iScience | |
Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life | |
Rahel Frick1 Jens Andre Alexander Fischer1 Jeannette Nilsen2 Tilman Schlothauer3 Kine Marita Knudsen Sand3 Simone Mester3 Victor Greiff3 Karine Flem-Karlsen4 Inger Sandlie5 Stian Foss5 Jan Terje Andersen5 Thomas Emrich6 Algirdas Grevys6 | |
[1] CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway;Corresponding author;Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway;Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, 82377 Penzberg, Germany;CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway;Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, 0371 Oslo, Norway; | |
关键词: Biological sciences; Immunology; Biophysics; | |
DOI : | |
来源: DOAJ |
【 摘 要 】
Summary: Monoclonal 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.
【 授权许可】
Unknown