title: Antibody-directed enzyme prodrug therapy (ADEPT). A three-phase study in ovarian tumor xenografts.
abstract: Antibody-directed enzyme prodrug therapy (ADEPT) has been studied in a human ovarian carcinoma xenograft grown subcutaneously in nude mice. Radioimmunoassay of supernatants obtained from tumor homogenates showed these to contain carcinoembryonic antigen (CEA). Biodistribution studies with 125I-labeled monoclonal anti-CEA antibody, A5B7, and its F(ab')2 fragment showed localization in these xenografts. The AB57-F(ab')2 fragment conjugated to a bacterial enzyme, carboxypeptidase G2 (CPG2), and, radiolabeled with 125iodine, also localized in the xenografts. The radiolabeled conjugate cleared from blood faster than the antibody alone. The percentage of injected dose per gram in tumor at 24 h postinjection was about fivefold lower than antibody alone. Tumor-to-blood ratio at 72 h after injection of the radiolabeled conjugate was 7 and the tumor-to-normal tissue ratios at this time point ranged from 20 (liver) to 75 (colon). A three-phase ADEPT antitumor study was carried out in which A5B7-F(ab')2-CPG2 was allowed to localize and was followed by accelerated inactivation/clearance of blood CPG2 by a galactosylated anti-CPG2 antibody (SB43gal). A benzoic acid mustard-derived prodrug was injected 24 h after the conjugate, which led to growth delay in this tumor compared to the control untreated group. Further antitumor studies in this model are in progress.
authors.affiliation: Department of Medical Oncology, Charing Cross Hospital, London, UK.
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: J A
authors.initials: JA
authors.lastname: Boden
authors.forename: C J
authors.initials: CJ
authors.lastname: Springer
authors.forename: P J
authors.initials: PJ
authors.lastname: Burke
authors.forename: K D
authors.initials: KD
authors.lastname: Bagshawe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D011623:gamma-Glutamyl Hydrolase
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D011355:Prodrugs; D011623:gamma-Glutamyl Hydrolase