Blakey D C, Valcaccia B E, East S, Wright A F, Boyle F T, Springer C J, Burke P J, Melton R G, Bagshawe K D
ICI Pharmaceuticals, Macclesfield, Cheshire.
Cell Biophys. 1993 Jan-Jun;22(1-3):1-8. doi: 10.1007/BF03033863.
The F(ab')2 fragment of the antitumor monoclonal antibody, A5B7, was covalently linked to the bacterial enzyme carboxypeptidase G2 (CPG2). The resulting conjugate was used in combination with a prodrug of a benzoic acid mustard alkylating agent to treat human colon tumor xenografts in a two-step targeting strategy, antibody-directed enzyme prodrug therapy (ADEPT). The prodrug, 4-[(2-chloroethyl) (2-mesyloxyethyl)amino]-benzoyl-L-glutamic acid is rapidly converted by CPG2 to a drug that is at least 15x more toxic in vitro against LS174T colorectal tumor cells than the prodrug. Optimal tumor/blood ratios of the A5B7-CPG2 were achieved 72 h after administration of the conjugate to athymic mice bearing established LS174T tumor xenografts. Significant antitumor activity was seen in LS174T tumor-bearing mice treated with the conjugate followed 3 d later by the prodrug. In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer.
抗肿瘤单克隆抗体A5B7的F(ab')2片段与细菌酶羧肽酶G2（CPG2）共价连接。所得偶联物与苯甲酸氮芥烷基化剂的前药联合使用，采用两步靶向策略——抗体导向酶前药疗法（ADEPT）治疗人结肠肿瘤异种移植瘤。前药4-[(2-氯乙基)(2-甲磺酰氧基乙基)氨基]-苯甲酰-L-谷氨酸被CPG2迅速转化为一种药物，该药物在体外对LS174T结肠直肠肿瘤细胞的毒性比前药至少高15倍。将偶联物给予患有已建立的LS174T肿瘤异种移植瘤的无胸腺小鼠后72小时，实现了A5B7-CPG2的最佳肿瘤/血液比率。在用偶联物治疗的LS174T荷瘤小鼠中观察到显著的抗肿瘤活性，3天后再给予前药。相比之下，单独使用前药、偶联物或活性药物在该肿瘤模型中均未产生任何抗肿瘤活性。这些研究证明了两步ADEPT系统在治疗结直肠癌方面的优势。
