2. Academic Validation
  3. A novel antibody-KSP inhibitor conjugate improves KSP inhibitor efficacy in vitro and in vivo

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

  • Biomaterials. 2023 Jul 28;301:122258. doi: 10.1016/j.biomaterials.2023.122258.
Yiquan Li 1,  Zihao Wang 2,  Yuchao Dong 2,  Xiaoyang Yu 3,  Jing Lu 3,  Ningyi Jin 4,  Chao Shang 5,  Xiao Li 6,  Shiyong Fan 7
Affiliations

Affiliations

  • 1 Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China.
  • 2 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
  • 3 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
  • 4 Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
  • 5 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. Electronic address: shangchao1290@126.com.
  • 6 Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China. Electronic address: skylee6226@163.com.
  • 7 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China. Electronic address: fansy@bmi.ac.cn.
PMID: 37523792 DOI: 10.1016/j.biomaterials.2023.122258
Abstract

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 valine-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.

Keywords

Antibody‒drug conjugates; Autophagy; HER2; Kinesin spindle protein.

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