Antibody-directed enzyme prodrug therapy (ADEPT)

Abstract

Since the concept was first described in 1987, the use of antibody-enzyme conjugates directed at tumor-associated antigens to achieve site-specific activation of prodrugs of potently cytotoxic species, termed Antibody Directed Enzyme Prodrug Therapy (ADEPT), has attracted considerable interest. Therapy can proceed in either two or three phases. In the two-phase system the unbound, non-localized antibody is allowed to clear naturally from the body and then a prodrug is administered. For the three-phase system the removal of unbound antibody is accelerated by the use of a 'clearance' antibody. Enzymes used in experimental ADEPT systems include carboxypeptidases, β-lactamases, alkaline phosphatase, β-glucosidase and β-glucuronidase. Prodrug forms of both current clinically used drugs and novel cytotoxic agents have been developed to take advantage of the range of prodrug-generating chemistry offered by these enzymes. Preliminary clinical studies using an enzyme (carboxypeptidase G2) conjugated to an anticarcinoembryonic antigen antibody and a mustard prodrug, were carried out in patients being treated for advanced metastatic colon or rectal cancer and have established the value of the technique with encouraging results. These included reduction in the size of liver metastases and subjective responses such as weight gain, pain reduction and improved health. However, these studies also highlighted the potential problems of ADEPT. These include: the immunogenicity of the conjugate; activation of the prodrug by unbound, circulating conjugate; conjugate heterogeneity and optimization of the pharmacology of the active drug. The major problem of immunogenicity of proteins of nonhuman origin was initially tackled by the use of immunosuppressive agents. The longer term solutions being investigated for development of future, second generation ADEPT systems include human antibody/human enzyme fusion proteins and catalytic antibodies. These advances, together with further optimization of the prodrug/drug element of the system, should mean that ADEPT-based approaches will be of considered clinical significance in the future treatment of cancer.