Impact of Immune Complex Size and Glycosylation on IgG Binding to Human FcγRs
Impact of Immune Complex Size and Glycosylation on IgG Binding to Human FcγRs
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DOI：
10.4049/jimmunol.1200501
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发表时间：
2013-04-15
影响因子：
4.4
通讯作者：
Nimmerjahn, Falk
中科院分区：
文献类型：
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作者：
Lux, Anja;Yu, Xiaojie;Nimmerjahn, Falk
IgG分子以完整Ab或Fc融合蛋白的形式广泛用作治疗剂。尽管IgG Fc片段与细胞Fc γ R的有效结合对于实现高细胞溶解活性可能是必需的，但是对于其他应用限制或消除这种相互作用可能是有利的。已使用遗传或生物化学方法来产生这些非Fc γ R结合IgG变体。通过使用Fc γ R的可溶形式和这些改变的IgG分子的单体形式，证明这些IgG变体不再结合Fc γ R。然而，重要的是，这些测定不能反映IgG与以多聚体免疫复合物形式发生的低亲和力细胞Fc γ R的生理相互作用。在本研究中，我们研究了免疫复合物的大小如何影响正常和各种形式的潜在非Fc γ R结合IgG变体与细胞Fc γ R的相互作用。我们表明，D265 A突变和EndoS处理均不能完全消除所有IgG亚类与细胞Fc γ R的相互作用，这表明IgG亚类特异性策略对于完全干扰人Fc γ R结合至关重要，所述D265 A突变和EndoS处理导致IgG分子仅具有一个N-乙酰葡糖胺和一个岩藻糖残基。免疫学杂志，2013，190：4315-4323。
IgG molecules are widely used as therapeutic agents either in the form of intact Abs or as Fc fusion proteins. Although efficient binding of the IgG Fc fragment to cellular Fc gamma Rs may be essential to achieve a high cytolytic activity, it may be advantageous for other applications to limit or abolish this interaction. Genetic or biochemical approaches have been used to generate these non-Fc gamma R-binding IgG variants. By using soluble versions of Fc gamma Rs and monomeric versions of these altered IgG molecules, it was demonstrated that these IgG variants no longer bind to Fc gamma Rs. Importantly, however, these assays do not reflect the physiologic interaction of IgG with low-affinity cellular Fc gamma Rs occurring in the form of multimeric immune complexes. In this study, we investigated how the size of an immune complex can affect the interaction of normal and various versions of potentially non-Fc gamma R-binding IgG variants with cellular Fc gamma Rs. We show that neither the D265A mutation nor EndoS treatment resulting in IgG molecules with only one N-acetylglucosamine and a fucose residue was fully able to abolish the interaction of all IgG subclasses with cellular Fc gamma Rs, suggesting that IgG subclass-specific strategies are essential to fully interfere with human Fc gamma R binding. The Journal of Immunology, 2013, 190: 4315-4323.