Specificity and affinity of human Fc{gamma} receptors and their polymorphic variants for human IgG subclasses.
Abstract
Distinct genes encode six human receptors for IgG (hFcgammaRs), three of which have two or three polymorphic variants. The specificity and affinity of individual hFcgammaRs for the four 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 FcgammaRI, FcgammaRIIA, IIB and IIC, FcgammaRIIIA and IIIB and all known polymorphic variants. Wt and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found: 1) that IgG1 and IgG3 bind to all hFcgammaRs; 2) that IgG2 bind not only to FcgammaRIIAH131, but also, with a lower affinity, to FcgammaRIIAR131 and FcgammaRIIIAV158; 3) that IgG4 bind to FcgammaRI, FcgammaRIIA, IIB and IIC and FcgammaRIIIAV158; 4) that the inhibitory receptor FcgammaRIIB has a lower affinity for IgG1, IgG2 and IgG3 than all other hFcgammaRs. We also identified parameters which determine the specificity and affinity of hFcgammaRs for IgG subclasses. These results document how hFcgammaR specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFcgammaRs in the therapeutic and pathogenic effects of antibodies in disease.