连接器
偶氮苯
结合
化学
组合化学
药品
抗体-药物偶联物
抗体
有机化学
分子
单克隆抗体
计算机科学
药理学
数学分析
操作系统
生物
免疫学
医学
数学
作者
Dian Xiao,Lianqi Liu,Fei Xie,Jingwen Dong,Yanming Wang,Xin Xu,Zhong Wu,Hongbin Deng,Xinbo Zhou,Li Song
标识
DOI:10.1002/ange.202310318
摘要
Existing antibody‒drug conjugate (ADC) linkers, whether cleavable linkers or non‐cleavable linkers, are designed to release highly toxic payloads or payload derivatives once ADCs are internalised into cells. However, clinical studies have shown that only <1% of the dosed ADCs accumulate in tumour cells. The remaining >99% of ADCs are nonspecifically distributed in healthy tissue cells, thus inevitably leading to off‐target toxicities of ADCs. Herein, we describe an intelligent tumour‐specific linker strategy to address these limitations. A tumour‐specific linker is constructed by introducing a hypoxia‐activated azobenzene group as a toxicity controller. We show that this azobenzene‐based linker is non‐cleavable in healthy tissues (O2 >10%), and the corresponding payload derivative, amino acid appendage Cysteine (Cys)‐azobenzene‐linker‐monomethyl auristatin E (MMAE), can serve as a safe prodrug to mask the toxicities of MMAE (switched off). Upon exposure to hypoxic tumour microenvironment (O2 <1%), this linker is cleaved to release MMAE and fully restores the high cytotoxicity of the ADC (switched on). Notably, azobenzene‐linker containing ADC exhibits satisfactory antitumour efficacy in vivo and a much better therapeutic window compared with the traditional cleavable linkers or non‐cleavable linkers containing ADCs. Thus, our azobenzene‐based linkers shed new light on the development of next‐generation ADC linkers.
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