Antibody-Directed Enzyme Prodrug Therapy (ADEPT) for Cancer
Antibody-directed enzyme prodrug therapy (ADEPT) is a system that aims to restrict the action of a high concentration of a cytotoxic drug to cancer sites. This is achieved by using an antibody (or antibody fragment) to deliver a non-human enzyme to cancer sites.
To avoid systemic toxicity, enzyme levels in blood must be very low at the time of prodrug administration. The rapid clearance of enzyme from blood may be achieved by either using a glycosylated fusion molecule or by addition of a second component that inactivates the enzyme before a non-toxic prodrug that is a substrate for the enzyme is given. The low molecular weight drug thus generated diffuses through the tumour mass but has a short half-life so that it does not reach normal cell renewal systems. Many pre-clinical studies using a variety of enzymes and prodrugs confirmed efficacy of this approach but only one system has progressed to clinical trials. These clinical studies identified new challenges that need to be addressed when developing new ADEPT systems.
KeywordsBacterial Enzyme Nitrogen Mustard Cytosine Deaminase Enzyme Conjugate Catalytic Antibody
Antibody-directed enzyme prodrug therapy
4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid
Benzoic acid mustard prodrug
Dimethyl sulphonic acid
- 18F FDG-PET
18fluorine-labelled fluoro-deoxy glucose -positron emission tomography
human chorionic gonadotropin
An anti-CEA scFv antibody
A recombinant fusion protein consisting of the anti-CEA scFv antibody MFE fused with enzyme carboxypeptidase G2
Maximal tolerable dose
- Tag 72
Tumour-associated glycoprotein 72 antigen
We thank Professor Richard Begent for the critical review of this manuscript and Cancer Research UK for grant support.
- 50.Searle F, Bier C, Buckley RG et al. (1986) The potential of carboxypeptidase G2-antibody conjugates as anti-tumour agents. I. Preparation of antihuman chorionic gonadotrophin-carboxypeptidase G2 and cytotoxicity of the conjugate against JAR choriocarcinoma cells in vitro. Br J Cancer 53:377–384.PubMedGoogle Scholar
- 57.Bagshawe KD, Sharma SK, Springer CJ et al. (1995)Antibody-directed enzyme prodrug therapy: a pilot scale clinical trial. Tumor Targeting 1:17–29.Google Scholar
- 70.Mayer A, Francis RJ, Sharma SK et al. (2006) A phase I study of single administration of antibody-directed enzyme prodrug therapy with the recombinant anti-carcinoembryonic antigen antibody-enzyme fusion protein MFECP1 and a bis-iodo phenol mustard prodrug. Clin Cancer Res 12:6509–6516.CrossRefPubMedGoogle Scholar
- 71.Wilkins DK, Mayer A, Sharma S et al. (2008) Evidence of efficacy of antibody directed enzyme prodrug therapy (ADEPT) in a phase I trial in patients with advanced carcinoma. AACR Meeting Abstracts, Apr 2008::LB-200.Google Scholar