Human IgG lacking effector functions demonstrate lower FcRn-binding and reduced transplacental transport
| Autor: | Lorna M. Williamson, Charlene Porter, Gestur Vidarsson, S. Armstrong-Fisher, Nigel M. Stapleton, Kenneth Robert Page, Kathryn L. Armour, C. Ellen van der Schoot, Mike Clark, Donald Wilson Falconer, Masja de Haas, Jan Terje Andersen |
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| Přispěvatelé: | Other departments, Landsteiner Laboratory |
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Placenta Immunology Receptors Fc medicine.disease_cause Umbilical vein 03 medical and health sciences Neonatal Fc receptor Pregnancy Human Umbilical Vein Endothelial Cells medicine Humans Receptor Maternal-Fetal Exchange Molecular Biology Cells Cultured Mutation biology Chemistry Histocompatibility Antigens Class I Receptors IgG Cell biology Kinetics 030104 developmental biology medicine.anatomical_structure Immunoglobulin G Paracellular transport biology.protein Female Mutant Proteins Antibody Ex vivo Protein Binding |
| Zdroj: | Molecular immunology, 95, 1-9. Elsevier Limited |
| ISSN: | 0161-5890 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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