WO2022099762A1 - Intermédiaire de conjugué d'anticorps et son procédé de préparation - Google Patents

Intermédiaire de conjugué d'anticorps et son procédé de préparation Download PDF

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Publication number
WO2022099762A1
WO2022099762A1 PCT/CN2020/130589 CN2020130589W WO2022099762A1 WO 2022099762 A1 WO2022099762 A1 WO 2022099762A1 CN 2020130589 W CN2020130589 W CN 2020130589W WO 2022099762 A1 WO2022099762 A1 WO 2022099762A1
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WIPO (PCT)
Prior art keywords
antibody
antibody conjugate
drug
compound
conjugate intermediate
Prior art date
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Ceased
Application number
PCT/CN2020/130589
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English (en)
Chinese (zh)
Inventor
宋云松
黄仰青
顾家宁
池建文
葛亮
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Brightgene Bio Medical Technology Co Ltd
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Brightgene Bio Medical Technology Co Ltd
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Application filed by Brightgene Bio Medical Technology Co Ltd filed Critical Brightgene Bio Medical Technology Co Ltd
Publication of WO2022099762A1 publication Critical patent/WO2022099762A1/fr
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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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • 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
    • 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

Definitions

  • the invention belongs to the cross field of biological drugs and chemical drugs, and in particular relates to an intermediate of an antibody conjugate and a preparation method thereof
  • Antibody-drug conjugate is a combination of the high specificity of monoclonal antibody drugs and the high activity of small molecule cytotoxic drugs to improve the targeting of tumor drugs and reduce toxic side effects. Compared with traditional fully or partially humanized antibodies or antibody fragments, ADCs are theoretically more effective because they can release highly active cytotoxins in tumor tissues. Compared with fusion proteins, it has higher tolerance or lower side effects.
  • the targeting of ADC drugs comes from the antibody part, and most of the toxicity comes from the toxic part of the small molecule drug.
  • the antibody moiety and the toxin moiety are linked to each other by a linker. After the antibody moiety binds to the targeted antigen on the tumor cell surface, the tumor cell will internalize the ADC. Afterwards, the ADC drug will be decomposed in the lysosome, releasing the active chemical toxin, destroying the DNA or preventing the tumor cell from dividing, and playing the role of killing the cell.
  • the linker should remain stable so that it does not cause off-target toxicity and efficiently release the toxicant inside the cell.
  • ADCs usually consist of a fully humanized monoclonal antibody, a cytotoxic drug, an appropriate linker, and an antigen specifically expressed on tumor cells. This structure mainly maintains the cytotoxicity, targeting, and stability of the ADC in the systemic circulation. The right combination of choices is the key to successful ADC development.
  • Patent CN201380053256.2 discloses an antibody-coupled drug.
  • its structural stability has not been studied.
  • the stability of ADC drugs has always been a common problem in the art. technical difficulties.
  • the present invention aims to provide an antibody conjugate intermediate with good stability. Specifically, the present invention provides an antibody conjugate intermediate, which is represented by the following structure: T-GGFG-L1-D;
  • T is a linker that can be connected to the antibody site, L1 linker, D represents a small molecule cytotoxic drug, G in -GGFG- represents glycine, and F represents phenylalanine;
  • T is selected from Where m is an integer of 0-6, n is an integer of 0-6, p is an integer of 0-12, and q is an integer of 0-6;
  • the L1 structure is Wherein the amino end is connected with -GGFG-, the carbonyl end is connected with D, r is an integer of 1-6, s is 0 or 1; t is an integer of 1-6;
  • R1 and R2 and R3 independently represent hydrogen, halogen, hydroxyl, amino, cyano, C2-C8 alkenyl, C2-C8 alkynyl, aldehyde group, carbamoyl, C1-C8 alkyl, C1-C8 alkoxy base;
  • the T is selected from one of the.
  • the T is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the L1 is selected from
  • the present invention provides a kind of antibody conjugate intermediate, and its structure is as follows:
  • the present invention provides a kind of antibody conjugate intermediate, and its structure is as follows:
  • the present invention provides an antibody conjugate obtained by connecting the above-mentioned antibody conjugate intermediate with an antibody or an antibody modification, and the antibody or antibody modification is an intermediate with an antibody conjugate the T-phase connection.
  • the present invention provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is an anti-tumor drug, an anti-immune disease drug or an anti-infectious disease drug, wherein the anti-tumor drug includes an anti-cancer drug.
  • the synthesis of compound 6 adopts solid-phase synthesis method, the coupling reagent adopts HOBT/DIC, DMF is used as the reaction solvent, and the reaction monitoring adopts ninhydrin detection method.
  • Compound 5 Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc -Gly-OH, Fmoc-Cys(Trt)-OH were connected to 2Cl-Trt resin, Fmoc was removed, DMF washing, DCM washing, methanol washing and drying, adding cleavage reagent 1% TFA/DCM, MTBE precipitation on ice, After washing, the crude product was purified by column chromatography, concentrated and dried to obtain 2.56 g of compound 6 as a white solid with a yield of 60.8%.
  • the aqueous solution of the above-mentioned antibody-antibody MC derivative 11 was added to a 10 ml reaction flask, a DMSO solution containing compound 9 (4.5eq) was added at room temperature, and dialyzed after 1 hour to obtain a solution of antibody-drug conjugate a.
  • the synthesis of compound 13 adopts solid phase synthesis method, the coupling reagent adopts HOBT/DIC, DMF is used as the reaction solvent, and the reaction monitoring adopts ninhydrin detection method.
  • Compound 5 Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc -Gly-OH, compound 12 was connected to 2Cl-Trt resin, Fmoc was removed, washed with DMF, DCM, methanol and then dried, cleavage reagent 1% TFA/DCM was added, MTBE on ice was precipitated, washed, and the crude product was passed through the column layer It was purified by analysis, concentrated and dried to obtain 2.86 g of compound 13 as a white solid with a yield of 62.9%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un intermédiaire de conjugué d'anticorps ayant une bonne stabilité. Non seulement l'intermédiaire de conjugué d'anticorps a une bonne stabilité, mais également le conjugué d'anticorps préparé a de bons effets inhibiteurs sur des cellules tumorales et présente de bonnes perspectives pour le développement de médicaments.
PCT/CN2020/130589 2020-11-12 2020-11-20 Intermédiaire de conjugué d'anticorps et son procédé de préparation Ceased WO2022099762A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011258028 2020-11-12
CN202011258028.7 2020-11-12

