Targeted payload delivery strategies, such as antibody‐drug conjugates (ADCs), have emerged as important therapeutics. Although considerable efforts have been made in the areas of antibody engineering and labeling methodology, improving the overall physicochemical properties of the linker/payload combination remains an important challenge. Here we report an approach to create an intrinsically hydrophilic linker domain. We find that benzyl α‐ammonium carbamates (BACs) undergo tandem 1,6–1,2‐elimination to release secondary amines. Using a fluorogenic hemicyanine as a model payload component, we show that a zwitterionic BAC linker improves labeling efficiency and reduces antibody aggregation when compared to a commonly used para‐amino benzyl (PAB) linker as well as a cationic BAC. Cellular and in vivo fluorescence imaging studies demonstrate that the model payload is specifically released in antigen‐expressing cells and tumors. The therapeutic potential of the BAC linker strategy was assessed using an MMAE payload, a potent microtubule‐disrupting agent frequently used for ADC applications. The BAC‐MMAE combination enhances labeling efficiency and cellular toxicity when compared to the routinely used PAB‐Val‐Cit ADC analogue. Broadly, this strategy provides a general approach to mask payload hydrophobicity and improve the properties of targeted agents.

中文翻译：

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氨基甲酸苄基铵酯经过两步接头切割并改善抗体偶联物的性能


为了鉴定本征极性接头结构域，我们报道了 α-氨基甲酸铵 （BAC） 经历串联的 1,6-1,2 消除序列以释放仲胺。与传统和阳离子 BAC 接头相比，发现两性离子 BAC 接头变体可改善标记并减少抗体聚集。最后，荧光成像研究表明，模型有效载荷在表达抗原的细胞和肿瘤中以高特异性释放。