Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life
Algirdas Grevys,
Rahel Frick,
Simone Mester,
Karine Flem-Karlsen,
Jeannette Nilsen,
Stian Foss,
Kine Marita Knudsen Sand,
Thomas Emrich,
Jens Andre Alexander Fischer,
Victor Greiff,
Inger Sandlie,
Tilman Schlothauer,
Jan Terje Andersen
Affiliations
Algirdas Grevys
Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, 0371 Oslo, Norway; CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; 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; Corresponding author
Rahel Frick
CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Simone Mester
Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, 0371 Oslo, Norway; CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Karine Flem-Karlsen
CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Jeannette Nilsen
CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Stian Foss
CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Kine Marita Knudsen Sand
Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, 0371 Oslo, Norway; CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Thomas Emrich
Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, 82377 Penzberg, Germany
Jens Andre Alexander Fischer
Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, 82377 Penzberg, Germany
Victor Greiff
Department of Immunology, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway
Inger Sandlie
Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, 0371 Oslo, Norway; CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
Tilman Schlothauer
Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, 82377 Penzberg, Germany
Jan Terje Andersen
CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway; Corresponding author
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.
