An antibody-drug conjugate carrying a microtubule inhibitor and a DNA alkylator exterts both mechani


I have often wondered how come I don't see an ADC conjugated to two warheads with unique mechanisms of action? At this years AACR meeting in April 2019, the innovative company Mersana Therapeutics (Fleximer platform) presented their conceptual design on a dual-payload ADC. Using their Synthemer platform, which enables the chemical attachment of several drugs per antibody. The prototype consisted of auristatin F hydroxypropyl amide (AF-HPA) and a DNA alkylator (I-BiP). They were able to construct the ADC and maintained target affinity and specificity. The target was not revealed in the poster. Unfortunately, the dual-payload ADC did not have improved cytotoxicity compared to a single payload ADC. Findings also showed that different tumor cell lines responded better to ADC AF-HPA compred to ADC-IBiP or vice versa. However, the dual-payload did not improve cytotoxicity relative to the more effective single-payload ADC. This suggests that independent action by a single dominating warhead is sufficient to cause potent cytotoxicity with an ADC drug class. This is a bit of a step back, but I think this line of research should be further pursued as synergy still seems a very attractive possibility.