药理学
治疗指标
药品
体内
抗体-药物偶联物
连接器
化学
药物输送
医学
抗体
免疫学
单克隆抗体
生物
生物技术
计算机科学
操作系统
有机化学
作者
Summer Y. Y. Ha,Yasuaki Anami,Chisato M. Yamazaki,Wei Xiong,Candice M. Haase,Scott D. Olson,Jangsoon Lee,Naoto T. Ueno,Ningyan Zhang,Zhiqiang An,Kyoji Tsuchikama
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2022-07-06
卷期号:21 (9): 1449-1461
被引量:17
标识
DOI:10.1158/1535-7163.mct-22-0362
摘要
Abstract Valine–citrulline is a protease-cleavable linker commonly used in many drug delivery systems, including antibody–drug conjugates (ADC) for cancer therapy. However, its suboptimal in vivo stability can cause various adverse effects such as neutropenia and hepatotoxicity, leading to dose delays or treatment discontinuation. Here, we report that glutamic acid–glycine–citrulline (EGCit) linkers have the potential to solve this clinical issue without compromising the ability of traceless drug release and ADC therapeutic efficacy. We demonstrate that our EGCit ADC resists neutrophil protease–mediated degradation and spares differentiating human neutrophils. Notably, our anti-HER2 ADC shows almost no sign of blood and liver toxicity in healthy mice at 80 mg kg−1. In contrast, at the same dose level, the FDA-approved anti-HER2 ADCs Kadcyla and Enhertu show increased levels of serum alanine aminotransferase and aspartate aminotransferase and morphologic changes in liver tissues. Our EGCit conjugates also exert greater antitumor efficacy in multiple xenograft tumor models compared with Kadcyla and Enhertu. This linker technology could substantially broaden the therapeutic windows of ADCs and other drug delivery agents, providing clinical options with improved efficacy and safety.
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