title: Site-specific prodrug activation by antibody-beta-lactamase conjugates: preclinical investigation of the efficacy and toxicity of doxorubicin delivered by antibody directed catalysis.
abstract: Antibody directed catalysis (ADC), the catalytic conversion of prodrugs to drugs by enzymes localized at disease targets by appropriate monoclonal antibodies, has shown promise in the treatment of cancer in nude mouse xenograft models. We investigated this concept using antibody enzyme conjugates constructed from beta-lactamase and Fab's reactive with carcinoembryonic antigen, CEA, and tumor associated glycoprotein, TAG-72, to convert prodrugs that are cephalosporin sulfoxide derivatives 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 xenografts for comparison with previous DAVLBHYD results. ADC enhanced the delivery of doxorubicin in the model systems investigated. Tumor growth suppression was equivalent to or greater than that observed with free 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.
authors.affiliation: Hybritech Incorporated, San Diego, California 92196, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Meyer
authors.forename: K L
authors.initials: KL
authors.lastname: Law
authors.forename: J K
authors.initials: JK
authors.lastname: Payne
authors.forename: S D
authors.initials: SD
authors.lastname: Mikolajczyk
authors.forename: H
authors.initials: H
authors.lastname: Zarrinmayeh
authors.forename: L N
authors.initials: LN
authors.lastname: Jungheim
authors.forename: J K
authors.initials: JK
authors.lastname: Kling
authors.forename: T A
authors.initials: TA
authors.lastname: Shepherd
authors.forename: J J
authors.initials: JJ
authors.lastname: Starling
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002384:Catalysis; D002460:Cell Line; D002511:Cephalosporins / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity*; D004337:Drug Carriers; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; C096732:CephDox; D002511:Cephalosporins; D004337:Drug Carriers; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D011355:Prodrugs; C047052:tumor-associated antigen 72; C075479:LY 266070; D014747:Vinblastine; D004317:Doxorubicin; D001618:beta-Lactamases