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

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. [Display omitted] •H2-921 has a novel chemical structure and can target her2+ cancer cells.•Under the action of cathepsin B, H2-921 will release SB-743921 in the lysosome.•It has excellent drug metabolism properties and solves the problem of short half-life of SB-743921 in vivo.•The anti-tumor mechanism of H2-921 was analyzed, which is helpful to guide rational drug use in clinical practice.