PE20241357A1 - Anticuerpo biespecifico anti-cldn4/anti-cd137 - Google Patents
Anticuerpo biespecifico anti-cldn4/anti-cd137Info
- Publication number
- PE20241357A1 PE20241357A1 PE2023002906A PE2023002906A PE20241357A1 PE 20241357 A1 PE20241357 A1 PE 20241357A1 PE 2023002906 A PE2023002906 A PE 2023002906A PE 2023002906 A PE2023002906 A PE 2023002906A PE 20241357 A1 PE20241357 A1 PE 20241357A1
- Authority
- PE
- Peru
- Prior art keywords
- variable region
- cldn4
- antibody
- polynucleotide
- bispecific antibody
- Prior art date
Links
Classifications
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
-
- 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
-
- 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
- C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- 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
-
- 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
- C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
-
- 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
- C12N15/80—Vectors or expression systems specially adapted for eukaryotic hosts for fungi
-
- 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
- C12N15/80—Vectors or expression systems specially adapted for eukaryotic hosts for fungi
- C12N15/81—Vectors or expression systems specially adapted for eukaryotic hosts for fungi for yeasts
-
- 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
-
- 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
-
- 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
- C07K16/2809—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 the T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- 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
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
-
- 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
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- 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
- C07K2317/90—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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Mycology (AREA)
- Cell Biology (AREA)
- Epidemiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2021072429 | 2021-04-22 | ||
| PCT/JP2022/018350 WO2022224997A1 (ja) | 2021-04-22 | 2022-04-21 | 抗ｃｌｄｎ４－抗ｃｄ１３７二重特異性抗体 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PE20241357A1 true PE20241357A1 (es) | 2024-07-03 |
Family
ID=83722348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PE2023002906A PE20241357A1 (es) | 2021-04-22 | 2022-04-21 | Anticuerpo biespecifico anti-cldn4/anti-cd137 |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US12227586B2 (https=) |
| EP (1) | EP4327823A4 (https=) |
| JP (2) | JP7365654B2 (https=) |
| KR (1) | KR20230171465A (https=) |
| CN (1) | CN117222672A (https=) |
| AR (1) | AR125398A1 (https=) |
| AU (1) | AU2022262542A1 (https=) |
| CA (1) | CA3217637A1 (https=) |
| CL (1) | CL2023003100A1 (https=) |
| CO (1) | CO2023015630A2 (https=) |
| CR (1) | CR20230490A (https=) |
| DO (2) | DOP2023000230A (https=) |
| EC (1) | ECSP23087918A (https=) |
| IL (1) | IL307744A (https=) |
| JO (1) | JOP20230261A1 (https=) |
| MX (1) | MX2023012432A (https=) |
| PE (1) | PE20241357A1 (https=) |
| SA (1) | SA523451235B1 (https=) |
| TW (1) | TW202309083A (https=) |
| WO (1) | WO2022224997A1 (https=) |
| ZA (1) | ZA202310292B (https=) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4524248A1 (en) | 2022-05-12 | 2025-03-19 | Astellas Pharma, Inc. | Anti-taa/anti-cd3 multispecific antibody |
| EP4606384A1 (en) * | 2022-10-19 | 2025-08-27 | Astellas Pharma, Inc. | Use of anti-cldn4-anti-cd137 bispecific antibody combined with pd-1 signal inhibitor for cancer treatment |
| WO2026042803A1 (ja) * | 2024-08-21 | 2026-02-26 | アステラス製薬株式会社 | がん治療におけるプラチナ系薬剤との組み合わせによる抗ｃｌｄｎ４－抗ｃｄ１３７二重特異性抗体の使用 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
| US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
| IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
| US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
