Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential

Nigel M. Stapleton, Jan Terje Andersen, Annette M. Stemerding, Stefania P. Bjarnarson, Ruurd C. Verheul, Jacoline Gerritsen, Yixian Zhao, Marion Kleijer, Inger Sandlie, Masja de Haas, Ingileif Jonsdottir, C. Ellen van der Schoot and Gestur Vidarsson ()
Additional contact information
Nigel M. Stapleton: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.
Jan Terje Andersen: Oslo University Hospital Rikshospitalet and University of Oslo, PO Box 4950 Nydalen, Oslo 0424, Norway.
Annette M. Stemerding: University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, The Netherlands.
Stefania P. Bjarnarson: Landspitali University Hospital, Faculty of Medicine, University of Iceland, Eiriksgata, hus 14, Reykjavik 101, Iceland.
Ruurd C. Verheul: University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, The Netherlands.
Jacoline Gerritsen: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.
Yixian Zhao: Utrecht University, Universiteitsweg 99, Utrecht 3584 CG, The Netherlands.
Marion Kleijer: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.
Inger Sandlie: University of Oslo, PO box 1041, Blindern, Oslo 0316, Norway.
Masja de Haas: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.
Ingileif Jonsdottir: Landspitali University Hospital, Faculty of Medicine, University of Iceland, Eiriksgata, hus 14, Reykjavik 101, Iceland.
C. Ellen van der Schoot: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.
Gestur Vidarsson: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract Human IgG3 displays the strongest effector functions of all IgG subclasses but has a short half-life for unresolved reasons. Here we show that IgG3 binds to IgG-salvage receptor (FcRn), but that FcRn-mediated transport and rescue of IgG3 is inhibited in the presence of IgG1 due to intracellular competition between IgG1 and IgG3. We reveal that this occurs because of a single amino acid difference at position 435, where IgG3 has an arginine instead of the histidine found in all other IgG subclasses. While the presence of R435 in IgG increases binding to FcRn at neutral pH, it decreases binding at acidic pH, affecting the rescue efficiency—but only in the presence of H435–IgG. Importantly, we show that in humans the half-life of the H435-containing IgG3 allotype is comparable to IgG1. H435–IgG3 also gave enhanced protection against a pneumococcal challenge in mice, demonstrating H435–IgG3 to be a candidate for monoclonal antibody therapies.

Date: 2011
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DOI: 10.1038/ncomms1608

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