Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells
申请人:Bristol-Myers Squibb Company
公开号:EP0302473A2
公开(公告)日:1989-02-08
This invention relates to a novel method for the delivery of cytotoxic drugs to tumor cells by the administration of a tumor-specific antibody-enzyme conjugate that binds to the tumor cells, and the additional administration of a prodrug that is converted at the tumor site, in the presence of the antibody-bound enzyme, to an active cytotoxic drug. According to preferred embodiments of this invention, antibody-enzyme conjugates containing the enzyme, alkaline phosphatase ("AP"), have been used in conjunction with the novel prodrug, etoposide-4′-phosphate or 7-(2′-aminoethyl phosphate)mitomycin or a combination thereof, to effect killing of tumor cells. According to another embodiment of the invention, an antibody-enzyme conjugate containing the enzyme, penicillin V amidase ("PVA"), has been used. in conjunction with a novel prodrug, N-(p-hydroxyphenoxyacetyl)adriamycin to effect killing of tumor cells. Still another embodiment of the invention relates to the use of an antibody-enzyme conjugate containing the enzyme, cytosine deaminase ("CD"), in combination with the prodrug, 5-fluorocytosine, to effect killing of tumor cells. The methods, antibody-enzyme conjugates, prodrugs, pharmaceutical compositions and combinations of this invention provide for enhanced selective killing of tumor cells and are thus useful in the treatment of cancers and other tumors.
本发明涉及一种向肿瘤细胞输送细胞毒性药物的新方法,该方法是通过施用能与肿瘤细胞结合的肿瘤特异性抗体-酶结合物,并额外施用一种原药,该原药在肿瘤部位,在抗体结合酶的存在下,转化为活性细胞毒性药物。根据本发明的优选实施方案,含有碱性磷酸酶("AP")的抗体-酶结合物与新型原药依托泊苷-4′-磷酸或 7-(2′-氨基乙基磷酸)丝裂霉素或它们的复合物一起使用,可杀死肿瘤细胞。根据本发明的另一个实施方案,一种含有青霉素 V 氨基酶("PVA")的抗体-酶结合物与一种新型原药 N-(对羟基苯氧乙酰)阿霉素结合使用,可杀死肿瘤细胞。本发明的另一个实施方案涉及使用含有胞嘧啶脱氨酶("CD")的抗体-酶结合物与原药 5-氟胞嘧啶结合来杀死肿瘤细胞。本发明的方法、抗体-酶结合物、原药、药物组合物和组合物可增强对肿瘤细胞的选择性杀伤,因此可用于癌症和其他肿瘤的治疗。