title: Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions.
abstract: Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge-CH2 region, structurally distant from the binding site for FcRn at the CH2-CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn-IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants.
authors.affiliation: Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway;
authors.forename: Algirdas
authors.initials: A
authors.lastname: Grevys
authors.affiliation: Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway;
authors.forename: Malin
authors.initials: M
authors.lastname: Bern
authors.affiliation: Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway;
authors.forename: Stian
authors.initials: S
authors.lastname: Foss
authors.affiliation: Department of Bacteriology and Immunology, Norwegian Institute of Public Health, 0403 Oslo, Norway;
authors.forename: Diane Bryant
authors.initials: DB
authors.lastname: Bratlie
authors.affiliation: Department of Biosciences and the Mass Spectrometry and Proteomics Unit, University of Oslo, 0371 Oslo, Norway; and.
authors.forename: Anders
authors.initials: A
authors.lastname: Moen
authors.affiliation: Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway;
authors.forename: Kristin Støen
authors.initials: KS
authors.lastname: Gunnarsen
authors.affiliation: Department of Bacteriology and Immunology, Norwegian Institute of Public Health, 0403 Oslo, Norway;
authors.forename: Audun
authors.initials: A
authors.lastname: Aase
authors.affiliation: Department of Bacteriology and Immunology, Norwegian Institute of Public Health, 0403 Oslo, Norway; Department of Chemical Pharmacy, School of Pharmacy, University of Oslo, 0316 Oslo, Norway.
authors.forename: Terje Einar
authors.initials: TE
authors.lastname: Michaelsen
authors.affiliation: Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway;
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.affiliation: Centre for Immune Regulation and Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, 0372 Oslo, Norway; j.t.andersen@medisin.uio.no.
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D002460:Cell Line; D015922:Complement C1q / Q000276:immunology*; D057809:HEK293 Cells; D052058:Hinge Exons / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology; D009592:Nitrohydroxyiodophenylacetate / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D015202:Protein Engineering; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D009592:Nitrohydroxyiodophenylacetate; D015922:Complement C1q; C100688:Fc receptor, neonatal