BR112021026580A2 - Conjugado anticorpo - fármaco, intermediário do mesmo, método de preparação e aplicação do mesmo - Google Patents
Conjugado anticorpo - fármaco, intermediário do mesmo, método de preparação e aplicação do mesmoInfo
- Publication number
- BR112021026580A2 BR112021026580A2 BR112021026580A BR112021026580A BR112021026580A2 BR 112021026580 A2 BR112021026580 A2 BR 112021026580A2 BR 112021026580 A BR112021026580 A BR 112021026580A BR 112021026580 A BR112021026580 A BR 112021026580A BR 112021026580 A2 BR112021026580 A2 BR 112021026580A2
- Authority
- BR
- Brazil
- Prior art keywords
- adc
- application
- drug
- preparation
- same
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- 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
- 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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
-
- 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
- C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910577909 | 2019-06-28 | ||
| PCT/CN2020/094767 WO2020259258A1 (zh) | 2019-06-28 | 2020-06-05 | 一种抗体偶联药物、其中间体、制备方法及应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BR112021026580A2 true BR112021026580A2 (pt) | 2022-05-03 |
Family
ID=74059658
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BR112021026580A BR112021026580A2 (pt) | 2019-06-28 | 2020-06-05 | Conjugado anticorpo - fármaco, intermediário do mesmo, método de preparação e aplicação do mesmo |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20220233708A1 (https=) |
| EP (1) | EP3991754A4 (https=) |
| JP (1) | JP7407845B2 (https=) |
| KR (1) | KR20220025861A (https=) |
| CN (1) | CN113766933B (https=) |
| AU (1) | AU2020301289B2 (https=) |
| BR (1) | BR112021026580A2 (https=) |
| CA (1) | CA3144790A1 (https=) |
| WO (1) | WO2020259258A1 (https=) |
Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20230054458A1 (en) * | 2019-12-12 | 2023-02-23 | Jiangsu Hengrui Medicine Co., Ltd. | Anti-claudin antibody-drug conjugate and pharmaceutical use thereof |
| AU2021289927A1 (en) * | 2020-06-08 | 2023-01-19 | Systimmune, Inc. | Camptothecin drug having high-stability hydrophilic connecting unit and conjugate thereof |
| WO2021252708A1 (en) * | 2020-06-11 | 2021-12-16 | President And Fellows Of Harvard College | Stabilized trioxacarcin antibody drug conjugates and uses thereof |
| JP7753372B2 (ja) * | 2020-10-12 | 2025-10-14 | シーチュアン バイリ ファーム シーオー. エルティーディー | 重水素化カンプトテシン系誘導体及びその抗体薬物複合体 |
| EP4257153B1 (en) * | 2020-12-04 | 2025-11-12 | Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. | Antibody-drug conjugate, and intermediate thereof, preparation method therefor, and application thereof |
| CN116583526B (zh) * | 2020-12-11 | 2025-09-26 | 微境生物医药科技(上海)有限公司 | 新型喜树碱衍生物、含其的组合物和其用途 |
| JP7564958B2 (ja) * | 2020-12-18 | 2024-10-09 | シャンハイ フダン-チャンジャン バイオ-ファーマシューティカル カンパニー リミテッド | B7-h3を標的とする抗体薬物複合体、その製造方法と使用 |
| EP4265275A4 (en) * | 2020-12-18 | 2024-03-20 | Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. | ANTIBODY-DRUG CONJUGATE TARGETING TROP2, PREPARATION METHOD AND USE THEREOF |
