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为大家介绍的是最近在Journal of the American Chemical Society 上报道的一篇标题为 “Site-Specific Antibody Prodrugs via S‑Arylation: a Bioconjugation Approach Toward Masked Tyrosine Analogues” 的文章。该文的通讯作者是麻省理工学院化学系的Stephen L Buchwald教授、Bradley L. Pentelute教授和百时美施贵宝研发部门的Yong Zhang。本文开发了一种抗体前药的设计方法，能够在目标抗体的互补决定区中引入掩蔽基团以减少抗体在正常组织中的脱靶毒性。并能在特定条件下脱保护变为一种酪氨酸模拟物，羟苯基半胱氨酸，基本维持原抗体的抗原结合活性。
抗体在包括癌症在内的多种人类疾病的治疗中有着里程碑式的应用意义，尤其是近年来逐渐兴起的肿瘤免疫疗法。细胞毒性T淋巴细胞相关蛋白4（CTLA-4）在T细胞的识别和免疫抑制过程中起到重要作用，是肿瘤细胞逃逸免疫系统杀伤的重要受体之一。用抗体来阻断CTLA-4与其配体的相互作用能够激活免疫系统，并允许T细胞杀死相关的细胞。然而，与许多抗体治疗药物一样，这一靶蛋白存在于病变和健康组织中，这可能通过与非肿瘤相关的CTLA-4相互作用导致肿瘤外毒性。因此，利用抗体前药的策略，使抗体在目标区域的刺激条件（如蛋白酶表达）下激活并恢复抗原结合能力，能够有效降低其毒性，并扩大治疗窗口。
现有的抗体前药制备策略主要集中于通过融合表达的方式在抗体的N端或C端添加掩蔽组件，但这种策略只将可掩蔽残基限制在20种天然氨基酸中。在抗体侧链进行修饰能够更有效地阻断其与抗原的结合，并且能够广泛添加反应位点，使响应类型多样化。此前作者团队研究过钯催化的半胱氨酸芳基化反应，并且验证了产物与酪氨酸结构和功能上的相似性。因此，在本文中，作者以CTLA-4的FDA批准抗体药物伊匹木单抗作为研究对象，用钯催化的氧化加成反应在其半胱氨酸侧链上引入功能化芳基，实现了用蛋白酶可切割序列连接的PEG链对抗体结合能力的掩蔽。 (图1)
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