title: Maternofetal transplacental transport of recombinant IgG antibodies lacking effector functions.
abstract: The neonatal Fc receptor (FcRn) directs the transfer of maternal immunoglobulin G (IgG) antibodies across the placenta and thus provides the fetus and newborn with passive protective humoral immunity. Pathogenic maternal IgG antibodies will also be delivered via the placenta and can cause alloimmunity, which may be lethal. A novel strategy to control pathogenic antibodies would be administration of a nondestructive IgG antibody blocking antigen binding while retaining binding to FcRn. We report on 2 human IgG3 antibodies with a hinge deletion and a C131S point mutation (IgG3ΔHinge) that eliminate complement activation and binding to all classical Fcγ receptors (FcγRs) and to C1q while binding to FcRn is retained. Additionally, 1 of the antibodies has a single point mutation in the Fc (R435H) at the binding site for FcRn (IgG3ΔHinge:R435H). We compared transplacental transport with wild-type IgG1 and IgG3, and found transport across trophoblast-derived BeWo cells and ex vivo placenta perfusions with hierarchies as follows: IgG3ΔHinge:R435H>wild-type IgG1≥IgG3ΔHinge and IgG3ΔHinge:R435H=wild-type IgG1=wild-type IgG3>>>IgG3ΔHinge, respectively. Collectively, IgG3ΔHinge:R435H was transported efficiently from the maternal to the fetal placental compartment. Thus, IgG3ΔHinge:R435H may be a good candidate for transplacental delivery of a nondestructive antibody to the fetus to combat pathogenic antibodies.
authors.affiliation: Department of Public Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Mathiesen
authors.forename: Leif K
authors.initials: LK
authors.lastname: Nielsen
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
authors.forename: Algirdas
authors.initials: A
authors.lastname: Grevys
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Terje E
authors.initials: TE
authors.lastname: Michaelsen
authors.forename: Morten
authors.initials: M
authors.lastname: Hedegaard
authors.forename: Lisbeth E
authors.initials: LE
authors.lastname: Knudsen
authors.forename: Morten Hanefeld
authors.initials: MH
authors.lastname: Dziegiel
mesh_terms: D000906:Antibodies / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport; D002822:Choriocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005333:Fetus / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D010920:Placenta / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D011961:Receptors, Fc / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology* / Q000378:metabolism; D014594:Uterine Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D011994:Recombinant Proteins; C100688:Fc receptor, neonatal