Publications (1)

Publication Number Publication Date
WO2022099762A1 true WO2022099762A1 (fr) 2022-05-19

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116789733A (zh) * 2022-07-05 2023-09-22 上海药明合联生物技术有限公司 偶联连接子
WO2024140935A1 (fr) * 2022-12-29 2024-07-04 Beigene, Ltd. Conjugués anticorps-médicament b7h3
US12539336B2 (en) 2022-07-15 2026-02-03 Genequantum Healthcare (Suzhou) Co., Ltd. Antibody, linkers, payload, conjugates and applications thereof
US12577325B2 (en) 2021-11-15 2026-03-17 Systimmune, Inc. Bispecific antibody-camptothecin drug conjugate and pharmaceutical use thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014057687A1 (fr) * 2012-10-11 2014-04-17 第一三共株式会社 Conjugué anticorps-médicament
WO2014061277A1 (fr) * 2012-10-19 2014-04-24 第一三共株式会社 Conjugué anticorps-médicament produit par liaison par l'intermédiaire d'un lieur ayant une structure hydrophile
WO2017002776A1 (fr) * 2015-06-29 2017-01-05 第一三共株式会社 Procédé pour la préparation sélective d'un conjugué anticorps-médicament
WO2018066626A1 (fr) * 2016-10-07 2018-04-12 第一三共株式会社 Traitement contre le cancer pharmacorésistant par administration d'un conjugué anticorps anti-her2/médicament
WO2020031936A1 (fr) * 2018-08-06 2020-02-13 第一三共株式会社 Association d'un conjugué anticorps-médicament et d'un inhibiteur de tubuline
WO2020059772A1 (fr) * 2018-09-20 2020-03-26 第一三共株式会社 Traitement d'un cancer à her3 mutant par l'administration d'un conjugué anticorps anti-her3-médicament
WO2020063676A1 (fr) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 Conjugué ligand-médicament d'un analogue de l'exatécan, son procédé de préparation et application associée
WO2020156513A1 (fr) * 2019-01-30 2020-08-06 同宜医药（苏州）有限公司 Conjugué médicament-ligand et utilisation de celui-ci
CN111689980A (zh) * 2019-05-26 2020-09-22 四川百利药业有限责任公司 一种喜树碱药物及其抗体偶联物

