The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, ADCs with microtubule inhibitors, DNA binding payloads, or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC payload classes with a novel mode of action will increase therapeutic options. The kinesin spindle protein (KSP/Eg5/KIF11) is an ATP-dependent motor protein involved in the separation of centrosomes in G2/M phase which is an essential event in mitosis. KSP inhibitors (KSPi) have generated interest due to their high antitumor activity in preclinical models. However, transferring the preclinical potency of small molecule KSP inhibitors (SMOL KSPis) into highly efficient clinical regimens with a sufficient therapeutic window has remained challenging. Targeted delivery of payloads selectively to tumor cells while sparing normal cells may enlarge the therapeutic window of KSPis.
We have investigated a new pyrrole subclass of KSPis. The KSP inhibitor was profiled on a large panel of 370 cancer cell lines and showed sub-nM potency against cell lines originating from different cancer indications. ADCs were generated through the conjugation of the KSPi to antibodies targeting different cancer antigens and characterized
KSPi-ADCs showed strong and specific internalization and displayed specific and potent anti-proliferative activity
Bayer AG
A. Sommer: Stock shareholder of Bayer AG. My husband is employed by Boehringer Ingelheim.
Has not received any funding