title: Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma.
abstract: In antibody-directed enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.v. and localizes in the tumor. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme prodrug therapy with A5B7 F(ab')2 antibody to carcinoembryonic antigen conjugated to carboxypeptidase G2 (CPG2). A galactosylated antibody directed against the active site of CPG2 (SB43-gal) was given to clear and inactivate circulating enzyme. A benzoic acid mustard-glutamate prodrug was given when plasma enzyme levels had fallen to a predetermined safe level, and this was converted by CPG2 in the tumor into a cytotoxic form. Enzyme levels derived from quantitative gamma camera imaging and from direct measurements in plasma and tumor biopsies showed that the median tumor:plasma ratio of enzyme exceeded 10000:1 at the time of prodrug administration. Enzyme concentrations in the tumor (median, 0.47 units g(-1)) were sufficient to generate cytotoxic levels of active drug. The concentration of prodrug needed for optimal conversion (Km) of 3 microM was achieved. Prodrug conversion to drug was shown by finding detectable levels of drug in plasma. There was evidence of tumor response; one patient had a partial response, and six patients had stable disease for a median of 4 months after previous tumor progression (one of these six had a tumor marker response). Manageable neutropenia and thrombocytopenia occurred. Conditions for effective antitumor therapy were met, and there was evidence of tumor response in colorectal cancer.
authors.affiliation: Department of Oncology, Royal Free and University College London Medical School, United Kingdom.
authors.forename: M P
authors.initials: MP
authors.lastname: Napier
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: C J
authors.initials: CJ
authors.lastname: Springer
authors.forename: K D
authors.initials: KD
authors.lastname: Bagshawe
authors.forename: A J
authors.initials: AJ
authors.lastname: Green
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: S M
authors.initials: SM
authors.lastname: Stribbling
authors.forename: N
authors.initials: N
authors.lastname: Cushen
authors.forename: D
authors.initials: D
authors.lastname: O'Malley
authors.forename: R H
authors.initials: RH
authors.lastname: Begent
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D005971:Glutamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D005971:Glutamates; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C092574:4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid; D011623:gamma-Glutamyl Hydrolase