Development of a Novel DNA Mono-alkylator Platform for Antibody–Drug Conjugates

• Published in: Molecular cancer therapeutics Vol. 23; no. 4; pp. 541 - 551
• Main Authors: Thomas, Joshua D., Yurkovetskiy, Aleksandr V., Yin, Mao, Bodyak, Natalya D., Tang, Shuyi, Protopopova, Marina, Kelleher, Eugene, Jones, Brian, Yang, Liping, Custar, Daniel, Catcott, Kalli C., Demady, Damon R., Collins, Scott D., Xu, Ling, Bu, Charlie, Qin, LiuLiang, Ter-Ovanesyan, Elena, Damelin, Marc, Toader, Dorin, Lowinger, Timothy B.
• Format: Journal Article
• Language: English
• Published: United States 02.04.2024
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-23-0622

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody–drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload “toolbox” to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.