Nigel M. Stapleton 1 , Jan Terje Andersen 2 , 3 , 7 , Annette M. Stemerding 4 , 7 , Stefania P. Bjarnarson 5 , Ruurd C. Verheul 4 , Jacoline Gerritsen 1 , Yixian Zhao 6 , Marion Kleijer 1 , Inger Sandlie 3 , Masja de Haas 1 , Ingileif Jonsdottir 5 , C. Ellen van der Schoot 1 , Gestur Vidarsson a , 1
20 December 2011
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.
The half-life of IgG is regulated by binding to the neonatal Fc receptor and, in the case of IgG3, is reduced compared to other IgG proteins. In this study, a mutation in IgG3 is shown to reduce binding to the neonatal Fc receptor, which can be competitively blocked by IgG1.