Human IgG lacking effector functions demonstrate lower FcRn-binding and reduced transplacental transport.

Autor: Stapleton NM; Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam, 1066 CX, The Netherlands., Armstrong-Fisher SS; RDI Clinical Transfusion Group, Scottish National Blood Transfusion Service, Foresterhill, Aberdeen, AB25 2ZW, UK; Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK., Andersen JT; Department of Immunology, Oslo University Hospital Rikshospitalet and University of Oslo, PO Box 4950, Nydalen, Oslo, 0424, Norway; Centre for Immune Regulation and Department of Biosciences, University of Oslo, PO box 1041, Blindern, Oslo, 0316, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Problemveien 7, 0315, Oslo, Norway., van der Schoot CE; Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam, 1066 CX, The Netherlands., Porter C; Immunology Laboratory, Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZB, UK., Page KR; Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK., Falconer D; Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK., de Haas M; Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam, 1066 CX, The Netherlands., Williamson LM; Department of Haematology, University of Cambridge, UK; NHS Blood and Transplant, Long Road, Cambridge, CB2 2PT, UK., Clark MR; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK., Vidarsson G; Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, Amsterdam, 1066 CX, The Netherlands. Electronic address: G.Vidarsson@sanquin.nl., Armour KL; Department of Haematology, University of Cambridge, UK; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2018 Mar; Vol. 95, pp. 1-9. Date of Electronic Publication: 2018 Feb 20.
DOI: 10.1016/j.molimm.2018.01.006
Abstrakt: We have previously generated human IgG1 antibodies that were engineered for reduced binding to the classical Fcγ receptors (FcγRI-III) and C1q, thereby eliminating their destructive effector functions (constant region G1Δnab). In their potential use as blocking agents, favorable binding to the neonatal Fc receptor (FcRn) is important to preserve the long half-life typical of IgG. An ability to cross the placenta, which is also mediated, at least in part, by FcRn is desirable in some indications, such as feto-maternal alloimmune disorders. Here, we show that G1Δnab mutants retain pH-dependent binding to human FcRn but that the amino acid alterations reduce the affinity of the IgG1:FcRn interaction by 2.0-fold and 1.6-fold for the two antibodies investigated. The transport of the modified G1Δnab mutants across monolayers of human cell lines expressing FcRn was approximately 75% of the wild-type, except that no difference was observed with human umbilical vein endothelial cells. G1Δnab mutation also reduced transport in an ex vivo placenta model. In conclusion, we demonstrate that, although the G1Δnab mutations are away from the FcRn-binding site, they have long-distance effects, modulating FcRn binding and transcellular transport. Our findings have implications for the design of therapeutic human IgG with tailored effector functions.
(Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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