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1. CN113842467 - Intermediate for preparing antibody and drug conjugate (ADC) and preparation method and application thereof

Office
China
Application Number 202010601915.3
Application Date 28.06.2020
Publication Number 113842467
Publication Date 28.12.2021
Publication Kind A
IPC
A61K 47/68
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
A61K 47/54
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
54the modifying agent being an organic compound
A61K 31/337
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
335having oxygen as the only ring hetero atom, e.g. fungichromin
337having four-membered rings, e.g. taxol
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
A61P 37/02
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
37Drugs for immunological or allergic disorders
02Immunomodulators
CPC
A61K 47/6889
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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
A61K 47/6803
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
A61K 47/545
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
54the modifying agent being an organic compound
545Heterocyclic compounds
A61K 31/337
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
335having oxygen as the only ring hetero atom, e.g. fungichromin
337having four-membered rings, e.g. taxol
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
A61P 37/02
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
37Drugs for immunological or allergic disorders
02Immunomodulators
Applicants DARTSBIO PHARMACEUTICALS LTD.
达石药业(广东)有限公司
SHANGHAI MAISHI BIOTECHNOLOGY CO., LTD.
上海迈石生物技术有限公司
Inventors WANG CHUNHE
王春河
SHAO TING
邵婷
CHEN TIANZHI
陈田志
WANG QI
王琪
CHEN YILI
陈艺丽
LIN YIJUN
林以均
Agents 上海一平知识产权代理有限公司 31266
上海一平知识产权代理有限公司 31266
Title
(EN) Intermediate for preparing antibody and drug conjugate (ADC) and preparation method and application thereof
(ZH) 用于抗体与药物偶联体(ADC)制备的中间体及其制备方法和应用
Abstract
(EN) The invention relates to an intermediate (a combination of a connexon and a load) for preparing an antibody and a drug conjugate (ADC) and a preparation method and application thereof. Specifically, the combination of the connexon and the load has a structure shown as a formula I, the compound shown as the formula I can be applied to coupling of high-hydrophobicity compound loads such as paclitaxel (PTX') and the like which are not easy to couple, and the prepared ADC molecule has good hydrophilicity and thermal stability and can reach a relatively high drug-to-antibody ratio (DAR) value. According to the intermediate, the Trop-2 targeting ADC prepared by using the connexon represented by the formula I shows the strong in vitro drug effect in the low expression cell line in the Trop-2 compared to the Trop-2 targeting ADC with the effective loads of MMAE and SN38, and shows the strong tumor inhibition ability in the mouse in vivo xenotransplantation tumor model, and the bystander effect is proved. Experimental results show that the problem that the paclitaxel compound is used as an ADC effective load can be solved by utilizing the hydrophilic connexon, and ADC molecules which are expected to be used for treating various human cancers are obtained.
(ZH) 本发明涉及一种用于抗体与药物偶联体(ADC)制备的中间体(连接子与载荷组合)及其制备方法和应用。具体地,本发明的连接子与载荷组合具有式I结构,式I化合物可以应用于紫杉醇类(PTX')等不易被偶联的高疏水性化合物载荷的偶联,制备的ADC分子具有良好的亲水性和热稳定性,并且可以达到较高的药物与抗体比例(DAR)值。利用式I连接子制备的靶向Trop‑2的ADC在Trop‑2中低表达的细胞系中显示出了比有效载荷为MMAE和SN38的靶向Trop‑2的ADC更强的体外药效,并在小鼠体内异种移植瘤模型中显示出了较强的肿瘤抑制能力,且被证明具有“旁观者效应”。实验结果表明,通过利用这种亲水性连接子可以解决将紫杉醇类化合物用作ADC有效载荷的问题,并获得了有望用于治疗多种人类癌症的ADC分子。
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