Antibody-directed enzyme prodrug therapy (ADEPT) for cancer

Abstract

Antibody-directed enzyme prodrug therapy was conceived as a means of restricting the action of cytotoxic drugs to tumor sites. Since antigenic targets were a central component of the approach, colonic cancer, with its virtually universal expression of carcinoembryonic antigen at the cellular level, presented an obvious starting point. The principle of antibody-directed enzyme prodrug therapy is to use an antibody directed at a tumor-associated antigen to vector an enzyme to tumor sites. The enzyme should be retained at tumor sites after it has cleared from blood and normal tissues. A nontoxic prodrug, a substrate for the enzyme, is then given and, by cleaving an inactivating component from the prodrug, a potent cytotoxic agent is generated. One of the potential advantages of such a system is that a small cytotoxic agent, generated within a tumor site, is much more diffusible than a large antibody molecule. Moreover, failure to express the target antigen by cancer cells does not protect them from the bystander action of the cytotoxic agent. This review will primarily consider the studies of the London group since this is the only group that has so far reported clinical trials and it is only through clinical trials that the requirements of a successful antibody-directed enzyme prodrug therapy system can be identified.