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

Distinct genes encode 6 human receptors for IgG (hFc gamma Rs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFc gamma Rs 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 Fc gamma RI; Fc gamma RIIA, IIB, and IIC; Fc gamma RIIIA 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 hFc gamma Rs; (2) IgG2 bind not only to Fc gamma RIIA(H131), but also, with a lower affinity, to Fc gamma RIIA(R131) and Fc gamma RIIIA(V158); (3) IgG4 bind to Fc gamma RI, Fc gamma RIIA, IIB and IIC and Fc gamma RIIIA(V158); and (4) the inhibitory receptor Fc gamma RIIB has a lower affinity for IgG1, IgG2, and IgG3 than all other hFc gamma Rs. We also identified parameters that determine the specificity and affinity of hFc gamma Rs for IgG subclasses. These results document how hFc gamma R specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFc gamma Rs in the therapeutic and pathogenic effects of antibodies in disease. (Blood. 2009; 113: 3716-3725)