Multiple event activation of a generic prodrug trigger by antibody catalysis

Chemotherapeutic regimes are typically limited by nonspecific toxicity. To address this problem we have developed a broadly applicable drug-masking ch emistry that operates in conjunction with a unique broad-scope catalytic an tibody. This masking chemistry is applicable to a wide range of drugs becau se it is compatible with virtually any heteroatom. We demonstrate that gene ric drug-masking groups may be selectively removed by sequential retro-aldo l-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 pro drugs with substantially reduced toxicity. These prodrugs are selectively u nmasked by the catalytic antibody when it is applied at therapeutically rel evant concentrations. We have demonstrated the efficacy of this approach by using human colon and prostate cancer cell lines. The antibody demonstrate d a long in vivo half-life after administration to mice. Based on these fin dings, we believe that the system described here has the potential to becom e a key tool in selective chemotherapeutic strategies.