In antibody-directed enzyme prodrug therapy (ADEPT), an antibody is used to target an enzyme to tumor. After tumor localization and deactivation or clearance of enzyme from blood and other normal tissue, a prodrug is given. The prodrug is converted into a toxic chemotherapeutic by the pretargeted enzyme at the tumor site (Figure 22.1). The ADEPT system, originally conceived in 1987, has a number of potential advantages over standard chemotherapy or the use of antibody-toxin conjugates. If a relatively nontoxic prodrug is used and there is no significant conversion of prodrug in nontarget organs, toxicity is restricted to the tumor site, allowing highly potent and specific treatments. Moreover, since one enzyme is able to turn over many prodrug molecules, the tumor essentially becomes a factory for generating its own means of destruction. Importantly, active drug can also diffuse to nearby cells, creating a local bystander effect where antigen negative cells and tumor-supportive stromal elements are destroyed.

ADEPT is a complex system that can be influenced by many components. These components, outlined inFigure 22.2, have been investigated by various workers over the last 2 decades and the results provide a platform of understanding for future applications of the treatment. Here we describe the progress of ADEPT since the first proofs-of-principle to recent advances in the clinic.