The number of cytotoxic payload classes successfully employed in antibody–drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) as a novel payload class providing highly potent ADCs against different targets, for instance HER‐2 or TWEAKR/Fn14. Aspects of technical optimization include the development of different linker attachment sites, the stabilization of ADC linkage to avoid payload deconjugation and finally, the tailor‐made design of active metabolites with a long lasting intracellular exposure in the tumor matching the mode of action of KSP inhibition. These KSPi‐ADCs are highly potent and selective in vitro and demonstrate in vivo efficacy in a broad panel of tumor models including complete regressions in a patient‐derived urothelial cancer model.

中文翻译：

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抗体-药物与基于吡咯的KSP抑制剂共轭为有效负载类别

成功用于抗体-药物偶联物（ADC）的细胞毒性有效载荷类别的数量仍然相当有限。具有新颖作用方式的ADC有效载荷的识别将增加治疗选择，并可能增加治疗范围。本文中，我们描述了驱动蛋白纺锤体蛋白抑制剂（KSPi）作为一种新型有效负载类的用途，该类有效负载类针对不同目标（例如HER-2或TWEAKR / Fn14）提供了高效的ADC。技术优化的方面包括开发不同的连接子连接位点，稳定ADC链接以避免有效负载解偶联以及最后，针对肿瘤的长期细胞内暴露与KSP抑制作用方式相匹配的活性代谢产物的量身定制设计。