application): The goal of this project is to produce a water-soluble anticancer prodrug and an antibody-enzyme conjugate for use in Antibody-Directed Enzyme Prodrug Therapy (ADEPT). The prodrug will be a derivative of 9-aminocamptothecin (9AC), a lipophilic topoisomerase I inhibitor that is not subject to P-glycoprotein resistance. Though it has demonstrated excellent preclinical antitumor activity against a number of xenografts, 9AC has shown disappointing clinical results, due to extremely poor (<0.5 percent) bioavailability of the therapeutically active lactone form of the drug in humans. Our novel prodrug design incorporates proprietary attachment chemistry to overcome instability problems with 9AC while reversibly masking the pharmacophore. This stabilization combined with immunotargeted therapy will significantly increase 9AC's bioavailability and reduces its toxicity to normal tissues. In Phase I, the applicant will prepare a novel water-soluble prodrug derivative of 9AC and an antibody-enzyme conjugate targeted to the KSA tumor-associated antigen. Using these reagents, the applicant will demonstrate antigen-specific targeting and enzymatic activation of the prodrug in vitro. The applicant will also confirm the ability of the immunoconjugate to localize to targeted colon adenocarcinoma xenografts in mice. Phase II will focus on preclinical optimization of the therapy in vivo.
9-aminocamptothecin is a potentially important anti-cancer agent, particularly if stability and formulation problems can be solved. A water soluble prodrug designed to be activated at solid tumor sites by an antibody-enzyme conjugate should increase tumor cell selectivity and reduce systemic toxicity. A clinically effective 9-aminocamptothecin prodrug would have significant commercial value as a pharmaceutical product.
