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MX2018004305A - Peptido derivado de mphosph1 y vacuna que lo incluye. - Google Patents

Peptido derivado de mphosph1 y vacuna que lo incluye.

Info

Publication number
MX2018004305A
MX2018004305A MX2018004305A MX2018004305A MX2018004305A MX 2018004305 A MX2018004305 A MX 2018004305A MX 2018004305 A MX2018004305 A MX 2018004305A MX 2018004305 A MX2018004305 A MX 2018004305A MX 2018004305 A MX2018004305 A MX 2018004305A
Authority
MX
Mexico
Prior art keywords
peptide
ctl
provides
present
antigen presenting
Prior art date
Application number
MX2018004305A
Other languages
English (en)
Other versions
MX393692B (es
Inventor
YAMASHITA Sachiko
HIKICHI Tetsuro
Original Assignee
Oncotherapy Science Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oncotherapy Science Inc filed Critical Oncotherapy Science Inc
Publication of MX2018004305A publication Critical patent/MX2018004305A/es
Publication of MX393692B publication Critical patent/MX393692B/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001148—Regulators of development
    • A61K39/001149—Cell cycle regulated proteins, e.g. cyclin, CDC, CDK or INK-CCR
    • 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
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • 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
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/998—Proteins not provided for elsewhere
    • 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
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system 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
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system cells
    • C12N2502/1114—T 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
    • C12N2510/00—Genetically modified cells

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Wood Science & Technology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Virology (AREA)
  • Urology & Nephrology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Oncology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Physics & Mathematics (AREA)
  • Toxicology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Gastroenterology & Hepatology (AREA)

Abstract

La presente invención provee un péptido de epítopo derivado de MPHOSPH1 que exhibe inducibilidad de linfocitos T citotóxicos. La presente invención también provee: un polinucleótido que codifica dicho péptido; una célula presentadora de antígeno que presenta dicho péptido; un linfocito T citotóxico (CTL) que hace blanco en dicho péptido; y un método para inducir la célula presentadora de antígeno o el CTL. Además, la presente invención provee una composición y una composición farmacéutica que incluyen como ingrediente activo el péptido, el polinucleótido, la célula presentadora de antígeno o el CTL. Además, la presente invención provee un método que utiliza el péptido, el polinucleótido, la célula presentadora de antígeno, el CTL o la composición farmacéutica para tratar y/o prevenir el cáncer y/o prevenir la recurrencia postoperatoria del cáncer. También se provee un método para inducir una respuesta inmunitaria contra el cáncer.
MX2018004305A 2015-10-08 2016-10-06 Peptido derivado de mphosph1 y vacuna que lo incluye. MX393692B (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015200220 2015-10-08
PCT/JP2016/079716 WO2017061522A1 (ja) 2015-10-08 2016-10-06 Ｍｐｈｏｓｐｈ１由来ペプチドおよびそれを含むワクチン

Publications (2)

Publication Number Publication Date
MX2018004305A true MX2018004305A (es) 2018-05-01
MX393692B MX393692B (es) 2025-03-24

Family

ID=58487779

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2018004305A MX393692B (es) 2015-10-08 2016-10-06 Peptido derivado de mphosph1 y vacuna que lo incluye.

Country Status (15)

Country Link
US (1) US10793599B2 (es)
EP (1) EP3360885A4 (es)
JP (1) JP6857909B2 (es)
KR (1) KR20180055892A (es)
CN (2) CN108699111B (es)
AU (1) AU2016334778B2 (es)
BR (1) BR112018006894A2 (es)
CA (1) CA3000808A1 (es)
HK (1) HK1251928A1 (es)
IL (1) IL258107B (es)
MX (1) MX393692B (es)
RU (1) RU2731099C2 (es)
SG (2) SG11201802286PA (es)
TW (2) TWI761316B (es)
WO (1) WO2017061522A1 (es)

