Stable and Potent Selenomab-Drug Conjugates.
Stable and Potent Selenomab-Drug Conjugates.
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DOI：
10.1016/j.chembiol.2017.02.012
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发表时间：
2017-04-20
影响因子：
8.6
通讯作者：
Rader C
中科院分区：
文献类型：
--
作者：
Li X;Nelson CG;Nair RR;Hazlehurst L;Moroni T;Martinez-Acedo P;Nanna AR;Hymel D;Burke TR Jr;Rader C
硒单克隆抗体是工程化的单克隆抗体，具有一个或多个掺入的硒代半胱氨酸残基。硒代半胱氨酸的硒醇基团的独特反应性允许药物的位点特异性缀合。与已用于产生位点特异性抗体-药物缀合物的其它天然和非天然氨基酸和碳水化合物残基相比，硒代半胱氨酸是特别反应性的，允许在接近生理条件下快速、单步和有效的反应。使用定制的缀合化学，我们产生了高度稳定的硒单抗-药物缀合物，并在体外和体内证明了它们的效力和选择性。这些位点特异性抗体-药物缀合物建立在硒代半胱氨酸界面上，在液体和固体恶性肿瘤模型中显示了广泛的治疗效用。Li等人利用第21天然氨基酸硒代半胱氨酸的高反应性来快速有效地组装抗体-药物缀合物，其在人类癌症的多种体外和体内模型中显示出优异的稳定性、效力和选择性。
Selenomabs are engineered monoclonal antibodies with one or more translationally incorporated selenocysteine residues. The unique reactivity of the selenol group of selenocysteine permits site-specific conjugation of drugs. Compared to other natural and unnatural amino acid and carbohydrate residues that have been used for the generation of site-specific antibody-drug conjugates, selenocysteine is particularly reactive, permitting fast, single-step, and efficient reactions under near physiological conditions. Using a tailored conjugation chemistry, we generated highly stable selenomab-drug conjugates and demonstrated their potency and selectivity in vitro and in vivo. These site-specific antibody-drug conjugates built on a selenocysteine interface revealed broad therapeutic utility in liquid and solid malignancy models. Li et al. harness the high reactivity of the 21st natural amino acid selenocysteine to rapidly and efficiently assemble antibody-drug conjugates that reveal excellent stability, potency, and selectivity in diverse in vitro and in vivo models of human cancers.