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.
authors.affiliation: From the ‡Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Pernille Foged
authors.identifier: 0000-0003-1495-6110
authors.initials: PF
authors.lastname: Jensen
authors.affiliation: §Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Penzberg, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schoch
authors.affiliation: ¶Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Penzberg, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Larraillet
authors.affiliation: ¶Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Penzberg, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Maximiliane
authors.initials: M
authors.lastname: Hilger
authors.affiliation: ¶Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Penzberg, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schlothauer
authors.affiliation: §Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Penzberg, Nonnenwald 2, 82377 Penzberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Emrich
authors.affiliation: From the ‡Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; kasper.rand@sund.ku.dk.
authors.forename: Kasper Dyrberg
authors.identifier: 0000-0002-6337-5489
authors.initials: KD
authors.lastname: Rand
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D001665:Binding Sites; D041961:Deuterium Exchange Measurement / Q000379:methods; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D011485:Protein Binding; D055550:Protein Stability; D011961:Receptors, Fc / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C544528:briakinumab; C100688:Fc receptor, neonatal