Antibody‐dependent cell‐mediated cytotoxicity (ADCC) has been identified as one of the potentially critical effector functions underlying the clinical efficacy of some therapeutic immunoglobin G1 (IgG1) antibodies. It has been well established that higher levels of afucosylated N‐linked glycan structures on the Fc region enhance the IgG binding affinity to the FcγIIIa receptor and lead to increased ADCC activity. However, whether terminal galactosylation of an IgG1 impacts its ADCC activity is less understood. Here, we used a new strategy for glycan enrichment and remodeling to study the impact of terminal galactose on ADCC activity for therapeutic IgG1s. Our results indicate that the degree of influence of terminal galactose on in vitro ADCC activity depends on the presence or absence of the core fucose, which is typically linked to the first N‐acetyl glucosamine residue of an N‐linked glycosylation core structure. Specifically, terminal galactose on afucosylated IgG1 mAbs enhanced ADCC activity with impact coefficients (ADCC%/Gal%) more than 20, but had minimal influence on ADCC activity on fucosylated structures with impact coefficient in the range of 0.1–0.2. Knowledge gained here can be used to guide product and process development activities for biotherapeutic antibodies that require effector function for efficacy, and also highlight the complexity in modulating the immune response through N‐linked glycosylation of antibodies.

中文翻译：

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聚糖工程揭示了末端半乳糖和核心岩藻糖对抗体依赖性细胞介导的细胞毒性的相关影响。

抗体依赖性细胞介导的细胞毒性 (ADCC) 已被确定为某些治疗性免疫球蛋白 G1 (IgG1) 抗体临床疗效的潜在关键效应功能之一。众所周知，Fc 区更高水平的无岩藻糖基化 N-连接聚糖结构可增强 IgG 与 FcγIIIa 受体的结合亲和力，并导致 ADCC 活性增加。然而，IgG1 的末端半乳糖基化是否会影响其 ADCC 活性尚不清楚。在这里，我们使用了一种新的聚糖富集和重构策略来研究末端半乳糖对治疗性 IgG1 的 ADCC 活性的影响。我们的结果表明，末端半乳糖对体外 ADCC 活性的影响程度取决于核心岩藻糖的存在与否，它通常连接到 N-连接糖基化核心结构的第一个 N-乙酰氨基葡萄糖残基。具体而言，无岩藻糖基化 IgG1 mAb 上的末端半乳糖以超过 20 的影响系数 (ADCC%/Gal%) 增强了 ADCC 活性，但对岩藻糖基化结构的 ADCC 活性影响最小，影响系数在 0.1-0.2 范围内。此处获得的知识可用于指导需要效应子功能才能发挥功效的生物治疗性抗体的产品和工艺开发活动，还可以突出通过抗体的 N-连接糖基化调节免疫反应的复杂性。但对岩藻糖基化结构的 ADCC 活性影响最小，影响系数在 0.1-0.2 范围内。此处获得的知识可用于指导需要效应子功能才能发挥功效的生物治疗性抗体的产品和工艺开发活动，还可以突出通过抗体的 N-连接糖基化调节免疫反应的复杂性。但对岩藻糖基化结构的 ADCC 活性影响最小，影响系数在 0.1-0.2 范围内。此处获得的知识可用于指导需要效应子功能才能发挥功效的生物治疗性抗体的产品和工艺开发活动，还可以突出通过抗体的 N-连接糖基化调节免疫反应的复杂性。