Monoclonal antibodies targeting the immune checkpoint PD-1 have provided significant clinical benefit across a number of solid tumors, with differences in efficacy and toxicity profiles possibly related to their intrinsic molecular properties. Here, we report that camrelizumab and cemiplimab engage PD-1 through interactions with its fucosylated glycan. Using a combination of protein and cell glycoengineering, we demonstrate that the two antibodies bind preferentially to PD-1 with core fucose at the asparagine N58 residue. We then provide evidence that the concentration of fucosylated PD-1 in the blood of non-small-cell lung cancer patients varies across different stages of disease. This study illustrates how glycoprofiling of surface receptors and related circulating forms can inform the development of differentiated antibodies that discriminate glycosylation variants and achieve enhanced selectivity, and paves the way toward the implementation of personalized therapeutic approaches.

中文翻译：

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可变的 PD-1 糖基化调节免疫检查点抑制剂的活性。

针对免疫检查点 PD-1 的单克隆抗体在许多实体瘤中提供了显着的临床益处，其功效和毒性特征的差异可能与其内在分子特性有关。在此，我们报告卡瑞利珠单抗和 cemiplimab 通过与其岩藻糖基化聚糖相互作用来结合 PD-1。通过结合蛋白质和细胞糖工程，我们证明这两种抗体优先与天冬酰胺 N58 残基处具有核心岩藻糖的 PD-1 结合。然后，我们提供证据表明，非小细胞肺癌患者血液中岩藻糖基化 PD-1 的浓度在不同疾病阶段存在差异。这项研究说明了表面受体和相关循环形式的糖谱分析如何为差异化抗体的开发提供信息，从而区分糖基化变异并实现增强的选择性，并为实施个性化治疗方法铺平道路。