ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY - POTENTIAL IN CANCER

Antibody-directed enzyme prodrug therapy (ADEPT) is a new approach to the treatment of solid cancers. In ADEPT, an antibody (or antibody fragment) is conjugated to an enzyme and is used to localise the enzyme at the site of the tumour. Once localised, the enzyme is used to activate a noncytotoxic prodrug to an active cytotoxic form. Therapy can proceed in either 2 or 3 phases. In the 2-phase system, the nonlocalised unbound antibody-enzyme conjugate is allowed to clear naturally from the body, and then the prodrug is administered. In the 3-phase system, clearance of unbound conjugate is accelerated by a 'clearance' antibody. Enzymes used in experimental ADEPT systems include carboxypeptidases, beta-lactamases, alkaline phosphatase, beta-glucosidase and beta-glucuronidase. All can generate either proven anticancer agents or highly cytotoxic small molecules from a range of prodrugs. In experimental systems, immunospecific antitumour effects have been demonstrated with ADEPT. These effects are much greater than can be achieved by systemic administration of either the prodrug or active drug alone. A limited clinical trial, using carboxypeptidase G2 to activate a mustard prodrug, has been performed in patients with advanced metastatic colon or rectal cancer; all had previously received extensive chemotherapy. ADEPT produced encouraging results, with reduction in the size of liver metastases and subjective responses such as weight gain, pain reduction and improved health. The limitations to ADEPT cannot be ignored. These include: (a) the immunogenicity of the conjugate; (b) activation of the prodrug by unbound circulating conjugate; (c) conjugate heterogeneity; and (d) optimisation of the pharmacology of the active drug. However, many of the problems can be addressed using recombinant DNA technology.