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Evidence of Variable Human Fcγ Receptor-Fc Affinities Across Differentially-Complexed IgG.

MABS(2023)

Dartmouth Coll | Univ Maryland

Cited 1|Views18
Abstract
Antibody-mediated effector functions are widely considered to unfold according to an associative model of IgG-Fcγ receptor (FcγR) interactions. The associative model presupposes that Fc receptors cannot discriminate antigen-bound IgG from free IgG in solution and have equivalent affinities for each. Therefore, the clustering of Fcγ receptors (FcγR) in the cell membrane, cross-activation of intracellular signaling domains, and the formation of the immune synapse are all the result of avid interactions between the Fc region of IgG and FcγRs that collectively overcome the individually weak, transient interactions between binding partners. Antibody allostery, specifically conformational allostery, is a competing model in which antigen-bound antibody molecules undergo a physical rearrangement that causes them to stand out from the background of free IgG by virtue of greater FcγR affinity. Various evidence exists in support of this model of antibody allostery, but it remains controversial. We report observations from multiplexed, label-free kinetic experiments in which the affinity values of FcγR were characterized for covalently immobilized, captured, and antigen-bound IgG. Across the strategies tested, receptors had greater affinity for the antigen-bound mode of IgG presentation. This phenomenon was observed across multiple FcγRs and generalized to multiple antigens, antibody specificities, and subclasses. Furthermore, the thermodynamic signatures of FcγR binding to free or immune-complexed IgG in solution differed when measured by an orthogonal label-free method, but the failure to recapitulate the trend in overall affinity leaves open questions as to what additional factors may be at play.
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Key words
Affinity,allostery,antibody,Fc receptor,immunoglobulin G
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要点】:本研究提出证据表明,人类Fcγ受体与不同形式复合的IgG亲和力存在差异,支持抗体别构模型而非传统关联模型。

方法】:通过_multiplexed、无标记的动力学实验,对共价固定、捕获和抗原结合的IgG的Fcγ受体亲和力进行了表征。

实验】:实验采用多种策略,在多个FcγR上观察到对抗原结合模式下的IgG表现出更高亲和力,这一现象推广到多种抗原、抗体特异性和亚类,并通过正交无标记方法测量了溶液中自由或免疫复合物IgG的FcγR结合热力学特征,但未能完全重现整体亲和力的趋势,留下额外因素可能影响的问题。数据集名称未在文中明确提及。