Reddy Joseph A, Westrick Elaine, Santhapuram Hari K R, Howard Stephen J, Miller Michael L, Vetzel Marilynn, Vlahov Iontcho, Chari Ravi V J, Goldmacher Victor S, Leamon Christopher P
Endocyte, Inc., West Lafayette, Indiana 47906, USA.
Cancer Res. 2007 Jul 1;67(13):6376-82. doi: 10.1158/0008-5472.CAN-06-3894.
EC131, a new folate receptor (FR)-targeted drug conjugate, was prepared by covalently attaching the vitamin folic acid (FA) to a potent microtubule-inhibiting agent, maytansinoid DM1, via an intramolecular disulfide bond. When tested on cells in culture, EC131 was found to retain high affinity for FR-positive cells and to provide FR-specific cytotoxicity with an IC(50) in the low nanomolar range. The activity of EC131 was completely blocked in the presence of an excess of free FA, and no activity was detected against FR-negative cells. When evaluated against s.c. FR-positive M109 tumors in BALB/c mice, EC131 showed marked antitumor efficacy. Furthermore, this therapeutic effect occurred in the apparent absence of weight loss or noticeable organ tissue degeneration. In contrast, no significant antitumor activity was observed in EC131-treated animals that were codosed with an excess of FA, thus demonstrating the targeted specificity of the in vivo activity. EC131 also showed marked antitumor activity against FR-positive human KB tumors, but not against FR-negative A549 tumors, in nude mice with no evidence of systemic toxicity during or after the therapy. In contrast, therapy with the free maytansinoid drug (in the form of DM1-S-Me) proved not to be effective against the KB model when administered at its maximum tolerated dose (MTD). Taken together, these results indicate that EC131 is a highly potent agent capable of producing therapeutic benefit in murine tumor models at sub-MTD levels.
EC131是一种新型的靶向叶酸受体（FR）的药物偶联物，它通过分子内二硫键将维生素叶酸（FA）与一种强效的微管抑制剂美登素类药物DM1共价连接而成。在细胞培养实验中，发现EC131对FR阳性细胞保持高亲和力，并在低纳摩尔范围内提供FR特异性细胞毒性，其半数抑制浓度（IC50）较低。在过量游离FA存在的情况下，EC131的活性被完全阻断，且对FR阴性细胞未检测到活性。在BALB/c小鼠中评估其对皮下接种的FR阳性M109肿瘤的疗效时，EC131显示出显著的抗肿瘤效果。此外，这种治疗效果出现时明显没有体重减轻或明显的器官组织退化。相比之下，在同时给予过量FA的情况下，接受EC131治疗的动物未观察到显著的抗肿瘤活性，从而证明了体内活性的靶向特异性。在裸鼠中，EC131对FR阳性的人KB肿瘤也显示出显著的抗肿瘤活性，但对FR阴性的A549肿瘤则无活性，且在治疗期间或之后均无全身毒性的证据。相反，当以最大耐受剂量（MTD）给予游离的美登素类药物（DM1-S-Me形式）时，对KB模型无效。综上所述，这些结果表明EC131是一种高效的药物，能够在低于MTD的剂量水平下对小鼠肿瘤模型产生治疗效果。
