GDEPT

Directed enzyme prodrug therapy (DEPT) uses enzymes artificially introduced into the body to convert Prodrugs, which have no or poor biological activity, to the active form in the desired location within the body. Many chemotherapy drugs for cancer lack tumour specificity and the doses required to reach therapeutic levels in the tumour are often toxic to other tissues. DEPT strategies are an experimental method of reducing the systemic toxicity of a drug, by achieving high levels of the active drug only at the desired site. This article describes the variations of DEPT technology.

ADEPT is a strategy to overcome the problems of lack of tumor selectivity. An antibody designed/developed against a tumor antigen is linked to an enzyme and injected to the blood, resulting in selective binding of the enzyme in the tumor. When the discrimination between tumor and normal tissue enzyme levels is sufficient, a prodrug is administrated into the blood circulation, which is converted to an active cytotoxic drug by the enzyme, only within the tumor. Selectivity is achieved by the tumor specificity of the antibody and by delaying prodrug administration until there is a large differential between tumor and normal tissue enzyme levels.

ADEPT has shown antitumor activity in animal tumor models of human choriocarcinoma and colonic and breast carcinoma.

The first pilot-scale clinical trial of ADEPT was carried out at Charing Cross Hospital, London, using an anti-CEA F(ab′)2 antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2).

The antibody used in the first ADEPT clinical trial was of murine origin and the enzyme was bacterial. Host antibodies to both components of the AEC were present in the blood of all non-immunosuppressed patients by day 10 after AEC infusion. Several patients received ciclosporin since it had been shown in rabbits that this could delay the appearance of host antibodies to soluble proteins.

A subsequent, small-scale trial at the Royal Free Hospital, London, used the same agents as in the Charing Cross Hospital trial but the protocol was modified to provide additional pharmacokinetic data and most patients received only a single course of treatment.

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