| CN114805377A (zh) * | 2021-01-29 | 2022-07-29 | 明慧医药(杭州)有限公司 | 适用于抗体-药物偶联物的毒素分子 |
| WO2022171115A1 (zh) * | 2021-02-09 | 2022-08-18 | 微境生物医药科技(上海)有限公司 | 用于adc制备的喜树碱衍生物 |
| CN116897149A (zh) * | 2021-03-30 | 2023-10-17 | 上海复旦张江生物医药股份有限公司 | 一种连接基药物偶联物的制备方法及其中间体 |
| CN116867789B (zh) * | 2021-03-31 | 2025-06-24 | 上海复旦张江生物医药股份有限公司 | 一种伊喜替康衍生物的制备方法及其中间体 |
| CN115385926B (zh) * | 2021-05-24 | 2025-06-03 | 上海复旦张江生物医药股份有限公司 | 一种连接基药物偶联物的制备方法及其中间体 |
| IL309457A (en) * | 2021-06-17 | 2024-02-01 | Minghui Pharmaceutical Hangzhou Ltd | Compound against tumors and its use |
| CN117715913A (zh) * | 2021-07-19 | 2024-03-15 | 芝诺管理公司 | 免疫缀合物和方法 |
| US11806405B1 (en) | 2021-07-19 | 2023-11-07 | Zeno Management, Inc. | Immunoconjugates and methods |
| TW202320858A (zh) | 2021-07-19 | 2023-06-01 | 美商薩諾管理公司 | 免疫接合物及方法 |
| WO2023006084A1 (zh) | 2021-07-30 | 2023-02-02 | 上海复旦张江生物医药股份有限公司 | 一种抗dll3抗体及其制备方法、其药物偶联物和应用 |
| MX2024003277A (es) * | 2021-09-15 | 2024-04-04 | Daiichi Sankyo Co Ltd | Conjugado de anticuerpo-farmaco para usarse en metodos de tratamiento del cancer resistente a la quimioterapia. |
| KR20240082348A (ko) * | 2021-09-27 | 2024-06-10 | 에보포인트 바이오사이언시스 컴퍼니 리미티드 | 항체, 이의 항체-약물 접합체 및 이의 용도 |
| CN118401258A (zh) * | 2021-12-09 | 2024-07-26 | 昆山新蕴达生物科技有限公司 | 一种亲和力改善的抗体-药物偶联物、其制备方法及应用 |
| CN119317447A (zh) | 2022-04-12 | 2025-01-14 | 米纳瓦生物技术公司 | 抗可变muc1*抗体及其用途 |
| WO2024008102A1 (en) * | 2022-07-05 | 2024-01-11 | Wuxi Xdc (Shanghai) Co., Ltd. | Linker for conjugation |
| EP4558506A1 (en) * | 2022-07-22 | 2025-05-28 | NJ Bio, Inc. | Hexacyclic topoisomerase inhibitors having cytotoxic activity on cancer cells |
| EP4562051A1 (en) * | 2022-07-26 | 2025-06-04 | Immunome, Inc. | Immunoconjugates and methods |
| JP2025524970A (ja) * | 2022-07-27 | 2025-08-01 | 明慧医藥(杭州)有限公司 | 抗体-薬物コンジュゲートおよびその使用 |
| CN117510515A (zh) * | 2022-07-28 | 2024-02-06 | 明慧医药(杭州)有限公司 | 适用于抗体-药物偶联物的毒素分子 |
| WO2024091437A1 (en) * | 2022-10-25 | 2024-05-02 | Merck Sharp & Dohme Llc | Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof |
| EP4623936A1 (en) * | 2022-11-22 | 2025-10-01 | Keymed Biosciences (Chengdu) Co., Ltd. | Fused ring compound, conjugate thereof and use thereof |
| KR20250111373A (ko) * | 2022-11-25 | 2025-07-22 | 밍훼이 파마슈티컬 (항저우) 리미티드 | 항종양 화합물 및 이의 응용 |
| WO2024114667A1 (zh) * | 2022-11-30 | 2024-06-06 | 正大天晴药业集团股份有限公司 | 抗cldn18.2抗体药物偶联物及其药物组合物和用途 |
| CN116178386B (zh) | 2022-12-30 | 2025-09-09 | 上海复旦张江生物医药股份有限公司 | 一种连接基药物偶联物的制备方法及其中间体 |
| CN116217655B (zh) * | 2022-12-30 | 2025-09-23 | 上海复旦张江生物医药股份有限公司 | 一种连接基药物偶联物的中间体的制备方法 |
| CN116217654B (zh) * | 2022-12-30 | 2025-09-26 | 上海复旦张江生物医药股份有限公司 | 一种连接基药物偶联物的制备方法及其中间体 |
| JPWO2024214685A1 (https=) | 2023-04-10 | 2024-10-17 | ||
| WO2025021152A1 (zh) * | 2023-07-26 | 2025-01-30 | 上海医药集团股份有限公司 | 喜树碱类小分子及其抗体药物偶联物、制备方法和应用 |
| WO2025049270A1 (en) * | 2023-08-25 | 2025-03-06 | Macrogenics, Inc. | B7-h3 antibody-drug conjugates |
