CN110573530A - 结合cd33、nkg2d和cd16的蛋白 - Google Patents
结合cd33、nkg2d和cd16的蛋白 Download PDFInfo
- Publication number
- CN110573530A CN110573530A CN201880026148.9A CN201880026148A CN110573530A CN 110573530 A CN110573530 A CN 110573530A CN 201880026148 A CN201880026148 A CN 201880026148A CN 110573530 A CN110573530 A CN 110573530A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2851—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/283—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
-
- 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
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/804—Blood cells [leukemia, lymphoma]
-
- 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
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- 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
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/524—CH2 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/75—Agonist effect on antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Display Devices Of Pinball Game Machines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762461145P | 2017-02-20 | 2017-02-20 | |
| US62/461,145 | 2017-02-20 | ||
| PCT/US2018/018768 WO2018152516A1 (en) | 2017-02-20 | 2018-02-20 | Proteins binding cd33, nkg2d and cd16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110573530A true CN110573530A (zh) | 2019-12-13 |
Family
ID=63169992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880026148.9A Pending CN110573530A (zh) | 2017-02-20 | 2018-02-20 | 结合cd33、nkg2d和cd16的蛋白 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US20210130471A1 (enExample) |
| EP (1) | EP3583131A4 (enExample) |
| JP (3) | JP2020510646A (enExample) |
| KR (1) | KR20190120775A (enExample) |
| CN (1) | CN110573530A (enExample) |
| AU (1) | AU2018220734B2 (enExample) |
| BR (1) | BR112019017277A2 (enExample) |
| CA (1) | CA3054078A1 (enExample) |
| IL (1) | IL268790A (enExample) |
| MA (1) | MA47508A (enExample) |
| SG (1) | SG11201907638QA (enExample) |
| WO (1) | WO2018152516A1 (enExample) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021136227A1 (zh) * | 2019-12-31 | 2021-07-08 | 周易 | Ch3 结构域改造诱导形成的异源二聚体及其制备方法和应用 |
| CN115197330A (zh) * | 2021-04-14 | 2022-10-18 | 广州百暨基因科技有限公司 | 同时靶向cll1和cd33的嵌合抗原受体及其应用 |
| WO2023201966A1 (zh) * | 2022-04-20 | 2023-10-26 | 南京融捷康生物科技有限公司 | 一种包含IgG类Fc区变体的抗体及其用途 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110944651A (zh) | 2017-02-08 | 2020-03-31 | 蜻蜓疗法股份有限公司 | 用于自然杀伤细胞激活的多特异性结合蛋白及其治疗癌症的治疗性用途 |
| EP4273258A3 (en) | 2017-02-20 | 2024-01-17 | Dragonfly Therapeutics, Inc. | Proteins binding her2, nkg2d and cd16 |
| CA3090244A1 (en) | 2018-02-08 | 2019-08-15 | Dragonfly Therapeutics, Inc. | Antibody variable domains targeting the nkg2d receptor |
| MX2020008333A (es) | 2018-02-08 | 2020-09-21 | Dragonfly Therapeutics Inc | Terapia de combinacion del cancer que incluye proteinas de union multiespecificas que activan a las celulas asesinas naturales. |
| CN112119093A (zh) | 2018-02-20 | 2020-12-22 | 蜻蜓治疗公司 | 结合cd33、nkg2d和cd16的多特异性结合蛋白和使用方法 |
| EA202091977A1 (ru) * | 2018-05-28 | 2021-02-09 | Драгонфлай Терапьютикс, Инк. | Мультиспецифические связывающие белки, которые связывают cd33, nkg2d и cd16, и способы применения |
| CN113164570B (zh) | 2018-08-08 | 2024-05-14 | 蜻蜓疗法股份有限公司 | 结合nkg2d、cd16和肿瘤相关抗原的蛋白质 |
| EA202091888A1 (ru) | 2018-08-08 | 2020-10-23 | Драгонфлай Терапьютикс, Инк. | Вариабельные домены антител, нацеленные на рецептор nkg2d |
| CA3108427A1 (en) | 2018-08-08 | 2020-02-13 | Dragonfly Therapeutics, Inc. | Multi-specific binding proteins that bind bcma, nkg2d and cd16, and methods of use |
| SG11202103832SA (en) * | 2018-11-07 | 2021-05-28 | Crispr Therapeutics Ag | Anti-cd33 immune cell cancer therapy |
