Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells
Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells
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DOI：
10.1182/blood-2008-03-144600
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发表时间：
2008-09-15
期刊：
影响因子：
20.3
通讯作者：
Valerius, Thomas
中科院分区：
文献类型：
--
作者：
Peipp, Matthias;van Bueren, Jeroen J. Lammerts;Valerius, Thomas
抗体Fc片段的糖基化是Fc受体介导的活性所必需的。已知碳水化合物的异质性可以调节血液中效应细胞的活性，其中岩藻糖基化尤其影响NK细胞介导的杀伤。在这里，我们研究了2F8的糖基化情况，2F8是一种临床开发中的人抗表皮生长因子受体的单抗，它的糖基化情况如何影响效应器功能。研究了Fc片段中复合型低聚糖岩藻糖基化、半乳糖化和唾液酸化的不同2F8批次。我们的结果证实，低水平的岩藻糖可增强单核细胞介导的抗体介导的细胞毒性(ADCC)。相反，发现多形核细胞优先通过高岩藻糖化抗体进行杀伤。全血ADCC检测，包含这两种类型的效应细胞，显示两批之间在肿瘤细胞杀伤方面几乎没有差异。然而，值得注意的是，高岩藻糖抗体在粒细胞集落刺激因子激活的多形核细胞数量较多的粒细胞集落刺激因子激活的供者的血液中诱导出更高的ADCC。总之，我们的数据首次证明，缺乏岩藻糖一般不会增加治疗性抗体的ADCC活性，Fc糖基化对ADCC的影响严重依赖于招募的效应细胞类型。
Glycosylation of the antibody Fc fragment is essential for Fc receptor mediated activity. Carbohydrate heterogeneity is known to modulate the activity of effector cells in the blood, in which fucosylation particularly affects NK cell-mediated killing. Here, we investigated how the glycosylation profile of 2F8, a human IgG(1) monoclonal antibody against epidermal growth factor receptor in clinical development, impacted effector function. Various 2F8 batches differing in fucosylation, galactosylation, and sialylation of the complex-type oligosaccharides in the Fc fragment were investigated. Our results confirmed that low fucose levels enhance mononuclear cell-mediated antibody-mediated cellular cytotoxicity ( ADCC). In contrast, polymorphonuclear cells were found to preferentially kill via high-fucosylated antibody. Whole blood ADCC assays, containing both types of effector cells, revealed little differences in tumor cell killing between both batches. Significantly, however, high-fucose antibody induced superior ADCC in blood from granulocyte colony-stimulating factor-primed donors containing higher numbers of activated polymorphonuclear cells. In conclusion, our data demonstrated for the first time that lack of fucose does not generally increase the ADCC activity of therapeutic antibodies and that the impact of Fc glycosylation on ADCC is critically dependent on the recruited effector cell type.