TARGETED PRODRUGS OF 9-AMINOCAMPTOTHECIN
DESCRIPTION (Adapted from the 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.
PROPOSED COMMERCIAL APPLICATION:
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.
Small Business Information at Submission:
Principal Investigator:Sean Omalley
HAWAII BIOTECHNOLOGY GROUP, INC.
99-193 AIEA HEIGHTS DR, STE 236 AIEA, HI 96701
Number of Employees: