Abstract A097: Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models

As antibody-drug conjugates (ADCs) find increasing clinical application, treatment-related resistance mechanisms may eventually impact efficacy. One resistance mechanism that emerges following prolonged exposure to auristatin-based ADCs such as brentuximab vedotin and polatuzumab vedotin involves upregulation of efflux pumps that confer the multidrug resistance positive (MDR+) phenotype. New payload technologies that retain activity in this context may be important for next-generation anti-tubulin ADCs. The tubulysins are a potent class of tubulin binders consisting of natural products and designed analogues which have become a compelling cytotoxic payload for drug targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express MDR-conferring transporters. Recently, we developed the quaternary ammonium linker system to conjugate tertiary amine-containing payloads and applied it to the tubulysins. In this work, β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads for activity in MDR+ models. The resulting conjugates displayed high potency in multiple MDR+ models at well-tolerated doses, including those resistant to MMAE-based ADCs. In addition to potency in resistant models, the tubulysin conjugates also retained bystander activity - a property in common with vedotin-based conjugates and important for indications characterized by heterogeneous antigen expression. Thus, the glucuronide-tubulysin M linker could enable future ADC programs designed for the treatment of resistant tumors due to emergence of MDR transporters. Citation Format: Patrick J Burke, Joseph Z Hamilton, Thomas A Pires, Kim K Emmerton, Peter D Senter, Scott C Jeffrey. Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A097. doi:10.1158/1535-7163.TARG-19-A097