A novel antibody-KSP inhibitor conjugate improves KSP inhibitor efficacy in vitro and in vivo

文献类型： 外文期刊

第一作者： Li, Yiquan

作者： Li, Yiquan;Jin, Ningyi;Li, Xiao;Wang, Zihao;Dong, Yuchao;Fan, Shiyong;Yu, Xiaoyang;Lu, Jing;Jin, Ningyi;Shang, Chao;Li, Xiao

作者机构：

关键词： Kinesin spindle protein; HER2; Antibody-drug conjugates; Autophagy

期刊名称：BIOMATERIALS （ 影响因子：14.0； 五年影响因子：13.8 ）

ISSN： 0142-9612

年卷期： 2023 年 301 卷

页码：

收录情况： SCI

摘要： Many clinical trials of kinesin spindle protein (KSP) inhibitors have failed due to issues such as high toxicity and a short circulation half-life in vivo. To address the limitations of current KSP inhibitors and thus broad its use in antitumor therapy, this study applied antibody-drug conjugate (ADC) technology to the KSP inhibitor SB-743921, which was coupled with the HER2-specific antibody trastuzumab using a cathepsin B-dependent vali-ne-alanine (Val-Ala, VA) dipeptide-type linker to generate H2-921. Ex vivo and in vivo analyses of H2-921 showed an increased half-life of SB-743921 and prolonged contact time with tumor cells. Furthermore, H2-921 induced apoptosis and incomplete autophagy in HER2-positive cells. In the in vivo analyses, H2-921 had significant tumor-targeting properties, and tumor inhibition by H2-921 was greater than that by traditional KSP inhibitors but similar to that by the positive control drug T-DM1. In conclusion, this study describes a novel application of ADC technology that enhances the antitumor effects of a KSP inhibitor and thus may effectively address the poor clinical efficacy of KSP inhibitors.

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