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WO2019149116A1 - Procédé de préparation d'un conjugué - Google Patents

Procédé de préparation d'un conjugué Download PDF

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Publication number
WO2019149116A1
WO2019149116A1 PCT/CN2019/072762 CN2019072762W WO2019149116A1 WO 2019149116 A1 WO2019149116 A1 WO 2019149116A1 CN 2019072762 W CN2019072762 W CN 2019072762W WO 2019149116 A1 WO2019149116 A1 WO 2019149116A1
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WO
WIPO (PCT)
Prior art keywords
group
cancer
conjugate
antibody
alkyl
Prior art date
Application number
PCT/CN2019/072762
Other languages
English (en)
Chinese (zh)
Inventor
宋帅
田强
唐祖建
邓汉文
汪静
刘登念
胡瑞斌
肖亮
薛彤彤
蔡家强
王利春
王晶翼
Original Assignee
四川科伦博泰生物医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川科伦博泰生物医药股份有限公司 filed Critical 四川科伦博泰生物医药股份有限公司
Priority to CN201980006094.4A priority Critical patent/CN111447939B/zh
Publication of WO2019149116A1 publication Critical patent/WO2019149116A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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

Definitions

  • a novel method for coupling a targeted drug to a biologically active molecule in the present invention that is, the use of a novel carboxyl activation method greatly improves the stability of the activated carboxyl group in the linker, and successfully overcomes
  • the coupling technique of using a pentafluorophenol to activate a carboxyl group cannot achieve the problem of stable pentafluorophenol ester, and at the same time, the coupling of the bioactive molecule with the targeted drug is achieved at a higher coupling ratio.
  • This coupling method can be widely applied to the synthesis of targeted drug-bioactive molecular conjugates.
  • A is a group obtained by removing ⁇ amino groups in a targeted drug, and the targeted drug includes a macromolecule and a small molecule having a targeting effect, such as an antibody, DNA, RNA or a small molecule ligand;
  • Figure 6 is a HIC analysis map of Compound 10 coupled to an antibody.
  • bispecific antibody is used interchangeably with "bifunctional antibody conjugate” and refers to a conjugate formed by a first antibody (fragment) and a second antibody (fragment) by a coupling arm.
  • the conjugate retains the activity of the respective antibody and is therefore bifunctional and bispecific.
  • the term "Probody” is a modified antibody comprising an antibody or an antibody fragment that specifically binds to its target and is capable of coupling to a masking group, wherein the masking group refers to an antibody or antibody fragment thereof
  • the cleavage constant of the binding ability of the target is at least 100-fold, 1000-fold or 10,000-fold greater than the cleavage constant of the binding ability of the antibody or antibody fragment without the coupling masking group to its target.
  • the compounds or conjugates of the invention are capable of inhibiting or killing cells expressing the ErbB2 receptor, such as breast cancer cells, ovarian cancer cells, gastric cancer cells, endometrial cancer cells, salivary gland cancer cells, lung cancer cells, Renal cancer cells, colon cancer cells, thyroid cancer cells, pancreatic cancer cells, bladder cancer cells or liver cancer cells.
  • cells expressing the ErbB2 receptor such as breast cancer cells, ovarian cancer cells, gastric cancer cells, endometrial cancer cells, salivary gland cancer cells, lung cancer cells, Renal cancer cells, colon cancer cells, thyroid cancer cells, pancreatic cancer cells, bladder cancer cells or liver cancer cells.
  • the term "6-12 membered fused heterocyclic group” means a group of 6 to 12 ring atoms formed by two or more ring structures sharing two adjacent atoms with each other (at least A ring structure in which a ring atom is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • a ring atom eg, a carbon atom, a nitrogen atom, or a sulfur atom
  • oxo e.g, a carbon atom, a nitrogen atom, or a sulfur atom
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • the invention includes isomers formed based on any stereo configuration of the chiral carbon, for example including racemates or any Mirror isomer. Moreover, the invention includes all other stereoisomers that may be present. That is, the compounds/conjugates of the present invention include all enantiomers, diastereomers, cis and trans isomers, racemates and the like.
  • the method comprises coupling a compound of formula (I) to a targeting drug comprising one or more amino groups (-NH 2 ),
  • the targeted drug is trastuzumab, pertuzumab or Sacituzumab.
  • the method comprises mixing a solution comprising a targeted drug with a compound of formula (I).
  • the process is carried out in water or an organic solvent.
  • the cancer disease is selected from the group consisting of esophageal cancer (eg, esophageal adenocarcinoma or esophageal squamous cell carcinoma), brain tumor, lung cancer (eg, small cell lung cancer or non-small cell lung cancer), squamous cell carcinoma , bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, salivary adenocarcinoma, colon cancer, colorectal cancer, liver cancer, kidney cancer, solid tumor, non-Hodge Gold lymphoma, central nervous system tumors (eg, glioma, glioblastoma multiforme or glioma or sarcoma), prostate cancer, and thyroid cancer.
  • esophageal cancer eg, esophageal adenocarcinoma or esophageal squamous cell carcinoma
  • brain tumor eg,
  • the tumor cell HCC1954 was first cultured, and the medium was RPMI1640 + 10% FBS.
  • HCC1954 is a Her2 positive cell with endocytosis to a conjugate (eg, an anti-Her2 antibody trastuzumab-drug conjugate).
  • the conjugate was diluted with the corresponding detection medium (containing 2% FBS) (starting at 1 ⁇ g/mL, diluted 2 times, diluted 10 concentration gradients), and the tumor cells were digested by conventional methods using trypsin to collect tumor cells. Resuspend with the corresponding assay medium (containing 2% FBS).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne également un procédé de préparation d'un conjugué cible médicament-molécule bioactif, un produit préparé par le procédé, et des utilisations du produit dans la prévention et/ou le traitement de maladies néoplasiques associées à l'activité cellulaire anormale (y compris, mais sans y être limitées, des maladies cancéreuses).
PCT/CN2019/072762 2018-01-30 2019-01-23 Procédé de préparation d'un conjugué WO2019149116A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980006094.4A CN111447939B (zh) 2018-01-30 2019-01-23 制备偶联物的方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810087078.X 2018-01-30
CN201810086794 2018-01-30
CN201810087078 2018-01-30
CN201810086794.6 2018-01-30