| AU2021268340A1 (en) | 2020-05-06 | 2022-12-08 | Dragonfly Therapeutics, Inc. | Proteins binding NKG2D, CD16 and CLEC12A |
| EP4175656A4 (en) * | 2020-07-03 | 2024-10-16 | The Trustees of Columbia University in the City of New York | POLYFUNCTIONAL ORTHOGONAL PROTEIN CHIMERA |
| EP4301774A4 (en) | 2021-03-03 | 2025-08-13 | Dragonfly Therapeutics Inc | METHODS OF TREATING CANCER USING MULTI-SPECIFIC BINDING PROTEINS THAT BIND TO NKG2D, CD16, AND A TUMOR-ASSOCIATED ANTIGEN |
| WO2024040195A1 (en) | 2022-08-17 | 2024-02-22 | Capstan Therapeutics, Inc. | Conditioning for in vivo immune cell engineering |
| EP4719352A1 (en) | 2023-05-31 | 2026-04-08 | Capstan Therapeutics, Inc. | Lipid nanoparticle formulations and compositions |
| US20250127728A1 (en) | 2023-10-05 | 2025-04-24 | Capstan Therapeutics, Inc. | Constrained Ionizable Cationic Lipids and Lipid Nanoparticles |
| WO2025076113A1 (en) | 2023-10-05 | 2025-04-10 | Capstan Therapeutics, Inc. | Ionizable cationic lipids with conserved spacing and lipid nanoparticles |
| US20250302763A1 (en) | 2024-02-22 | 2025-10-02 | Capstan Therapeutics, Inc. | Immune engineering amplification |
| WO2025217452A1 (en) | 2024-04-11 | 2025-10-16 | Capstan Therapeutics, Inc. | Constrained ionizable cationic lipids and lipid nanoparticles |
| WO2025217454A2 (en) | 2024-04-11 | 2025-10-16 | Capstan Therapeutics, Inc. | Ionizable cationic lipids and lipid nanoparticles |
| WO2025245271A1 (en) * | 2024-05-21 | 2025-11-27 | Dragonfly Therapeutics, Inc. | Anti-nkg2d antibodies and methods of use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040038339A1 (en) * | 2000-03-24 | 2004-02-26 | Peter Kufer | Multifunctional polypeptides comprising a binding site to an epitope of the nkg2d receptor complex |
| CN101589062A (zh) * | 2006-09-20 | 2009-11-25 | 安姆根有限公司 | 与胰高血糖素受体抗体相关的组合物和方法 |
| US20160122432A1 (en) * | 2013-06-11 | 2016-05-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-her2 single domain antibodies, polypeptides comprising thereof and their use for treating cancer |
| EP3029137A1 (en) * | 2014-12-06 | 2016-06-08 | GEMoaB Monoclonals GmbH | Genetic modified pluri- or multipotent stem cells and uses thereof |
| WO2016201304A1 (en) * | 2015-06-10 | 2016-12-15 | Nantkwest, Inc. | Modified nk-92 cells for treating cancer |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009077483A1 (en) * | 2007-12-14 | 2009-06-25 | Novo Nordisk A/S | Antibodies against human nkg2d and uses thereof |
| TW201109438A (en) * | 2009-07-29 | 2011-03-16 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
| DE102009045006A1 (de) * | 2009-09-25 | 2011-04-14 | Technische Universität Dresden | Anti-CD33 Antikörper und ihre Anwendung zum Immunotargeting bei der Behandlung von CD33-assoziierten Erkrankungen |
| EP2332994A1 (en) * | 2009-12-09 | 2011-06-15 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Trispecific therapeutics against acute myeloid leukaemia |
| EP3587448B1 (en) * | 2013-03-15 | 2021-05-19 | Xencor, Inc. | Heterodimeric proteins |
| EP4050026A1 (en) * | 2014-04-01 | 2022-08-31 | Adimab, LLC | Method of obtaining or identifying one or more common light chains for use in preparing a multispecific antibody |
| US10647768B2 (en) * | 2014-05-29 | 2020-05-12 | Macrogenics, Inc. | Multi-chain polypeptide-containing tri-specific binding molecules |
| EP2985294A1 (en) * | 2014-08-14 | 2016-02-17 | Deutsches Krebsforschungszentrum | Recombinant antibody molecule and its use for target cell restricted T cell activation |
| EP3180359A1 (en) * | 2014-08-14 | 2017-06-21 | Novartis AG | Treatment of cancer using gfr alpha-4 chimeric antigen receptor |
