Academic Journal
Azobenzene‐Based Linker Strategy for Selective Activation of Antibody–Drug Conjugates
| العنوان: | Azobenzene‐Based Linker Strategy for Selective Activation of Antibody–Drug Conjugates |
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| المؤلفون: | Xiao, Dian, Liu, Lianqi, Xie, Fei, Dong, Jingwen, Wang, Yanming, Xu, Xin, Zhong, Wu, Deng, Hongbin, Zhou, Xinbo, Li, Song |
| المساهمون: | National Natural Science Foundation of China, Beijing Nova Program |
| المصدر: | Angewandte Chemie International Edition ; volume 63, issue 16 ; ISSN 1433-7851 1521-3773 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2024 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | Existing antibody–drug conjugate (ADC) linkers, whether cleavable or non‐cleavable, are designed to release highly toxic payloads or payload derivatives upon internalisation of the ADCs 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 toxicity. 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 (O 2 >10 %), and the corresponding payload derivative, cysteine‐appended azobenzene‐linker–monomethyl auristatin E (MMAE), can serve as a safe prodrug to mask the toxicity of MMAE (switched off). Upon exposure to the hypoxic tumour microenvironment (O 2 <1 %), this linker is cleaved to release MMAE and fully restores the high cytotoxicity of the ADC (switched on). Notably, the azobenzene linker‐containing ADC exhibits satisfactory antitumour efficacy in vivo and a larger therapeutic window compared with ADCs containing traditional cleavable or non‐cleavable linkers. Thus, our azobenzene‐based linker sheds new light on the development of next‐generation ADC linkers. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/anie.202310318 |
| الاتاحة: | http://dx.doi.org/10.1002/anie.202310318 https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202310318 |
| Rights: | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: | edsbas.870BBA14 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/anie.202310318 |
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