Little is known of the impact of Fc receptor (FcR) polymorphism in macaques on the binding of human (hu)IgG, and nothing is known of this interaction in the pig-tailed macaque (Macaca nemestrina), which is used in preclinical evaluation of vaccines and therapeutic Abs. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating Fc gamma RIIa (mnFc gamma RIIa) and inhibitory Fc gamma RIIb (mnFc gamma RIIb) and predicted their structures using the huIgGFc/huFc gamma RIIa crystal structure. Large differences were observed in the binding of huIgG by mnFc gamma RIIa and mnFc gamma RIIb compared with their human FcR counterparts. MnFc gamma RIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFc gamma RIIa (His(131)). In contrast, mnFc gamma RIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFc gamma RIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFc gamma RIIa showed that Pro(159) and Tyr(160) impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFc gamma RIIb was shown to be dependent on His(131) and Met(132). Significantly, both His 131 and Met 132 are conserved across Fc gamma RIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFc gamma RIIa wherein proline at position 131, also an important polymorphic site in huFc gamma RIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFc gamma RIIa His(131). These marked interspecies differences in IgG binding between human and macaque FcRs and polymorphisms within species have implications for preclinical evaluation of Abs and vaccines in macaques.
↧