Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential
By N. M. Stapleton, J. Andersen, A. Stemerding, Stefania P. Bjarnarson, R. Verheul, Jorrit Gerritsen, Yixia Zhao, M. Kleijer, I. Sandlie, M. Haas and 3 more. 2011
288 citations recorded by the source corpus.
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.
Subfields: Epidemiology, Molecular Biology, Radiology, Nuclear Medicine and Imaging
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Citations in the corpus
- IgG Subclasses and Allotypes: From Structure to Effector Functions (2014, background): “Consequently, IgG3 has a normal half-life of 3 weeks and is transported efficiently across the placenta in individuals containing H435-containing IgG3 allotypes (g3m, 15, or 16) (20, 172).”
- Antibody drug conjugate: the “biological missile” for targeted cancer therapy (2022, background): “Unlike the other three subtypes with half-lives of approximately 21 days, the half-life of IgG3 is only approximately 7 days in serum.(33) IgG2 often shows tendency to form dimers and aggregations in vivo, which leads to a decrease of the concentration of ADC drugs.”