Research Project
6075928
CPT-11 is a clinically approved anticancer agent. When administered in people, CPT-11 acts as a prodrug, and is converted by carboxylesterases to the active drug, SN-38, an agent with approximately 1 ,000 times more cytotoxic activity. Since only 2 - 5% of the injected CPT-11 is converted to SN-38, a great opportunity exists to improve its activity and to lower its systemic toxicity by generating the active drug intratumorally. This will be accomplished in a two-step approach to cancer chemotherapy, in which a monoclonal antibody-carboxylesterase conjugate is allowed to bind to cell- surface antigens prior to the administration of CPT-11. Upon contact with the bound conjugate, CPT-11 will be converted to SN-38. A form of human carboxylesterase has been identified that can effect CPT-11 activation approximately as well as the most efficient enzymes reported from rabbit, guinea pig, and rhesus monkey. The aims of this study are to identify this human carboxylesterase from its amino acid sequence, attach the enzyme to antitumor monoclonal antibodies, and to characterize the conjugates for their abilities to activate CPT-11 both in vitro and in vivo. This mAb-enzyme/prodrug combination is unique, in that it utilizes a human enzyme and a clinically approved anticancer drug to achieve therapeutic efficacy. PROPOSED COMMERCIAL APPLICATIONS: CPT-11 is used widely, either as a single agent, or in drug combinations for the treatment of many common carcinomas, lymphomas and leukemia, even though it has severe dose limiting toxicities. Generation of the active form of CPT-11 inside solid tumors by mAb-carboxylesterase conjugates could lead to better therapeutic efficacy and lower levels of systemic toxicity. This would constitute a major advancement in the clinical treatment of cancer.
