旁观者效应
抗体-药物偶联物
体内分布
结合
癌症研究
渗透(战争)
医学
曲妥珠单抗
抗体
药品
肿瘤微环境
药理学
癌症
单克隆抗体
化学
肿瘤细胞
免疫学
内科学
体外
生物化学
乳腺癌
数学分析
工程类
运筹学
数学
作者
Wei Qing,Teng Yang,Jiayu Zhu,Ziwen Zhang,Le Yang,Yuchao Zhang,Can Hu,Jiahui Chen,Jinchao Wang,Xuefei Tian,Takaya Shimura,Jianmin Fang,Jieer Ying,Mengyang Fan,Peng Guo,Xiangdong Cheng
标识
DOI:10.1158/1078-0432.ccr-23-1725
摘要
Abstract Purpose:Antibody drug conjugate (ADC) has had a transformative effect on the treatment of many solid tumors, yet it remains unclear how ADCs exert bystander activity in the tumor microenvironment. Experimental Design: Here, we directly visualized and spatiotemporally quantified the intratumor biodistribution and pharmacokinetics of different ADC components by developing dual-labeled fluorescent probes. Results: Mechanistically, we found that tumor penetration of ADCs is distinctly affected by their ability to breach the binding site barrier (BSB) in perivascular regions of tumor vasculature, and bystander activity of ADC can only partially breach BSB. Furthermore, bystander activity of ADCs can work in synergy with co-administration of their parental antibodies, leading to fully bypassing BSBs and enhancing tumor penetration via a two-step process. Conclusions: These promising preclinical data allowed us to initiate a phase I/II clinical study of co-administration of RC48 and trastuzumab in patients with malignant stomach cancer to further evaluate this treatment strategy in humans.
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