title: Therapeutic effects of monoclonal antibody-beta-lactamase conjugates in combination with a nitrogen mustard anticancer prodrug in models of human renal cell carcinoma.
abstract: A panel of 13 renal cell carcinoma cell lines was evaluated for the expression of antigens recognized by the L6 and L49 monoclonal antibodies. All of the cell lines were strongly positive for the L6 antigen, and 9/13 bound 96.5, which, like the L49 monoclonal antibody, recognizes the p97 melanotransferrin antigen. The L6 and L49 antibodies were chemically conjugated to Enterobacter cloacae beta-lactamase (bL), and their abilities to effect site-selective anticancer prodrug activation on two of the renal cell carcinoma cell lines (SN12P and 1934J) were evaluated in vitro and in vivo. L49-bL was 10-90-fold more potent in vitro than L6-bL for the activation of 7-(4-carboxybutanamido)cephalosporin mustard (CCM), a cephalosporin prodrug of phenylenediamine mustard (PDM). In addition, L49-bL showed higher degrees of specific SN12P and 1934J intratumoral uptake than L6-bL, even though the expression of L6 antigen was 2-fold higher than that of p97. These differences might be due to the high-affinity antigen binding of L49-bL relative to L6-bL. In vivo studies utilizing nude mice with established subcutaneous SN12P and 1934J tumor xenografts demonstrated that L49-bL/CCM combinations led to regressions and cures at well-tolerated doses, while L6-bL/CCM and the nonbinding control conjugate P1.17-bL in combination with CCM were ineffective. Conjugate localization in 1934J tumors was much lower than that observed in SN12P tumors, a finding that might acount for the higher activities of L49-bL/CCM in the latter model. These data show that the p97 antigen on renal cell carcinomas can be exploited for selective prodrug activation, even on tumors that localize very small amounts of the L49-bL conjugate.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, 3005 First Avenue, Seattle, Washington 98121, USA.
authors.forename: H P
authors.initials: HP
authors.lastname: Svensson
authors.forename: I S
authors.initials: IS
authors.lastname: Frank
authors.forename: K K
authors.initials: KK
authors.lastname: Berry
authors.forename: P D
authors.initials: PD
authors.lastname: Senter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D016972:Enterobacter cloacae / Q000201:enzymology; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D058950:Melanoma-Specific Antigens; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001618:beta-Lactamases / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D002511:Cephalosporins; D018796:Immunoconjugates; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C085091:7-(4-carboxybutanamido)cephalosporin mustard; C074075:TM4SF1 protein, human; D001618:beta-Lactamases