Antibody-dependent enzyme prodrug therapy (ADEPT ) is a unique anti- cancer strategy which takes advantage of the catalytic power of enzymes to amplify the cytotoxicity-targeting power of antibodies. Tumor-specific antibody-enzyme conjugates concentrate at the tumor and activate prodrugs to produce the highest possible concentrations of cytotoxins at the tumor site with minimal threat to other tissues. The efficacy of ADEPT is compromised, however, by the immunogenicity of the non-human enzymes which must be used. Catalytic antibodies offer a potential solution to this problem in that they can be """"""""humanized"""""""" to avoid immunogenicity. However, their utility is severely limited by catalytic inefficiency. We have developed a systematic method for optimizing the catalytic efficiencies of prodrug-activating abzymes. The method is based on non-toxic prodrug analogs in which the leaving group confers a selectable phenotype, whereby cell viability in the presence of the prodrug analog is dependent on the expression of a prodrug-activating enzyme. In Phase I we will use tyrosine auxotrophy to select tyrosine carbamate prodrug-activating abzymes from antibody repertoires cloned from ice which were immunized with a transition state analog of prodrug hydrolysis. In Phase II we will optimize selected abzymes using Parsimonious Mutagenesis (PM), a proprietary computer-assisted method for oligonucleotide-directed scanning mutagenesis.
The primary goal of this research is to develop novel chemotherapeutic strategies for cancer based on tumor-targeted catalytic antibodies and prodrugs. If successful, such therapies will have substantial commercial value.