Publications (1)

Publication Number Publication Date
WO2019149116A1 true WO2019149116A1 (fr) 2019-08-08

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PCT/CN2019/072762 WO2019149116A1 (fr) 2018-01-30 2019-01-23 Procédé de préparation d'un conjugué

Country Status (2)

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CN (2) CN110090308B (fr)
WO (1) WO2019149116A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341521A (zh) * 2019-08-09 2021-02-09 上海翰森生物医药科技有限公司 一种小分子活性化合物及其抗体偶联物、其制备方法和医药用途
CN112526022A (zh) * 2020-11-27 2021-03-19 内蒙古伊利实业集团股份有限公司 一种乳中母乳低聚糖的检测方法
WO2021228141A1 (fr) * 2020-05-15 2021-11-18 四川科伦博泰生物医药股份有限公司 Conjugué anticorps-médicament, son procédé de préparation et son utilisation
WO2023232142A1 (fr) * 2022-06-02 2023-12-07 映恩生物制药（苏州）有限公司 Composé pharmaceutique et son utilisation
WO2024193682A1 (fr) * 2023-03-23 2024-09-26 Xadcera Biopharmaceutical (Suzhou) Co., Ltd. Anticorps anti-tpbg/met et leurs utilisations
WO2024235136A1 (fr) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2024235130A1 (fr) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 Composé polycyclique, son procédé de préparation et son utilisation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
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WO2024179381A1 (fr) * 2023-02-28 2024-09-06 四川科伦博泰生物医药股份有限公司 Lieur de couplage chimique et son utilisation
CN117430660B (zh) * 2023-09-04 2024-10-18 诺灵生物医药科技(北京)有限公司 奥瑞他汀f类似物及其抗体药物偶联物与应用

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US5410024A (en) * 1993-01-21 1995-04-25 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory pentapeptide amides
CN1938046A (zh) * 2003-11-06 2007-03-28 西雅图基因公司 能够与配体偶联的单甲基缬氨酸化合物
US20140017265A1 (en) * 2012-07-05 2014-01-16 Mersana Therapeutics, Inc. Terminally Modified Polymers and Conjugates Thereof
CN106729743A (zh) * 2015-11-23 2017-05-31 四川科伦博泰生物医药股份有限公司 抗ErbB2抗体-药物偶联物及其组合物、制备方法和应用
CN107206101A (zh) * 2014-12-03 2017-09-26 基因泰克公司 季铵化合物及其抗体‑药物缀合物

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CA2718942A1 (fr) * 2008-03-18 2009-09-24 Seattle Genetics, Inc. Conjugues auristatine-lieur de medicament
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WO2014208987A1 (fr) * 2013-06-24 2014-12-31 한화케미칼 주식회사 Conjugué anticorps-médicament présentant une stabilité améliorée et son utilisation
EP3100731A4 (fr) * 2014-01-29 2017-12-20 Shanghai Hengrui Pharmaceutical Co., Ltd. Conjugué de médicaments cytotoxiques et de ligands, son procédé de préparation et ses applications
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US5410024A (en) * 1993-01-21 1995-04-25 Arizona Board Of Regents Acting On Behalf Of Arizona State University Human cancer inhibitory pentapeptide amides
CN1938046A (zh) * 2003-11-06 2007-03-28 西雅图基因公司 能够与配体偶联的单甲基缬氨酸化合物
US20140017265A1 (en) * 2012-07-05 2014-01-16 Mersana Therapeutics, Inc. Terminally Modified Polymers and Conjugates Thereof
CN107206101A (zh) * 2014-12-03 2017-09-26 基因泰克公司 季铵化合物及其抗体‑药物缀合物
CN106729743A (zh) * 2015-11-23 2017-05-31 四川科伦博泰生物医药股份有限公司 抗ErbB2抗体-药物偶联物及其组合物、制备方法和应用

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341521A (zh) * 2019-08-09 2021-02-09 上海翰森生物医药科技有限公司 一种小分子活性化合物及其抗体偶联物、其制备方法和医药用途
CN112341521B (zh) * 2019-08-09 2024-06-25 上海翰森生物医药科技有限公司 一种小分子活性化合物及其抗体偶联物、其制备方法和医药用途
WO2021228141A1 (fr) * 2020-05-15 2021-11-18 四川科伦博泰生物医药股份有限公司 Conjugué anticorps-médicament, son procédé de préparation et son utilisation
CN112526022A (zh) * 2020-11-27 2021-03-19 内蒙古伊利实业集团股份有限公司 一种乳中母乳低聚糖的检测方法
WO2023232142A1 (fr) * 2022-06-02 2023-12-07 映恩生物制药（苏州）有限公司 Composé pharmaceutique et son utilisation
WO2024193682A1 (fr) * 2023-03-23 2024-09-26 Xadcera Biopharmaceutical (Suzhou) Co., Ltd. Anticorps anti-tpbg/met et leurs utilisations
WO2024235136A1 (fr) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation
WO2024235130A1 (fr) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 Composé polycyclique, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
CN110090308A (zh) 2019-08-06
CN111447939B (zh) 2024-07-12
CN111447939A (zh) 2020-07-24
CN110090308B (zh) 2023-03-24

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