| US7288638B2 (en) | 2003-10-10 | 2007-10-30 | Bristol-Myers Squibb Company | Fully human antibodies against human 4-1BB |
| AU2006301492B2 (en) | 2005-10-11 | 2011-06-09 | Amgen Research (Munich) Gmbh | Compositions comprising cross-species-specific antibodies and uses thereof |
| KR100999844B1 (ko) | 2006-07-19 | 2010-12-13 | 네오벌브 테크놀러지스 인크 | 고효율 방열 모듈을 구비한 고출력 ｌｅｄ 조명장치 |
| WO2008114733A1 (ja) | 2007-03-16 | 2008-09-25 | Kyowa Hakko Kirin Co., Ltd. | 抗Claudin-4抗体 |
| EP2346994B1 (en) | 2008-09-30 | 2022-02-16 | Ablexis, LLC | Knock-in mice for the production of chimeric antibodies |
| JP2014193853A (ja) | 2013-03-01 | 2014-10-09 | Japan Health Sciences Foundation | 抗体、フラグメント、医薬組成物、分子及び腫瘍マーカー |
| CN118440206A (zh) | 2014-04-07 | 2024-08-06 | 中外制药株式会社 | 免疫活化抗原结合分子 |
| KR20170138574A (ko) | 2015-05-04 | 2017-12-15 | 피어이스 파마슈티컬즈 게엠베하 | 항암 융합 폴리펩타이드 |
| WO2019048040A1 (en) | 2017-09-06 | 2019-03-14 | Ganymed Pharmaceuticals Gmbh | ANTIBODIES USEFUL IN THE DIAGNOSIS OF CANCER |
| US20210054076A1 (en) | 2018-01-05 | 2021-02-25 | Chugai Seiyaku Kabushiki Kaisha | Cytotoxicity-inducing therapeutic agent |
| AU2019235900B2 (en) * | 2018-03-14 | 2025-12-11 | Dana-Farber Cancer Institute, Inc. | Engineered cells, T cell immune modulating antibodies and methods for using the same |
| BR112021000282A2 (pt) | 2018-07-12 | 2021-04-06 | F-Star Beta Limited | Moléculas de anticorpo que se ligam a cd137 e ox40 |
-
2022
- 2022-04-21 KR KR1020237039211A patent/KR20230171465A/ko active Pending
- 2022-04-21 CA CA3217637A patent/CA3217637A1/en active Pending
- 2022-04-21 TW TW111115193A patent/TW202309083A/zh unknown
- 2022-04-21 WO PCT/JP2022/018350 patent/WO2022224997A1/ja not_active Ceased
- 2022-04-21 PE PE2023002906A patent/PE20241357A1/es unknown
- 2022-04-21 AU AU2022262542A patent/AU2022262542A1/en active Pending
- 2022-04-21 AR ARP220101032A patent/AR125398A1/es unknown
- 2022-04-21 EP EP22791768.9A patent/EP4327823A4/en active Pending
- 2022-04-21 CN CN202280029125.XA patent/CN117222672A/zh active Pending
- 2022-04-21 JP JP2023515503A patent/JP7365654B2/ja active Active
- 2022-04-21 CR CR20230490A patent/CR20230490A/es unknown
- 2022-04-21 US US18/556,606 patent/US12227586B2/en active Active
- 2022-04-21 MX MX2023012432A patent/MX2023012432A/es unknown
- 2022-04-21 IL IL307744A patent/IL307744A/en unknown
-
2023
- 2023-09-29 JP JP2023169033A patent/JP7822576B2/ja active Active
- 2023-10-18 CL CL2023003100A patent/CL2023003100A1/es unknown
- 2023-10-19 JO JOJO/P/2023/0261A patent/JOP20230261A1/ar unknown
- 2023-10-19 DO DO2023000230A patent/DOP2023000230A/es unknown
- 2023-10-22 SA SA523451235A patent/SA523451235B1/ar unknown
- 2023-11-03 ZA ZA2023/10292A patent/ZA202310292B/en unknown
- 2023-11-20 CO CONC2023/0015630A patent/CO2023015630A2/es unknown
- 2023-11-21 EC ECSENADI202387918A patent/ECSP23087918A/es unknown
-
2025
- 2025-01-14 US US19/020,859 patent/US20250154272A1/en active Pending
- 2025-09-09 DO DO2025000223A patent/DOP2025000223A/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CR20230490A (es) | 2023-11-16 |
| JPWO2022224997A1 (https=) | 2022-10-27 |
| IL307744A (en) | 2023-12-01 |
| CL2023003100A1 (es) | 2024-03-22 |
| TW202309083A (zh) | 2023-03-01 |
| JP7365654B2 (ja) | 2023-10-20 |
| US20240209108A1 (en) | 2024-06-27 |
| EP4327823A1 (en) | 2024-02-28 |
| US12227586B2 (en) | 2025-02-18 |
| ZA202310292B (en) | 2025-03-26 |
| US20250154272A1 (en) | 2025-05-15 |
| BR112023021950A2 (pt) | 2023-12-19 |
| KR20230171465A (ko) | 2023-12-20 |
| JP2023182689A (ja) | 2023-12-26 |
| SA523451235B1 (ar) | 2024-11-25 |
| AU2022262542A1 (en) | 2023-11-02 |
| JP7822576B2 (ja) | 2026-03-03 |
| MX2023012432A (es) | 2023-11-01 |
| CN117222672A (zh) | 2023-12-12 |
| DOP2023000230A (es) | 2023-12-15 |
| WO2022224997A1 (ja) | 2022-10-27 |
| JOP20230261A1 (ar) | 2023-10-19 |
| CA3217637A1 (en) | 2022-10-27 |
| AR125398A1 (es) | 2023-07-12 |
| ECSP23087918A (es) | 2023-12-29 |
| CO2023015630A2 (es) | 2023-11-30 |
| EP4327823A4 (en) | 2025-04-30 |
| DOP2025000223A (es) | 2025-10-15 |
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