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014057687A1 (fr) * 2012-10-11 2014-04-17 第一三共株式会社 Conjugué anticorps-médicament
WO2014061277A1 (fr) * 2012-10-19 2014-04-24 第一三共株式会社 Conjugué anticorps-médicament produit par liaison par l'intermédiaire d'un lieur ayant une structure hydrophile
WO2017002776A1 (fr) * 2015-06-29 2017-01-05 第一三共株式会社 Procédé pour la préparation sélective d'un conjugué anticorps-médicament
WO2018066626A1 (fr) * 2016-10-07 2018-04-12 第一三共株式会社 Traitement contre le cancer pharmacorésistant par administration d'un conjugué anticorps anti-her2/médicament
WO2020031936A1 (fr) * 2018-08-06 2020-02-13 第一三共株式会社 Association d'un conjugué anticorps-médicament et d'un inhibiteur de tubuline
WO2020059772A1 (fr) * 2018-09-20 2020-03-26 第一三共株式会社 Traitement d'un cancer à her3 mutant par l'administration d'un conjugué anticorps anti-her3-médicament
WO2020063676A1 (fr) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 Conjugué ligand-médicament d'un analogue de l'exatécan, son procédé de préparation et application associée
WO2020156513A1 (fr) * 2019-01-30 2020-08-06 同宜医药（苏州）有限公司 Conjugué médicament-ligand et utilisation de celui-ci
CN111689980A (zh) * 2019-05-26 2020-09-22 四川百利药业有限责任公司 一种喜树碱药物及其抗体偶联物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AGATSUMA TOSHINORI,: "Development of New ADC Technology with Topoisomerase I Inhibitor,", YAKUGAKU ZASSHI,, vol. 137, no. 5, 31 December 2017 (2017-12-31), XP055698408, DOI: 10.1248/yakushi.16-00255-4 *
WEI LI, KAREN H. VEALE, QIFENG QIU, KERSTIN W. SINKEVICIUS, ERIN K. MALONEY, JULIET A. COSTOPLUS, JANET LAU, HELEN L. EVANS, YULIU: "Synthesis and Evaluation of Camptothecin Antibody–Drug Conjugates", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 10, no. 10, 10 October 2019 (2019-10-10), US , pages 1386 - 1392, XP055758576, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.9b00301 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12577325B2 (en) 2021-11-15 2026-03-17 Systimmune, Inc. Bispecific antibody-camptothecin drug conjugate and pharmaceutical use thereof
CN116789733A (zh) * 2022-07-05 2023-09-22 上海药明合联生物技术有限公司 偶联连接子
WO2024008102A1 (fr) * 2022-07-05 2024-01-11 Wuxi Xdc (Shanghai) Co., Ltd. Lieur pour conjugaison
TWI868779B (zh) * 2022-07-05 2025-01-01 大陸商上海藥明合聯生物技術有限公司 偶聯連接子
US12539336B2 (en) 2022-07-15 2026-02-03 Genequantum Healthcare (Suzhou) Co., Ltd. Antibody, linkers, payload, conjugates and applications thereof
WO2024140935A1 (fr) * 2022-12-29 2024-07-04 Beigene, Ltd. Conjugués anticorps-médicament b7h3

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