A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Half-life

The success of recombinant monoclonal immunoglobulins (IgG) is rooted in their ability to target distinct antigens with high affinity combined with an extraordinarily long serum half-life, typically around 3 weeks. The pharmacokinetics of IgGs is intimately linked to the recycling mechanism of the n...

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Bibliographic Details
Published in:Molecular & cellular proteomics 2017-03, Vol.16 (3), p.451-456
Main Authors: Jensen, Pernille Foged, Schoch, Angela, Larraillet, Vincent, Hilger, Maximiliane, Schlothauer, Tilman, Emrich, Thomas, Rand, Kasper Dyrberg
Format: Article
Language:English
Subjects:
Affinity
Affinity chromatography
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - metabolism
Antibodies, Monoclonal, Humanized
Antigens
Binding
Binding Sites
Control stability
Deuterium
Deuterium Exchange Measurement - methods
Fab
Fc receptors
Half-Life
Histocompatibility Antigens Class I - metabolism
Humans
Hydrogen ions
Hydrogen-Ion Concentration
Immunoglobulin G
Immunoglobulin G - chemistry
Immunoglobulin G - metabolism
Immunoglobulins
Mass spectrometry
Mass Spectrometry - methods
Mass spectroscopy
Models, Molecular
Neonates
pH effects
Pharmacokinetics
Pharmacology
Protein Binding
Protein Stability
Receptors, Fc - metabolism
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Summary:The success of recombinant monoclonal immunoglobulins (IgG) is rooted in their ability to target distinct antigens with high affinity combined with an extraordinarily long serum half-life, typically around 3 weeks. The pharmacokinetics of IgGs is intimately linked to the recycling mechanism of the neonatal Fc receptor (FcRn). For long serum half-life of therapeutic IgGs, the highly pH-dependent interaction with FcRn needs to be balanced to allow efficient FcRn binding and release at slightly acidic pH and physiological pH, respectively. Some IgGs, like the antibody briakinumab has an unusually short half-life of ∼8 days. Here we dissect the molecular origins of excessive FcRn binding in therapeutic IgGs using a combination of hydrogen/deuterium exchange mass spectrometry and FcRn affinity chromatography. We provide experimental evidence for a two-pronged IgG-FcRn binding mechanism involving direct FcRn interactions with both the Fc region and the Fab regions of briakinumab, and correlate the occurrence of excessive FcRn binding to an unusually strong Fab-FcRn interaction.
ISSN:1535-9476
1535-9484
DOI:10.1074/mcp.M116.064675