HUMAN CARBOXYLESTERASES FOR TARGETED CPT-11 ACTIVATION

CPT-11是一种临床批准的抗癌药物。当在人中施用时，CPT-11充当前药，并且通过羧酸酯酶转化为活性药物SN-38，其是具有大约1，000倍的细胞毒性活性的药剂。由于注射的CPT-11中只有2 - 5%转化为SN-38，因此存在通过瘤内产生活性药物来提高其活性并降低其全身毒性的巨大机会。这将在癌症化疗的两步法中实现，其中在施用CPT-11之前允许单克隆抗体-羧酸酯酶缀合物结合细胞表面抗原。CPT-11与结合偶联物接触后将转化为SN-38。已鉴定出一种人羧酸酯酶，其可影响CPT-11活化，与从兔、豚鼠和恒河猴中报道的最有效的酶大致相同。本研究的目的是确定这种人羧酸酯酶从其氨基酸序列，附加酶的抗肿瘤单克隆抗体，并表征其能力的共轭物激活CPT-11在体外和体内。这种mAb-酶/前药组合是独特的，因为它利用人酶和临床批准的抗癌药物来实现治疗功效。拟议的商业应用：CPT-11被广泛使用，无论是作为单一药物，或在药物组合中用于治疗许多常见的癌症，淋巴瘤和白血病，即使它具有严重的剂量限制毒性。通过mAb-羧酸酯酶缀合物在实体瘤内产生CPT-11的活性形式可以导致更好的治疗效果和更低的全身毒性水平。这将构成癌症临床治疗的重大进步。

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.