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

Many clinical trials involving kinesin spindle protein (KSP) inhibitors have failed due to issues like high toxicity and a short circulation half-life in vivo. To overcome these limitations and expand the therapeutic potential of KSP inhibitors in cancer treatment, this study employed antibody-drug conjugate (ADC) technology with the KSP inhibitor SB-743921. By coupling SB-743921 with the HER2-specific antibody trastuzumab, using a cathepsin B-sensitive valine-alanine (Val-Ala, VA) dipeptide-type linker, the novel compound H2-921 was created. Ex vivo and in vivo studies of H2-921 demonstrated an extended half-life for SB-743921 and prolonged interaction with tumor cells. Additionally, H2-921 induced apoptosis and incomplete autophagy in HER2-positive cells. In vivo, H2-921 exhibited strong tumor-targeting abilities, and its tumor-inhibitory effects were more pronounced than those of traditional KSP inhibitors, closely matching the efficacy of the positive control drug T-DM1. In summary, this study presents a novel application of ADC technology that enhances the antitumor activity of a KSP inhibitor, potentially addressing the clinical challenges associated with current KSP inhibitors.