| WO2025106278A1 (en) | 2023-11-17 | 2025-05-22 | Mersana Therapeutics, Inc. | Treatment of cancer using b7-h4-targeted antibody-drug conjugates |
| WO2025238587A1 (en) | 2024-05-16 | 2025-11-20 | Daiichi Sankyo Company, Limited | Combination of anti-b7-h3 antibody-drug conjugate and androgen receptor signaling inhibitor |
| CN120617538B (zh) * | 2025-07-21 | 2026-04-03 | 南京滴力生物科技有限公司 | 一种用于治疗肿瘤的抗体药物偶联物 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8802820B2 (en) * | 2004-11-12 | 2014-08-12 | Xencor, Inc. | Fc variants with altered binding to FcRn |
| EP2240495B1 (en) * | 2008-02-01 | 2015-07-15 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| NZ610239A (en) * | 2008-04-30 | 2014-11-28 | Immunogen Inc | Cross-linkers and their uses |
| ES2647317T3 (es) * | 2008-11-03 | 2017-12-20 | Syntarga B.V. | Análogos de CC-1065 y sus conjugados |
| WO2013173337A2 (en) * | 2012-05-15 | 2013-11-21 | Seattle Genetics, Inc. | Self-stabilizing linker conjugates |
| ES2773710T3 (es) * | 2012-10-11 | 2020-07-14 | Daiichi Sankyo Co Ltd | Enlazadores para conjugados de anticuerpo - fármaco |
| IL310627B2 (en) * | 2014-01-31 | 2026-04-01 | Daiichi Sankyo Co Ltd | Anti-HER2 antibody-drug conjugates, compositions containing them and uses thereof |
| JP2017114763A (ja) | 2014-03-26 | 2017-06-29 | 第一三共株式会社 | 抗cd98抗体−薬物コンジュゲート |
| EP3209334A2 (en) * | 2014-10-20 | 2017-08-30 | Igenica Biotherapeutics, Inc. | Novel antibody-drug conjugates and related compounds, compositions, and methods of use |
| EP4321523A3 (en) * | 2017-08-10 | 2024-04-24 | Sumitomo Pharma Co., Ltd. | Hemiasterlin derivatives and antibody-drug conjugates including same |
| WO2019034176A1 (zh) * | 2017-08-18 | 2019-02-21 | 四川百利药业有限责任公司 | 一种喜树碱-抗体偶联物 |
| WO2019034177A1 (zh) * | 2017-08-18 | 2019-02-21 | 四川百利药业有限责任公司 | 具有两种不同药物的抗体药物偶联物 |
| CN109200291B (zh) * | 2018-10-24 | 2021-06-08 | 中国医学科学院医药生物技术研究所 | 一种靶向于egfr的抗体偶联药物及其制备方法和其用途 |
-
2020
- 2020-06-05 CN CN202080030918.4A patent/CN113766933B/zh active Active
- 2020-06-05 AU AU2020301289A patent/AU2020301289B2/en active Active
- 2020-06-05 BR BR112021026580A patent/BR112021026580A2/pt unknown
- 2020-06-05 CA CA3144790A patent/CA3144790A1/en active Pending
- 2020-06-05 US US17/622,500 patent/US20220233708A1/en active Pending
- 2020-06-05 JP JP2021578171A patent/JP7407845B2/ja active Active
- 2020-06-05 EP EP20833007.6A patent/EP3991754A4/en active Pending
- 2020-06-05 KR KR1020227002873A patent/KR20220025861A/ko active Pending
- 2020-06-05 WO PCT/CN2020/094767 patent/WO2020259258A1/zh not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP3991754A1 (en) | 2022-05-04 |
| CN113766933B (zh) | 2024-09-06 |
| JP7407845B2 (ja) | 2024-01-04 |
| KR20220025861A (ko) | 2022-03-03 |
| JP2022542222A (ja) | 2022-09-30 |
| US20220233708A1 (en) | 2022-07-28 |
| CA3144790A1 (en) | 2020-12-30 |
| EP3991754A4 (en) | 2023-05-17 |
| AU2020301289B2 (en) | 2024-11-07 |
| CN113766933A (zh) | 2021-12-07 |
| WO2020259258A1 (zh) | 2020-12-30 |
| AU2020301289A1 (en) | 2022-02-24 |
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