Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France; and.
Immunitrack ApS, 2100 Copenhagen East, Denmark.
J Immunol. 2020 Nov 15;205(10):2850-2860. doi: 10.4049/jimmunol.2000732. Epub 2020 Oct 19.
Neonatal Fc receptor (FcRn) has a key role in the homeostasis of IgG. Despite its physiological and clinical importance, the interaction of IgG and FcRn remains not completely comprehended. Thus, IgG molecules with identical constant portions but with minor differences in their V regions have been demonstrated to interact with FcRn with a considerable heterogeneity in the binding affinity. To understand this discrepancy, we dissected the physicochemical mechanism of the interaction of 10 human IgG1 to human FcRn. The interactions of two Abs in the presence of their cognate Ags were also examined. Data from activation and equilibrium thermodynamics analyses as well as pH dependence of the kinetics revealed that the V region of IgG could modulate a degree of conformational changes and binding energy of noncovalent contacts at the FcRn binding interface. These results suggest that the V domains modulate FcRn binding site in Fc by allosteric effects. These findings contribute for a deeper understanding of the mechanism of IgG-FcRn interaction. They might also be of relevance for rational engineering of Abs for optimizing their pharmacokinetic properties.
新生儿 Fc 受体（FcRn）在 IgG 的体内平衡中起着关键作用。尽管其具有生理和临床重要性，但 IgG 和 FcRn 的相互作用仍未完全被理解。因此，已经证明具有相同恒定部分但在其 V 区有微小差异的 IgG 分子与 FcRn 相互作用，其结合亲和力具有相当大的异质性。为了理解这种差异，我们剖析了 10 个人 IgG1 与人 FcRn 的相互作用的物理化学机制。还检查了两个 Abs 在其同源 Ag 存在下的相互作用。来自激活和平衡热力学分析以及动力学的 pH 依赖性的数据表明，IgG 的 V 区可以调节 FcRn 结合界面处非共价接触的构象变化程度和结合能。这些结果表明，V 结构域通过变构效应调节 Fc 中的 FcRn 结合位点。这些发现有助于更深入地了解 IgG-FcRn 相互作用的机制。它们对于合理设计 Abs 以优化其药代动力学特性也可能具有相关性。
