Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses

P Bruhns, B Iannascoli, P England… - Blood, The Journal …, 2009 - ashpublications.org
P Bruhns, B Iannascoli, P England, DA Mancardi, N Fernandez, S Jorieux, M Daëron
Blood, The Journal of the American Society of Hematology, 2009ashpublications.org
Distinct genes encode 6 human receptors for IgG (hFcγRs), 3 of which have 2 or 3
polymorphic variants. The specificity and affinity of individual hFcγRs for the 4 human IgG
subclasses is unknown. This information is critical for antibody-based immunotherapy which
has been increasingly used in the clinics. We investigated the binding of polyclonal and
monoclonal IgG1, IgG2, IgG3, and IgG4 to FcγRI; FcγRIIA, IIB, and IIC; FcγRIIIA and IIIB; and
all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti …
Abstract
Distinct genes encode 6 human receptors for IgG (hFcγRs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFcγRs for the 4 human IgG subclasses is unknown. This information is critical for antibody-based immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3, and IgG4 to FcγRI; FcγRIIA, IIB, and IIC; FcγRIIIA and IIIB; and all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found that (1) IgG1 and IgG3 bind to all hFcγRs; (2) IgG2 bind not only to FcγRIIAH131, but also, with a lower affinity, to FcγRIIAR131 and FcγRIIIAV158; (3) IgG4 bind to FcγRI, FcγRIIA, IIB and IIC and FcγRIIIAV158; and (4) the inhibitory receptor FcγRIIB has a lower affinity for IgG1, IgG2, and IgG3 than all other hFcγRs. We also identified parameters that determine the specificity and affinity of hFcγRs for IgG subclasses. These results document how hFcγR specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFcγRs in the therapeutic and pathogenic effects of antibodies in disease.
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