Antibody-directed enzyme/prodrug therapy (ADEPT)

Abstract

Studies on the Adept approach over the last 6 years have indicated its general feasibility. The therapeutic responses observed so far in the clinic are modest but have been obtained with a prodrug that will be surpassed. Substantial progress has been made in understanding and controlling the distribution of the enzyme which is critical to a major advance in the distribution of a cytotoxic drug. In Adept the distinction between a prodrug and its active component provides a further opportunity to improve selectivity by using a second enzyme system which must be retained within the vascular compartment to inactivate any active drug which is generated within or otherwise enters the vascular compartment (IVIAD). A third way in which enzymes can be used to improve the selectivity of cancer chemotherapy relates to those agents whose action can be reversed by a ‘rescue agent’. Here the enzyme is delivered to tumor sites, as in Adept, by conjugation to an antibody directed to a tumor associated antigen. The cytotoxic drug is given together with a rescue agent to protect normal tissues but enzyme inactivates the rescue agent at tumor sites (IRATS) thereby leaving the tumour exposed to the unopposed action of the drug. Oncological experience does not encourage us to think that any form of ‘one shot’ therapy, however efficient, will have a major impact on the course of common cancers. Non-immunogenic antibodies and conjugates are already being developed but where immunogenic agents are used, control of the host response will be necessary to allow adequate treatment to be given. Present experience with cyclosporin suggests that this is attainable.