  • a demethylating agent was added to the culture medium of prostate cancer cell lines LNCaP, DU145, and PC3 cells at a final concentration of 200 nM, and cultured for 48 hours.
  • the expression of the CXorf48 gene was examined by RT-PCR (indicated by DAC+ in FIG. 5).
  • DAC- in FIG. 5 As a control, the expression of the CXorf48 gene was examined in cells similarly cultured in a medium without DAC (indicated by DAC- in FIG. 5).
  • the leukemia cell line K562 was used as a positive control.
  • the expression of the GAPDH gene was examined at the same time.
  • the primer sequences used for PCR are as follows.
  • CXorf48-F forward: 5-gttgtgcctcgccatctttatg-3' (SEQ ID NO: 7)
  • GAPDH-F forward: 5-tgaacgggaagctcactgg-3' (SEQ ID NO: 9)
  • GAPDH-R reverse: 5-tccaccaccctgttgctgta-3' (SEQ ID NO: 10)
  • the present invention has made it possible to provide a novel antitumor agent.

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WO2024163292A1 (en) * 2023-01-30 2024-08-08 Board Of Regents, The University Of Texas System T-cell receptors targeting her2 and methods of use thereof

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WO2020082130A1 (en) * 2018-10-25 2020-04-30 The Council Of The Queensland Institute Of Medical Research T-cell receptors and uses thereof
WO2020172332A1 (en) * 2019-02-20 2020-08-27 Fred Hutchinson Cancer Research Center Binding proteins specific for ras neoantigens and uses thereof

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