SITE-SPECIFIC PRODRUG ACTIVATION BY ANTIBODY-BETA-LACTAMASE CONJUGATES - PRECLINICAL INVESTIGATION OF THE EFFICACY AND TOXICITY OF DOXORUBICIN DELIVERED BY ANTIBODY-DIRECTED CATALYSIS

Antibody directed catalysis (ADC), the catalytic conversion of prodrug s to drugs by enzymes localized at disease targets by appropriate mono clonal antibodies, has shown promise in the treatment of cancer in nud e mouse xenograft models. We investigated this concept using antibody enzyme conjugates constructed from beta-lactamase and Fab's reactive w ith carcinoembryonic antigen, CEA, and tumor associated glycoprotein, TAG-72, to convert prodrugs that are cephalosporin sulfoxide derivativ es into oncolytic drugs. Previous work focused on ADC delivery of the potent vinca alkaloid derivative desacetylvinblastine carboxhydrazide (DAVLBHYD). In the current study the ability of the system to deliver doxorubicin was tested in MCF7 breast carcinoma xenografts and OVCAR3 ovarian carcinoma xenografts, and in T380 and LS174T colon tumor xenog rafts for comparison with previous DAVLBHYD results. ADC enhanced the delivery of doxorubicin in the model systems investigated. Tumor growt h suppression was equivalent to or greater than that observed with fre e doxorubicin at its maximum tolerated dose (MTD). In contrast to the DAVLBHYD results, ADC delivery of doxorubicin did not regress tumors, but did result in a substantial increase in the MTD.