Resumen
Antibody-directed enzyme prodrug therapy (ADEPT) is a promising alternative to conventional chemotherapy. The idea is to activate a prodrug into a cytotoxic agent at the tumor site with the aid of an enzyme that has been delivered to the tumor by a therapeutic antibody. Thereby offering reduced off-target toxicity and improved selectivity. Telcyta is a glutathione transferase pi-class (GST P1-1) activated prodrug. The human enzyme has modest activity with Telcyta, although being the most efficient enzyme known. The aim of this work was to molecularly redesign human GST P1-1 for enhanced activity with the prodrug Telcyta to achieve a higher therapeutic index for ADEPT. A single-point mutation improved the activity 2.9-fold over the wildtype value, albeit at the cost of thermal stability. Additional mutations restored stability to GST P1-1 with preserved elevated activity. Our findings represent a first step towards a functional ADEPT application for Telcyta.