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

doi:10.1016/j.isci.2022.103746

Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life

iScience. 2022 Jan 10;25(2):103746. doi: 10.1016/j.isci.2022.103746. eCollection 2022 Feb 18.

Authors

Algirdas Grevys^{1

2

3

4}, Rahel Frick^{2

3}, Simone Mester^{1

2

3}, Karine Flem-Karlsen^{2

3}, Jeannette Nilsen^{2

3}, Stian Foss^{2

3}, Kine Marita Knudsen Sand^{1

2

3}, Thomas Emrich⁴, Jens Andre Alexander Fischer⁴, Victor Greiff⁵, Inger Sandlie^{1

2

3}, Tilman Schlothauer⁴, Jan Terje Andersen^{2

3}

Affiliations

¹ Centre for Immune Regulation (CIR) and Department of Biosciences, University of Oslo, 0371 Oslo, Norway.
² CIR and Department of Immunology, Oslo University Hospital Rikshospitalet, 0372 Oslo, Norway.
³ Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway.
⁴ Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, 82377 Penzberg, Germany.
⁵ Department of Immunology, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway.

Abstract

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.

Keywords: Biological sciences; Biophysics; Immunology.