title: IgG1 Allotypes Influence the Pharmacokinetics of Therapeutic Monoclonal Antibodies through FcRn Binding.
abstract: Because IgG1 allotypes might have different half-lives, their influence on infliximab (G1m17,1 allotype) pharmacokinetics was investigated in a group of spondyloarthritis patients. Infliximab was found to have a shorter half-life in patients homozygous for the G1m17,1 allotypes than in those carrying the G1m3 with no G1m1 (G1m3,-1) allotype. Because the neonatal FcR (FcRn) is involved in the pharmacokinetics of mAbs, the interaction of different IgG1 allotypes with FcRn was examined using cellular assays and surface plasmon resonance. G1m17,1 mAbs, such as infliximab and rituximab, were shown to bind more efficiently to FcRn and to be transcytosed better than the G1m3,-1 mAb cetuximab, which explains why infliximab is a better competitor for endogenous IgG1 in G1m3,-1 allotype-bearing patients. A set of four allotype variants of adalimumab (G1m17,1; G1m17,-1; G1m3,1; and G1m3,-1) was also tested for its binding to FcRn, revealing that the G1m3,1 variant, not present in commercial mAbs, binds more efficiently to FcRn and is transcytosed better than the other three variants, all of which are found in therapeutic mAbs.
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Laboratoire de Pharmacologie-Toxicologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France;
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.affiliation: INSERM, U1194, Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier; Montpellier F-34298, France;
authors.forename: Martine
authors.initials: M
authors.lastname: Pugnière
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Dhommée
authors.affiliation: InvivoGen, Toulouse F-31400, France;
authors.forename: Daniel
authors.initials: D
authors.lastname: Drocourt
authors.affiliation: InvivoGen, Toulouse F-31400, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Perouzel
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Laboratoire d'Immunologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Passot
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France;
authors.forename: Nadine
authors.identifier: http://orcid.org/0000-0003-1783-7002
authors.initials: N
authors.lastname: Baroukh
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Service de Rhumatologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Mulleman
authors.affiliation: InvivoGen, Toulouse F-31400, France;
authors.forename: Gérard
authors.initials: G
authors.lastname: Tiraby
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Laboratoire d'Immunologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France; and.
authors.forename: Hervé
authors.identifier: http://orcid.org/0000-0002-2139-4171
authors.initials: H
authors.lastname: Watier
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Laboratoire de Pharmacologie-Toxicologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France;
authors.forename: Gilles
authors.identifier: http://orcid.org/0000-0003-0158-1356
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: Université François Rabelais de Tours, CNRS UMR7292, Tours F-37032, France; Laboratoire d'Immunologie, Centre Hospitalier Régional Universitaire de Tours, Tours F-37032, France; and valerie.gouilleux@univ-tours.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007126:Immunoglobulin Allotypes / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics* / Q000378:metabolism; D000069285:Infliximab / Q000493:pharmacokinetics*; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011961:Receptors, Fc / Q000378:metabolism*; D025241:Spondylarthritis / Q000188:drug therapy* / Q000235:genetics*; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007126:Immunoglobulin Allotypes; D007074:Immunoglobulin G; D011961:Receptors, Fc; D000069285:Infliximab; C100688:Fc receptor, neonatal