SITE-SPECIFIC PRODRUG ACTIVATION BY ANTIBODY-BETA-LACTAMASE CONJUGATES - REGRESSION AND LONG-TERM GROWTH-INHIBITION OF HUMAN COLON-CARCINOMA XENOGRAFT MODELS

Antibody-directed catalysis (ADC) is a two-step method for the deliver y of chemotherapeutic agents in which enzyme-antibody conjugate, prelo calized to antigen-bearing tumor cells, catalyzes the site-specific co nversion of prodrug to drug. An ADC system consisting of F(ab')-beta-l actamase conjugates and a cephalosporin derivative of the oncolytic ag ent 4-desacetylvinblastine-3-carboxhydrazide was investigated. The abi lity of the system to mediate antitumor activity was compared with tha t of free drug given alone and with covalent drug-antibody conjugates in LS174T and T380 colon carcinoma xenografts in nude mice. Efficacy i ncreased from moderate tumor growth inhibition by using free 4-desacet ylvinblastine-3-carboxhydrazide to tumor regression and long-term stab ilization with the ADC system. Labile covalent drug-antibody conjugate s prepared from the same antibodies were less effective than ADC and r equired much higher antibody doses. The antigens KS1/4, carcinoembryon ic antigen, and tumor-associated glycoprotein-72, TAG-72, present on t he model cell lines, were chosen to investigate the effect of differen ces in subcellular location and expression heterogeneity on the effica cy of ADC delivery. Response was equivalent with the three tumor antig ens. Hence, heterogeneous expression and membrane shedding of carcinoe mbryonic antigen and TAG-72, did not diminish the suitability of these antigens as targets for ADC therapy. In contrast, drug-antibody conju gate efficacy was more sensitive to subcellular location and heterogen eity. Thus, ADC is a highly effective form of immunochemotherapy in pr eclinical models, with applicability toward a variety of antigen targe ts.