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; Gestur Vidarsson

doi:https://doi.org/10.1038/ncomms1608

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, Gestur Vidarsson

Research output: Contribution to journal › Article › Academic › peer-review

213 Citations (Scopus)

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

Original language	English
Pages (from-to)	599
Journal	Nature communications
Volume	2
DOIs	https://doi.org/10.1038/ncomms1608
Publication status	Published - 2011

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https://doi.org/10.1038/ncomms1608

Cite this

Stapleton, N. M., Andersen, J. T., Stemerding, A. M., Bjarnarson, S. P., Verheul, R. C., Gerritsen, J., Zhao, Y., Kleijer, M., Sandlie, I., de Haas, M., Jonsdottir, I., van der Schoot, C. E., & Vidarsson, G. (2011). Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential. Nature communications, 2, 599. https://doi.org/10.1038/ncomms1608

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

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",

author = "Stapleton, {Nigel M.} and Andersen, {Jan Terje} and Stemerding, {Annette M.} and Bjarnarson, {Stefania P.} and Verheul, {Ruurd C.} and Jacoline Gerritsen and Yixian Zhao and Marion Kleijer and Inger Sandlie and {de Haas}, Masja and Ingileif Jonsdottir and {van der Schoot}, {C. Ellen} and Gestur Vidarsson",

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Stapleton, NM, Andersen, JT, Stemerding, AM, Bjarnarson, SP, Verheul, RC, Gerritsen, J, Zhao, Y, Kleijer, M, Sandlie, I, de Haas, M, Jonsdottir, I, van der Schoot, CE & Vidarsson, G 2011, 'Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential', Nature communications, vol. 2, pp. 599. https://doi.org/10.1038/ncomms1608

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AU - Stapleton, Nigel M.

AU - Andersen, Jan Terje

AU - Stemerding, Annette M.

AU - Bjarnarson, Stefania P.

AU - Verheul, Ruurd C.

AU - Gerritsen, Jacoline

AU - Zhao, Yixian

AU - Kleijer, Marion

AU - Sandlie, Inger

AU - de Haas, Masja

AU - Jonsdottir, Ingileif

AU - van der Schoot, C. Ellen

AU - Vidarsson, Gestur

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AB - 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

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