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

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  • 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.
    University of Oslo, PO box 1041, Blindern, Oslo 0316, 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.)

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.

Suggested Citation

  • 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 & Ingile, 2011. "Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1608
    DOI: 10.1038/ncomms1608
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    Cited by:

    1. Janice Z. Jia & Carolyn A. Cohen & Haogao Gu & Milla R. McLean & Raghavan Varadarajan & Nisha Bhandari & Malik Peiris & Gabriel M. Leung & Leo L. M. Poon & Tim Tsang & Amy W. Chung & Benjamin J. Cowli, 2024. "Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Arman Izadi & Yasaman Karami & Eleni Bratanis & Sebastian Wrighton & Hamed Khakzad & Maria Nyblom & Berit Olofsson & Lotta Happonen & Di Tang & Martin Sundwall & Magdalena Godzwon & Yashuan Chao & Ale, 2024. "The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    3. Leoni Abendstein & Douwe J. Dijkstra & Rayman T. N. Tjokrodirijo & Peter A. Veelen & Leendert A. Trouw & Paul J. Hensbergen & Thomas H. Sharp, 2023. "Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Maximilian Brinkhaus & Erwin Pannecoucke & Elvera J. Kooi & Arthur E. H. Bentlage & Ninotska I. L. Derksen & Julie Andries & Bianca Balbino & Magdalena Sips & Peter Ulrichts & Peter Verheesen & Hans H, 2022. "The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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