A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Half-life
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A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Half-life. / Jensen, Pernille Foged; Schoch, Angela; Larraillet, Vincent; Hilger, Maximiliane; Schlothauer, Tilman; Emrich, Thomas; Rand, Kasper Dyrberg.
In: Molecular and Cellular Proteomics, Vol. 16, No. 3, 03.2017, p. 451-456.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Half-life
AU - Jensen, Pernille Foged
AU - Schoch, Angela
AU - Larraillet, Vincent
AU - Hilger, Maximiliane
AU - Schlothauer, Tilman
AU - Emrich, Thomas
AU - Rand, Kasper Dyrberg
N1 - © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal/chemistry
KW - Binding Sites
KW - Deuterium Exchange Measurement/methods
KW - Half-Life
KW - Histocompatibility Antigens Class I/metabolism
KW - Humans
KW - Hydrogen-Ion Concentration
KW - Immunoglobulin G/chemistry
KW - Mass Spectrometry/methods
KW - Models, Molecular
KW - Protein Binding
KW - Protein Stability
KW - Receptors, Fc/metabolism
U2 - 10.1074/mcp.M116.064675
DO - 10.1074/mcp.M116.064675
M3 - Journal article
C2 - 28062799
VL - 16
SP - 451
EP - 456
JO - Molecular and Cellular Proteomics
JF - Molecular and Cellular Proteomics
SN - 1535-9476
IS - 3
ER -
ID: 195554006