title: Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential.
abstract: Human IgG3 displays the strongest effector functions of all IgG subclasses but has a short half-life for unresolved reasons. Here we show that IgG3 binds to IgG-salvage receptor (FcRn), but that FcRn-mediated transport and rescue of IgG3 is inhibited in the presence of IgG1 due to intracellular competition between IgG1 and IgG3. We reveal that this occurs because of a single amino acid difference at position 435, where IgG3 has an arginine instead of the histidine found in all other IgG subclasses. While the presence of R435 in IgG increases binding to FcRn at neutral pH, it decreases binding at acidic pH, affecting the rescue efficiency-but only in the presence of H435-IgG. Importantly, we show that in humans the half-life of the H435-containing IgG3 allotype is comparable to IgG1. H435-IgG3 also gave enhanced protection against a pneumococcal challenge in mice, demonstrating H435-IgG3 to be a candidate for monoclonal antibody therapies.
authors.affiliation: Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands.
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Stapleton
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
authors.forename: Annette M
authors.initials: AM
authors.lastname: Stemerding
authors.forename: Stefania P
authors.initials: SP
authors.lastname: Bjarnarson
authors.forename: Ruurd C
authors.initials: RC
authors.lastname: Verheul
authors.forename: Jacoline
authors.initials: J
authors.lastname: Gerritsen
authors.forename: Yixian
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marion
authors.initials: M
authors.lastname: Kleijer
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Masja
authors.initials: M
authors.lastname: de Haas
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
mesh_terms: D000361:Agammaglobulinemia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D001120:Arginine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006207:Half-Life; D006639:Histidine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport / Q000276:immunology*; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D006639:Histidine; D001120:Arginine; C100688:Fc receptor, neonatal