文章基本信息

标题：Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life
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作者：Algirdas Grevys ; Rahel Frick ; Simone Mester 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：2
页码：1-22
DOI：10.1016/j.isci.2022.103746
语种：English
出版社：Elsevier
摘要：SummaryMonoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells. When the variable sequences are masked by the cognate antigen, it influences both their transport behavior and binding to the neonatal Fc receptor (FcRn), a key regulator of IgG plasma half-life. Furthermore, we show how charge patch differences in the variable domains modulate both binding and transport properties and that a short plasma half-life, due to unfavorable charge patches, may partly be overcome by Fc-engineering for improved FcRn binding.Graphical abstractDisplay OmittedHighlights•IgG variable region sequences greatly affect cellular uptake and recycling•Variable region charge patches affect FcRn binding and transport•The presence of cognate antigen modulates cellular transport and FcRn binding•Fc-engineering for improved FcRn binding can overcome unfavorable charge patchesBiological sciences; Immunology; Biophysics