Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody-drug conjugates
Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody-drug conjugates
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DOI：
10.1038/nbt.2968
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发表时间：
2014-10-01
影响因子：
46.9
通讯作者：
Senter, Peter D.
中科院分区：
文献类型：
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作者：
Lyon, Robert P.;Setter, Jocelyn R.;Senter, Peter D.
许多抗体-药物缀合物（ADC）在体内是不稳定的，因为它们由缀合至反应性硫醇的含马来酰亚胺的组分形成。这些硫代琥珀酰亚胺键在血浆中经历两个竞争性反应：通过逆迈克尔反应消除马来酰亚胺，这导致药物-接头从ADC中丢失，以及硫代琥珀酰亚胺环的水解，这导致对消除反应具有抗性的衍生物。为了创建具有改进的稳定性特征的接头技术，我们使用二氨基丙酸（DPR）来制备药物-接头，其并入与马来酰亚胺相邻的碱性氨基，定位成提供硫代琥珀酰亚胺环水解的分子内催化。该碱性基团诱导硫代琥珀酰亚胺在中性pH和室温下进行快速水解。一旦水解，药物-接头不再经历马来酰亚胺消除反应，防止非特异性解缀合。体内研究表明，增加的稳定性特征可以导致ADC抗肿瘤活性的改善和中性粒细胞减少的减少。
Many antibody-drug conjugates (ADCs) are unstable in vivo because they are formed from maleimide-containing components conjugated to reactive thiols. These thiosuccinimide linkages undergo two competing reactions in plasma: elimination of the maleimide through a retro-Michael reaction, which results in loss of drug-linker from the ADC, and hydrolysis of the thiosuccinimide ring, which results in a derivative that is resistant to the elimination reaction. In an effort to create linker technologies with improved stability characteristics, we used diaminopropionic acid (DPR) to prepare a drug-linker incorporating a basic amino group adjacent to the maleimide, positioned to provide intramolecular catalysis of thiosuccinimide ring hydrolysis. This basic group induces the thiosuccinimide to undergo rapid hydrolysis at neutral pH and room temperature. Once hydrolyzed, the drug-linker is no longer subject to maleimide elimination reactions, preventing nonspecific deconjugation. In vivo studies demonstrate that the increased stability characteristics can lead to improved ADC antitumor activity and reduced neutropenia.