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Antibody-directed Enzyme Prodrug Therapy: Efficacy and Mechanism of Action in Colorectal Carcinoma¹

Cancer Research Campaign Targeting and Imaging Group, Department of Oncology, Royal Free and University College London Medical School, London NW3 2PF [M. P. N., S. K. S., K. D. B., A. J. G., N. C., D. O., R. H. J. B.], with the Cancer Research Campaign Phase I/II Trials Committee, and Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road Sutton, Surrey SM2 5NG [C. J. S., J. M., S. M. S.], United Kingdom

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 (K_m) of 3 µM 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.

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