IMMUNOCHEMOTHERAPY FOR OVARIAN CANCER

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DESCRIPTION (provided by applicant) We propose to use water-soluble synthetic copolymers based on N-(2 hydroxypropyl) methacrylamide (HPMA) as carriers for pharmacologically active molecules. Specifically, we will synthesize an agonistic antibody - i.e. anti-TRAIL receptor (anti-DR4 or anti-DR5)-HPMA copolymer conjugates designed to induce selective apoptotic death in TRAIL-sensitive ovarian cancer cells. The agonistic antibodies resemble the cytokine and death ligand TRAIL. After binding to DR4 and DR5 death receptors they induce selective apoptotic death in a number of different cancer cells, including ovarian cancer cells. In this application, the agonistic antibody serves both as a death-inducing (cytotoxic) molecule and a targeting moiety. The development of multiple drug resistance (frequently seen in ovarian carcinoma) is a consequence of conventional cancer chemotherapy and remains the major obstacle in its treatment. Since the drug (doxorubicin) and TRAIL death-signaling pathways cross-sensitize each other, we suggest to use HPMA copolymer conjugates containing two molecules that act in synergy (agonistic anti-DR4 and/or anti-DR5 antibody plus doxorubicin) or HPMA copolymer-bound antibody and HPMA copolymer-bound drug for combination immunochemotherapy. This is intended to overcome both TRAIL- and drug-resistance in ovarian cancer. This HPMA copolymer carrier-based therapy should stabilize the agonistic antibody, increase its proapoptotic activity, decrease its immunogenicity, prolong its availability in the blood stream, and allow a dosage reduction, thereby minimizing unwanted side effects while simultaneously enhancing cytotoxicity.