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

Pernille Foged Jensen; Angela Schoch; Vincent Larraillet; Maximiliane Hilger; Tilman Schlothauer; Thomas Emrich; Kasper Dyrberg Rand

doi:10.1074/mcp.M116.064675

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

Pernille Foged Jensen, Angela Schoch, Vincent Larraillet, Maximiliane Hilger, Tilman Schlothauer, Thomas Emrich, Kasper Dyrberg Rand

13 Citationer (Scopus)

63 Downloads (Pure)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Molecular and Cellular Proteomics
Vol/bind	16
Udgave nummer	3
Sider (fra-til)	451-456
Antal sider	6
ISSN	1535-9476
DOI	https://doi.org/10.1074/mcp.M116.064675
Status	Udgivet - mar. 2017

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10.1074/mcp.M116.064675Licens: CC BY

451.fullLicens: CC BY

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

abstract = "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.",

keywords = "Antibodies, Monoclonal/chemistry, Binding Sites, Deuterium Exchange Measurement/methods, Half-Life, Histocompatibility Antigens Class I/metabolism, Humans, Hydrogen-Ion Concentration, Immunoglobulin G/chemistry, Mass Spectrometry/methods, Models, Molecular, Protein Binding, Protein Stability, Receptors, Fc/metabolism",

author = "Jensen, {Pernille Foged} and Angela Schoch and Vincent Larraillet and Maximiliane Hilger and Tilman Schlothauer and Thomas Emrich and Rand, {Kasper Dyrberg}",

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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

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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

SN - 1535-9476

VL - 16

SP - 451

EP - 456

JO - Molecular and Cellular Proteomics

JF - Molecular and Cellular Proteomics

IS - 3

ER -

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

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