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3738395B2 (ja) 1991-08-26 2006-01-25 エピミューン，インコーポレイティド Ｈｌａ−制限型ｂ型肝炎ウィルスのｃｔｌエピトープ
FR2766205B1 (fr) 1997-07-16 2002-08-30 Inst Nat Sante Rech Med Nouveau procede de sensibilisation de cellules presentatrices d'antigene et nouveaux moyens pour la mise en oeuvre du procede
US6291663B1 (en) 1999-03-03 2001-09-18 Board Of Trustees Of The University Of Arkansas TADG-12: a novel transmembrane serine protease overexpressed in a ovarian carcinoma
JP2003518364A (ja) 1999-05-28 2003-06-10 ルードヴィッヒ インスティテュート フォー キャンサー リサーチ 乳癌、胃癌および前立腺癌関連抗原ならびにそれらの使用
EP1911461B1 (en) 2000-10-19 2011-12-07 Epimmune Inc. HLA class I and II binding peptides and their uses
US7919467B2 (en) 2000-12-04 2011-04-05 Immunotope, Inc. Cytotoxic T-lymphocyte-inducing immunogens for prevention, treatment, and diagnosis of cancer
US20040142325A1 (en) 2001-09-14 2004-07-22 Liat Mintz Methods and systems for annotating biomolecular sequences
US20040002455A1 (en) 2002-01-29 2004-01-01 Aventis Pasteur, Ltd. Targeted immunogens
US20060024692A1 (en) 2002-09-30 2006-02-02 Oncotherapy Science, Inc. Method for diagnosing non-small cell lung cancers
TW200413725A (en) 2002-09-30 2004-08-01 Oncotherapy Science Inc Method for diagnosing non-small cell lung cancers
JP5109131B2 (ja) 2005-02-10 2012-12-26 オンコセラピー・サイエンス株式会社 膀胱癌を診断する方法
CA2625403A1 (en) 2005-10-17 2007-04-26 Institute For System Biology Tissue-and serum-derived glycoproteins and methods of their use
JP2010501827A (ja) 2006-08-25 2010-01-21 オンコセラピー・サイエンス株式会社 Ｍｐｈｏｓｐｈ１とｐｒｃ１の結合を阻害する作用物質のスクリーニング方法
SG175566A1 (en) 2006-10-17 2011-11-28 Oncotherapy Science Inc Peptide vaccines for cancers expressing mphosph1 or depdc1 polypeptides
DK2742133T3 (en) 2011-08-12 2017-12-04 Oncotherapy Science Inc MPHOSPH1 PEPTIDES AND VACCINES CONTAINING THESE
EP2872531A4 (en) 2012-07-10 2016-04-06 Oncotherapy Science Inc LY6K EPITOPE PEPTIDES FOR TH1 CELLS AND VACCINES CONTAINING SAME

Also Published As

Publication number Publication date
BR112018006894A2 (pt) 2018-10-16
TWI761316B (zh) 2022-04-21
RU2018116623A3 (es) 2020-01-28
SG11201802286PA (en) 2018-04-27
JPWO2017061522A1 (ja) 2018-07-26
TWI784388B (zh) 2022-11-21
AU2016334778A1 (en) 2018-04-26
RU2018116623A (ru) 2019-11-08
IL258107B (en) 2022-08-01
WO2017061522A1 (ja) 2017-04-13
AU2016334778B2 (en) 2020-12-17
SG10201913531PA (en) 2020-03-30
TW201726705A (zh) 2017-08-01
RU2731099C2 (ru) 2020-08-28
CN116199738A (zh) 2023-06-02
US20180362581A1 (en) 2018-12-20
CN108699111B (zh) 2022-11-01
KR20180055892A (ko) 2018-05-25
IL258107A (en) 2018-05-31
US10793599B2 (en) 2020-10-06
CN108699111A (zh) 2018-10-23
HK1251928A1 (en) 2019-05-03
EP3360885A1 (en) 2018-08-15
CA3000808A1 (en) 2017-04-13
MX393692B (es) 2025-03-24
EP3360885A4 (en) 2019-04-24
JP6857909B2 (ja) 2021-04-14
TW202124412A (zh) 2021-07-01

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