Site-specific prodrug activation by antibody-β-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 delivery of chemotherapeutic agents in which enzyme-antibody conjugate, prelocalized to antigen-bearing tumor cells, catalyzes the site-specific conversion of prodrug to drug. An ADC system consisting of F(ab')-beta-lactamase conjug...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 53; no. 17; pp. 3956 - 3963
Main Authors:	MEYER, D. L, JUNGHEIM, L. N, LAW, K. L, MIKOLAJCZYK, S. D, SHEPHERD, T. A, MARCKENSEN, S. G, BRIGGS, S. L, STARLING, J. J
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-09-1993
Subjects:	Animals Antigens, Neoplasm - metabolism Antineoplastic agents beta-Lactamases - metabolism Biological and medical sciences Carcinoembryonic Antigen - metabolism Cell Division - drug effects Chemotherapy Colonic Neoplasms - drug therapy Colonic Neoplasms - immunology Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Glycoproteins - metabolism Humans Immunoglobulin Fab Fragments - metabolism Immunotoxins - therapeutic use Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Prodrugs - metabolism Prodrugs - therapeutic use Transplantation, Heterologous Tumor Cells, Cultured Vinblastine - analogs & derivatives Vinblastine - metabolism Vinblastine - therapeutic use Antineoplastic agent Activation Monoclonal antibody β-Lactamase Target Intestinal disease Fab'-Fragment Colon Chemical uptake Tumor associated antigen Enzyme Rodentia Prodrug Malignant tumor Vertebrata Chemotherapy Cephalosporin derivatives Experimental disease Mammalia Treatment Mouse Analog Animal Distribution Covalent bond Digestive diseases Conjugated compound Pharmacokinetics
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Summary:	Antibody-directed catalysis (ADC) is a two-step method for the delivery of chemotherapeutic agents in which enzyme-antibody conjugate, prelocalized to antigen-bearing tumor cells, catalyzes the site-specific conversion of prodrug to drug. An ADC system consisting of F(ab')-beta-lactamase conjugates and a cephalosporin derivative of the oncolytic agent 4-desacetylvinblastine-3-carboxhydrazide was investigated. The ability of the system to mediate antitumor activity was compared with that of free drug given alone and with covalent drug-antibody conjugates in LS174T and T380 colon carcinoma xenografts in nude mice. Efficacy increased from moderate tumor growth inhibition by using free 4-desacetylvinblastine-3-carboxhydrazide to tumor regression and long-term stabilization with the ADC system. Labile covalent drug-antibody conjugates prepared from the same antibodies were less effective than ADC and required much higher antibody doses. The antigens KS1/4, carcinoembryonic antigen, and tumor-associated glycoprotein-72, TAG-72, present on the model cell lines, were chosen to investigate the effect of differences in subcellular location and expression heterogeneity on the efficacy of ADC delivery. Response was equivalent with the three tumor antigens. Hence, heterogeneous expression and membrane shedding of carcinoembryonic antigen and TAG-72, did not diminish the suitability of these antigens as targets for ADC therapy. In contrast, drug-antibody conjugate efficacy was more sensitive to subcellular location and heterogeneity. Thus, ADC is a highly effective form of immunochemotherapy in preclinical models, with applicability toward a variety of antigen targets.
ISSN:	0008-5472 1538-7445