抗体-药物偶联物
化学
胰腺癌
结合
体内
癌症研究
抗体
药理学
连接器
细胞凋亡
癌症
癌症免疫疗法
抗原
免疫疗法
单克隆抗体
免疫学
生物化学
内科学
医学
生物
数学分析
数学
生物技术
计算机科学
操作系统
作者
Liping Sun,Weiqi Bai,Dandan Zhou,Xiaofan Wu,Lan-wen Zhang,A-Long Cui,Zi-hui Xie,Ruijuan Gao,Yong‐Su Zhen,Zhuorong Li,Qing-fang Miao
标识
DOI:10.1021/acs.jmedchem.3c01210
摘要
Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity. With a DAR of 3.92, it binds specifically to both recombinant antigen (KD ∼ 0.687 nM) and cancer cells and could be internalized by target cells and selectively kill them with IC50 values at nanomolar/subnanomolar levels by inducing apoptosis and G2/M phase arrest. hIMB1636-MMAE also inhibited cell migration, induced ADCC effects, and had bystander effects. It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.
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