JP7770760B2 - ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用 - Google Patents

ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用

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Publication number
JP7770760B2
JP7770760B2 JP2020143359A JP2020143359A JP7770760B2 JP 7770760 B2 JP7770760 B2 JP 7770760B2 JP 2020143359 A JP2020143359 A JP 2020143359A JP 2020143359 A JP2020143359 A JP 2020143359A JP 7770760 B2 JP7770760 B2 JP 7770760B2
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Japan
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independently
cancer
antibody
seq
nos
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JP2020143359A
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Japanese (ja)
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JP2021063058A (ja
JP2021063058A5 (https=
Inventor
パーク,ユン-ヒ
ヨン ソン,ホ
ミン リュー,ヒュン
ミン キム,スン
ユエル ベク,ジュ
ヘ オー,ジ
ハン,ナラ
レ キム,ヒョン
ウン パーク,キュン
ジョン リ,ヒュン
ヨン リ,ジュ
ヒュク カン,デ
ヤン,ヨン-ジェ
ヨウ,ジ-ナ
ズ キム,ヨン
スン リ,チャン
チェ,ジェイウク
ジュン,ジンウォン
キム,ジュヒ
リ,ボラ
ソン,デヘ
スン,ビュンジェ
イェオム,ドンフン
エオム,ジェヒュン
ホン,ヨンギュン
アン,ジンヒュン
リ,ヤンスン
パーク,キュンジン
ユ,ジソン
パーク,ミンジ
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Ligachem Biosciences Inc
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Ligachem Biosciences Inc
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Priority to JP2023135580A priority Critical patent/JP7570474B2/ja
Publication of JP2021063058A5 publication Critical patent/JP2021063058A5/ja
Priority to JP2025135500A priority patent/JP2025186244A/ja
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6835Medicinal 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
    • A61K47/6849Medicinal 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 receptor, a cell surface antigen or a cell surface determinant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6835Medicinal 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
    • A61K47/6851Medicinal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/68Medicinal 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
    • A61K47/6889Conjugates 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [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

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
JP2020143359A 2019-09-04 2020-08-27 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用 Active JP7770760B2 (ja)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2023135580A JP7570474B2 (ja) 2019-09-04 2023-08-23 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用
JP2025135500A JP2025186244A (ja) 2019-09-04 2025-08-15 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020190109807A KR20210028544A (ko) 2019-09-04 2019-09-04 인간 ror1에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도
KR10-2019-0109807 2019-09-04

Related Child Applications (2)

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JP2023135580A Division JP7570474B2 (ja) 2019-09-04 2023-08-23 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用
JP2025135500A Division JP2025186244A (ja) 2019-09-04 2025-08-15 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用

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JP2021063058A JP2021063058A (ja) 2021-04-22
JP2021063058A5 JP2021063058A5 (https=) 2023-08-31
JP7770760B2 true JP7770760B2 (ja) 2025-11-17

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JP2020143359A Active JP7770760B2 (ja) 2019-09-04 2020-08-27 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用
JP2023135580A Active JP7570474B2 (ja) 2019-09-04 2023-08-23 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用
JP2025135500A Pending JP2025186244A (ja) 2019-09-04 2025-08-15 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用

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JP2023135580A Active JP7570474B2 (ja) 2019-09-04 2023-08-23 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用
JP2025135500A Pending JP2025186244A (ja) 2019-09-04 2025-08-15 ヒトror1に対する抗体を含む抗体-薬物コンジュゲートおよびその使用

Country Status (12)

Country Link
US (2) US11707533B2 (https=)
EP (2) EP4025257A4 (https=)
JP (3) JP7770760B2 (https=)
KR (1) KR20210028544A (https=)
CN (2) CN113521300B (https=)
AU (2) AU2020343888A1 (https=)
BR (1) BR112022003589A2 (https=)
CA (1) CA3153069A1 (https=)
IL (2) IL314603A (https=)
MX (1) MX2022002592A (https=)
TW (2) TW202122115A (https=)
WO (1) WO2021044208A1 (https=)

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HRP20240795T1 (hr) 2015-11-25 2024-09-13 Ligachem Biosciences Inc. Konjugati koji se sastoje od samozapaljujućih skupina i postupci povezani s njima
MX2019011655A (es) 2017-03-29 2019-12-19 Legochem Biosciences Inc Profarmaco de dimero de pirrolobenzodiazepina y compuesto conjugado ligando-conector de este.
JP7459063B2 (ja) 2018-05-09 2024-04-01 レゴケム バイオサイエンシズ, インク. 抗-cd19抗体薬物複合体に関連する組成物および方法
KR20210028544A (ko) 2019-09-04 2021-03-12 주식회사 레고켐 바이오사이언스 인간 ror1에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도
KR20220158181A (ko) * 2021-05-21 2022-11-30 주식회사 레고켐 바이오사이언스 Ror1 및 b7-h3에 결합하는 항체-약물 접합체 및 그 용도
CN115626949B (zh) * 2021-07-14 2026-04-14 南京科默生物医药有限公司 一种bet蛋白靶向降解化合物及其制备方法和用途
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
CN118574845A (zh) * 2022-01-29 2024-08-30 杭州中美华东制药有限公司 一种靶向ror1的抗体或其抗原结合片段及其应用
KR20250008730A (ko) * 2022-03-09 2025-01-15 산유 바이오파마슈티컬스 씨오., 엘티디. Ror1-표적화 결합 분자 및 이의 용도
WO2023217227A1 (zh) 2022-05-12 2023-11-16 先声再明医药有限公司 喜树碱类衍生物及配体-药物偶联物
WO2024008112A1 (en) * 2022-07-06 2024-01-11 Nona Biosciences (Suzhou) Co., Ltd. Anti-ror1 antibodies
CN119816519A (zh) * 2022-07-15 2025-04-11 Abl生物公司 抗ror1抗体、包含其的双特异性抗体及其用途
WO2024032761A1 (en) * 2022-08-11 2024-02-15 Hansoh Bio Llc Ligand-cytotoxicity drug conjugates and pharmaceutical uses thereof
KR20250130409A (ko) * 2023-01-11 2025-09-01 젠맵 에이/에스 링커, 약물 링커 및 그의 접합체 및 그의 사용 방법
TW202444425A (zh) * 2023-03-23 2024-11-16 大陸商江蘇恆瑞醫藥股份有限公司 抗ror1抗體與pbd類化合物的偶聯物、其製備方法及其應用
EP4696329A1 (en) * 2023-04-11 2026-02-18 BioRay Pharmaceutical Co., Ltd. Anti-ror1 antibody and drug conjugate thereof
CN119744272A (zh) * 2023-07-31 2025-04-01 石药集团巨石生物制药有限公司 一种抗ror1蛋白的抗体及其缀合物
WO2025039809A1 (zh) * 2023-08-21 2025-02-27 上海麦科思生物医药有限公司 抗ror1抗体及其用途
WO2025140358A1 (en) * 2023-12-27 2025-07-03 Genequantum Healthcare (Suzhou) Co., Ltd. A pharmaceutical composition of anti-fgfr3 antibody drug conjugate and applications thereof
CN120829509A (zh) * 2024-04-18 2025-10-24 上海医药集团股份有限公司 抗ror1抗体、其免疫缀合物及其应用
CN118580358B (zh) * 2024-08-08 2024-11-29 南京优宁维生物科技有限公司 抗ror1重组单克隆抗体及其制备与应用

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