title: Multiple event activation of a generic prodrug trigger by antibody catalysis.
abstract: Chemotherapeutic regimes are typically limited by nonspecific toxicity. To address this problem we have developed a broadly applicable drug-masking chemistry that operates in conjunction with a unique broad-scope catalytic antibody. This masking chemistry is applicable to a wide range of drugs because it is compatible with virtually any heteroatom. We demonstrate that generic drug-masking groups may be selectively removed by sequential retro-aldol-retro-Michael reactions catalyzed by antibody 38C2. This reaction cascade is not catalyzed by any known natural enzyme. Application of this masking chemistry to the anticancer drugs doxorubicin and camptothecin produced prodrugs with substantially reduced toxicity. These prodrugs are selectively unmasked by the catalytic antibody when it is applied at therapeutically relevant concentrations. We have demonstrated the efficacy of this approach by using human colon and prostate cancer cell lines. The antibody demonstrated a long in vivo half-life after administration to mice. Based on these findings, we believe that the system described here has the potential to become a key tool in selective chemotherapeutic strategies.
authors.affiliation: The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: D
authors.initials: D
authors.lastname: Shabat
authors.forename: C
authors.initials: C
authors.lastname: Rader
authors.forename: B
authors.initials: B
authors.lastname: List
authors.forename: R A
authors.initials: RA
authors.lastname: Lerner
authors.forename: C F
authors.initials: CF
authors.lastname: Barbas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D011355:Prodrugs; D004317:Doxorubicin; D002166:Camptothecin