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: M P Napier, S K Sharma, C J Springer, K D Bagshawe, A J Green, J Martin, S M Stribbling, N Cushen, D O'Malley, R H Begent
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 3 Pg. 765-72 (Mar 2000) ISSN: 1078-0432 [Print] United States
• PMID: 10741695 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Carcinoembryonic Antigen
• Glutamates
• Nitrogen Mustard Compounds
• Prodrugs
• 4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid
• gamma-Glutamyl Hydrolase

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, blood, chemistry)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Carcinoembryonic Antigen (immunology)
• Colorectal Neoplasms (metabolism, pathology, therapy)
• Female
• Glutamates (adverse effects, pharmacokinetics, therapeutic use)
• Humans
• Male
• Middle Aged
• Neutropenia (chemically induced)
• Nitrogen Mustard Compounds (adverse effects, pharmacokinetics, therapeutic use)
• Prodrugs (adverse effects, pharmacokinetics, therapeutic use)
• Survival Analysis
• Thrombocytopenia (chemically induced)
• Treatment Outcome
• gamma-Glutamyl Hydrolase (administration & dosage, blood, chemistry)