| ES2688035T3 (es) * | 2014-08-29 | 2018-10-30 | Gemoab Monoclonals Gmbh | Receptor de antígeno universal que expresa células inmunes para direccionamiento de antígenos múltiples diversos, procedimiento para fabricación del mismo y utilización del mismo para tratamiento de cáncer, infecciones y enfermedades autoinmunes |
| CN107530424A (zh) * | 2015-02-20 | 2018-01-02 | 俄亥俄州国家创新基金会 | 针对nkg2d和肿瘤相关抗原的二价抗体 |
| JP6840682B2 (ja) * | 2015-06-23 | 2021-03-10 | イナート・ファルマ・ソシエテ・アノニムInnate Pharma Pharma S.A. | 多重特異的抗原結合タンパク質 |
| US11291721B2 (en) * | 2016-03-21 | 2022-04-05 | Marengo Therapeutics, Inc. | Multispecific and multifunctional molecules and uses thereof |
| CN110944651A (zh) * | 2017-02-08 | 2020-03-31 | 蜻蜓疗法股份有限公司 | 用于自然杀伤细胞激活的多特异性结合蛋白及其治疗癌症的治疗性用途 |
-
2018
- 2018-02-20 AU AU2018220734A patent/AU2018220734B2/en not_active Expired - Fee Related
- 2018-02-20 KR KR1020197026921A patent/KR20190120775A/ko not_active Ceased
- 2018-02-20 US US16/486,921 patent/US20210130471A1/en not_active Abandoned
- 2018-02-20 SG SG11201907638QA patent/SG11201907638QA/en unknown
- 2018-02-20 BR BR112019017277-7A patent/BR112019017277A2/pt not_active IP Right Cessation
- 2018-02-20 CN CN201880026148.9A patent/CN110573530A/zh active Pending
- 2018-02-20 JP JP2019545316A patent/JP2020510646A/ja active Pending
- 2018-02-20 EP EP18753685.9A patent/EP3583131A4/en active Pending
- 2018-02-20 WO PCT/US2018/018768 patent/WO2018152516A1/en not_active Ceased
- 2018-02-20 CA CA3054078A patent/CA3054078A1/en active Pending
- 2018-02-20 MA MA047508A patent/MA47508A/fr unknown
-
2019
- 2019-08-19 IL IL26879019A patent/IL268790A/en unknown
-
2023
- 2023-01-05 JP JP2023000416A patent/JP2023052214A/ja active Pending
-
2025
- 2025-01-07 JP JP2025002125A patent/JP2025061059A/ja active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040038339A1 (en) * | 2000-03-24 | 2004-02-26 | Peter Kufer | Multifunctional polypeptides comprising a binding site to an epitope of the nkg2d receptor complex |
| CN101589062A (zh) * | 2006-09-20 | 2009-11-25 | 安姆根有限公司 | 与胰高血糖素受体抗体相关的组合物和方法 |
| US20160122432A1 (en) * | 2013-06-11 | 2016-05-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-her2 single domain antibodies, polypeptides comprising thereof and their use for treating cancer |
| EP3029137A1 (en) * | 2014-12-06 | 2016-06-08 | GEMoaB Monoclonals GmbH | Genetic modified pluri- or multipotent stem cells and uses thereof |
| WO2016201304A1 (en) * | 2015-06-10 | 2016-12-15 | Nantkwest, Inc. | Modified nk-92 cells for treating cancer |
Non-Patent Citations (3)
| Title |
|---|
| MICHELLE K GLEASON等: "CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets", 《BLOOD》 * |
| 罗晶等: "《医学免疫学与病原生物学》", 31 January 2013, 上海科学技术出版社 * |
| 马建岗等: "《基因工程学原理(第3版)》", 28 February 2013, 西安交通大学出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021136227A1 (zh) * | 2019-12-31 | 2021-07-08 | 周易 | Ch3 结构域改造诱导形成的异源二聚体及其制备方法和应用 |
| CN115197330A (zh) * | 2021-04-14 | 2022-10-18 | 广州百暨基因科技有限公司 | 同时靶向cll1和cd33的嵌合抗原受体及其应用 |
| WO2023201966A1 (zh) * | 2022-04-20 | 2023-10-26 | 南京融捷康生物科技有限公司 | 一种包含IgG类Fc区变体的抗体及其用途 |
| CN116948029A (zh) * | 2022-04-20 | 2023-10-27 | 南京融捷康生物科技有限公司 | 一种包含IgG类Fc区变体的抗体及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL268790A (en) | 2019-10-31 |
| JP2025061059A (ja) | 2025-04-10 |
| KR20190120775A (ko) | 2019-10-24 |
| EP3583131A1 (en) | 2019-12-25 |
| WO2018152516A1 (en) | 2018-08-23 |
| RU2019129174A3 (enExample) | 2021-07-02 |
| MA47508A (fr) | 2021-03-17 |
| RU2019129174A (ru) | 2021-03-22 |
| US20210130471A1 (en) | 2021-05-06 |
| SG11201907638QA (en) | 2019-09-27 |
| AU2018220734A1 (en) | 2019-09-12 |
| AU2018220734B2 (en) | 2025-03-06 |
| CA3054078A1 (en) | 2018-08-23 |
| BR112019017277A2 (pt) | 2020-04-14 |
| JP2020510646A (ja) | 2020-04-09 |
| EP3583131A4 (en) | 2021-03-17 |
| JP2023052214A (ja) | 2023-04-11 |
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Application publication date: 20191213 |