KSPi-ADCs: ADCs with novel kinesin spindle protein inhibitor payloads and a tailor-made linker chemistry

Inhibitors of kinesin spindle protein (KSP/Eg5) have raised great interest because of their high antitumor potency which, however, could not be transferred into highly efficient clinical regimens due to dose limiting side effects such as neutropenia. We have developed a new, highly potent pyrrole subclass of KSPis as a novel payload class in ADCs. To increase the therapeutic window, a tailor-made effector chemistry has been designed. The tumor associated protease legumain (LGMN) is utilized for ADC cleavage to provide active metabolites with high and long-lasting exposure in tumors, thus matching the KSPi mode of action. LGMN is a lysosomal asparaginyl endopeptidase overexpressed in solid tumors which is associated with invasion, metastasis and poor survival. In our studies, we show an efficient LGMN mediated linker cleavage and payload release from different ADCs. In addition, the unique LGMN substrate sequence allows for high cleavage specificity and discrimination versus other proteases such as elastase, which has been associated with an undesired extracellular cleavage of e.g. vc-MMAE ADCs resulting in neutropenia. Variations of the linker chemistry were performed to retain high potency of the KSPi-ADCs against tumor cells while decreasing the activation of KSPi-ADCs in cells of healthy organs such as the liver. From this approach, highly potent KSPi-ADCs with improved tumor/organ ratios of active metabolites were obtained. In conclusion, ADC metabolism under legumain control is a versatile strategy to provide KSPi-ADCs with high potency and an improved safety profile. Citation Format: Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Anette Sommer, Sandra Berndt, Anne-Sophie Rebstock, Sarah Johannes, Leo Marx, Christoph Mahlert, Simone Greven, Lisa Dietz, Hannah Joerissen, Hilmar Weinmann. KSPi-ADCs: ADCs with novel kinesin spindle protein inhibitor payloads and a tailor-made linker chemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 228.