Contribution of linker stability to the activities of anticancer immunoconjugates
Contribution of linker stability to the activities of anticancer immunoconjugates
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DOI：
10.1021/bc7004329
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发表时间：
2008-03-01
影响因子：
4.7
通讯作者：
Senter, Peter D.
中科院分区：
文献类型：
--
作者：
Alley, Stephen C.;Benjamin, Dennis R.;Senter, Peter D.
抗体-药物结合物(ADC)的连接体成分是开发高活性且耐受性好的优化治疗剂的关键特征。为了最大限度地释放肿瘤内的药物，需要在体循环中高度稳定的连接物，同时允许在靶部位有效地释放药物。在这方面，基于酰胺键的技术是一种技术进步，因为在循环中的连接基的半衰期(t(1/2)类似于7天)比在1-2天内分解的前一代连接基要长得多。通过硫醚/马来酰亚胺加合物将酰胺连接物(其中一些含有多肽)添加到mAb载体上。在这里，我们描述了使用溴乙酰胺丙基(BAC)代替马来酰亚胺丙基(Me)来增加所得硫醚ADC的血浆稳定性。一种针对淋巴瘤和肾癌CD70抗原的ADC 1F6-C4v2-bac-MMAF是在药物(MMAF)和单抗载体(1F6-C4v2)之间含有BAC硫醚间隔物。在给药后2周，该ADC在小鼠体内没有可测量到的全身药物释放。为了评估在含有ADC的MC之外改善连接子稳定性的影响，比较了一系列Me和Bac连接的1F6-MMAF结合物在裸鼠肾癌移植瘤中的耐受性、瘤内给药和治疗效果。尽管BAC接头技术导致肿瘤内药物暴露在7天期间比相应的ME接头高25%，但Me和含有ADC的BAC组之间的疗效没有统计学意义上的差异。从马来酰亚胺-加合物中释放药物的机制可能涉及在血浆中发生的逆迈克尔反应，体外研究表明，一些释放的药物-马来酰亚胺衍生物与血清白蛋白的半胱氨酸-34共价结合。综上所述，数据表明，通过用乙酰胺取代马来酰亚胺，可以获得具有更好体内稳定性的新连接体，但得到的ADC具有相似的耐受性和活性分布。
The linker component of antibody-drug conjugates (ADC) is a key feature in developing optimized therapeutic agents that are highly active at well tolerated doses. For maximal intratumoral drug delivery, linkers are required that are highly stable in the systemic circulation, yet allow for efficient drug release at the target site. In this respect, amide bond-based technologies constitute a technological advancement, since the linker half-lives in circulation (t(1/2) similar to 7 days) are much longer than earlier generation linkers that break down within 1-2 days. The amide linkers, some of which contain peptides, are appended to the mAb carriers through thioether/maleimide adducts. Here, we describe that use of a bromoacetamidecaproyl (bac) in place of the maleimidocaproyl (me) increases the plasma stability of resulting thioether ADCs. One such ADC, 1F6-C4v2-bac-MMAF, which is directed against the CD70 antigen on lymphomas and renal cell carcinoma, was prepared containing a bac thioether spacer between the drug (MMAF) and the mAb carrier (1F6-C4v2). There was no measurable systemic drug release from this ADC for 2 weeks postadministration in mice. In order to assess the impact of improving linker stability beyond mc containing ADCs, a series of me and bac-linked 1F6-MMAF conjugates were compared for tolerability, intratumoral drug delivery, and therapeutic efficacy in nude mice with renal cell carcinoma xenografts. There were no statistically significant efficacy differences between sets of me and bac containing ADCs, although the bac linker technology led to 25% higher intratumoral drug exposure over a 7 day period compared to the corresponding me linker. The mechanism of drug release from maleimide-adducts likely involves a retro-Michael reaction that takes place in plasma, based on in vitro studies demonstrating that some of the released drug-maleimide derivative became covalently bound to cysteine-34 of serum albumin. In summary, the data indicate that new linkers can be obtained with improved in vivo stability by replacing the maleimide with an acetamide, but the resulting ADCs had similar tolerability and activity profiles.