Enzyme / Abzyme Prodrug Activation Systems: Potential Use in Clinical Oncology

Yoshisuke      Nishi

Abstract

Clinically useful prodrug activation systems for cancer therapy can be applied in combination with the exogenous activating enzymes, by which masked prodrugs are able to unmask to exert cytotoxic effects on the target tumors. In essence, designing prodrugs not to be degenerated or activated by the endogenous enzymes is needed. Prodrug activation systems are to be delivered to the tumor site by delivery tools, including antibodies, genes, viral vectors and synthetic polymers, directed to the target tumors. Highly selective accumulation of the prodrug activation system at the tumor site is critically important for the efficacy of the prodrug activations. Genetic engineering of antibodies have made it possible to create a bispecific antibody and its derivatives, which are of special value to the functional antibodies with one arm to direct the target tumor tissues, and another to recruit the effector cells or molecules that can effectively kill the tumor cells. The technology has further opened the window for catalytic antibodies as a prodrug activating system. Catalytic antibodies have two distinct advantages over the enzymes: First, they can be selected to catalyze the reaction that is not catalyzed by the endogenous enzymes. Second, in order to minimize immunogenicity, humanization is applicable to catalytic antibodies. In viewing the concept and experimental data with a few clinical trials of recent approaches of prodrug activation systems, their potential utility in clinical oncology is further discussed.

Keywords: antibody-directed enzyme, prodrug activation, antibody-directed abzyme prodrug therapy, gene-directed enzyme prodrug therapy, virus-directed enzyme, prodrug therapy, polymer-directed enzyme

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