title: Site-specific prodrug activation by antibody-beta-lactamase conjugates: regression and long-term growth inhibition of human colon carcinoma xenograft models.
abstract: 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.
authors.affiliation: Hybritech Incorporated, San Diego, California 92196-9006.
authors.forename: D L
authors.initials: DL
authors.lastname: Meyer
authors.forename: L N
authors.initials: LN
authors.lastname: Jungheim
authors.forename: K L
authors.initials: KL
authors.lastname: Law
authors.forename: S D
authors.initials: SD
authors.lastname: Mikolajczyk
authors.forename: T A
authors.initials: TA
authors.lastname: Shepherd
authors.forename: D G
authors.initials: DG
authors.lastname: Mackensen
authors.forename: S L
authors.initials: SL
authors.lastname: Briggs
authors.forename: J J
authors.initials: JJ
authors.lastname: Starling
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D011355:Prodrugs; C047052:tumor-associated antigen 72; C055170:4-desacetylvinblastine hydrazide; D014747:Vinblastine; D001618:beta-Lactamases