Preclinical antitumor activity of a novel folate-targeted dual drug conjugate
Preclinical antitumor activity of a novel folate-targeted dual drug conjugate
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DOI：
10.1021/mp070049c
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Wang, Yu
中科院分区：
文献类型：
--
作者：
Leamon, Christopher P.;Reddy, Joseph A.;Wang, Yu
我们设计了一种新型的肿瘤靶向药物，通过将两种不同的药物分子连接到同一个配体上，具有不同的生物学作用机制。该化合物，命名为EC0225，代表了“第一个”多药，叶酸受体（FR）靶向剂被公开。它是由一个单一的叶酸分子构成的，通过一个亲水性的肽基间隔区延伸，后者又通过两个单独的含二硫化物的接头连接到丝裂霉素和阿米卡星生物碱单元上。EC0225在体外产生有效的剂量反应活性，并且在给予耐受良好的给药方案后观察到对FIR阳性同基因和异种移植肿瘤的治疗活性。当使用EC 0225治疗最初携带体积高达750 mm（3）的肿瘤的小鼠时，也观察到多个完全缓解和治愈。总的来说，EC0225令人印象深刻的临床前活性使其被选为开发候选药物，并开始了2007年3月开始的治疗晚期恶性肿瘤的1期临床试验。
We have designed a new type of tumor-targeted agent by tethering two different drug molecules, with distinct biological mechanisms of action, to the same ligand. This compound, named EC0225, represents the "first in class" multidrug, folate receptor (FR)-targeted agent to be disclosed. It was constructed with a single folate molecule, extended by a hydrophilic peptide-based spacer, which was in turn attached to mitomycin and Vinca alkaloid units via two separate disulfide-containing linkers. EC0225 produced potent, dose-responsive activity in vitro, and curative activity was observed against FIR-positive syngeneic and xenograft tumors following the administration of well-tolerated dosing regimens. Multiple complete responses and cures were also noted when EC0225 was used to treat mice initially bearing tumors as large as 750 mm(3) in volume. Overall, EC0225's impressive preclinical activity allowed for its selection as a development candidate and for the start of Phase 1 clinical trials, which began in March of 2007, for the treatment of advanced malignancies.