Polymorphisms and Interspecies Differences of the Activating and Inhibitory FcγRII of Macaca nemestrina Influence the Binding of Human IgG Subclasses

Abstract

Little is known of the impact of Fc receptor polymorphism in macaques on the binding of human IgG (huIgG) and nothing is known of this interaction in the pigtail macaque (M. nemestrina) which is used in preclinical evaluation of vaccines and therapeutic antibodies. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating FcγRIIa (mnFcγRIIa) and inhibitory FcγRIIb (mnFcγRIIb) and predicted their structures using the huIgGFc:huFcγRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcγRIIa and mnFcγRIIb compared to their human FcR counterparts. MnFcγRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared to huFcγRIIa (His131). In contrast, mnFcγRIIb has enhanced binding of huIgG1 and broader specificity as, unlike huFcγRIIb, it avidly binds IgG2. Mutagenesis and molecular modelling of mnFcγRIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcγRIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across FcγRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcγRIIa, wherein Pro at position 131, also an important polymorphic site in huFcγRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared to mnFcγRIIa His131. These marked interspecies differences in IgG-binding between human and macaque FcRs and polymorphisms within species have implications for pre-clinical evaluation of antibodies and vaccines in macaques.

Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs

“…Second, some effector functions in the Fc portion of the human MAb may not be optimal in rhesus macaques. While both IgG and cell surface Fc␥ receptors show considerable sequence similarity between humans and macaques, there are species differences with respect to Fc␥ receptor tissue expression as well as the specificity and affinity for human IgG (44)(45)(46), which may have limited the spectrum of human MAb-mediated antiviral activities. Third, we used intravenous inoculation to establish a model with consistent and relatively synchronous viremia, whereas most human infections are via a mucosal route.…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…Despite the high homology of the of FcγRIIa and FcγRIIb ectodomains, human FcγRIIb has lower affinity than its activatory counterpart. However, this is not the case in macaques where the binding affinities of IgG to pig-tailed macaque mnFcγRIIa and mnFcγRIIb are reversed when compared with the human receptors [32]. This higher affinity of macaque FcγRIIb and lower affinity of the macaque FcγRIIa raises the possibility of somewhat different regulation of FcγRIIa by FcγRIIb in macaque compared to human myeloid cells.…”

“…The pig-tail [32] and rhesus macaque receptor [33] has lower affinity than the human counterpart and a low activity form (Pro-131) occurs in both macaque species. At least eight variants of FcγRIIa have been observed in a small cohort of pig-tailed macaque [32] and five in rhesus macaques [33,83].…”

“…However it should also be noted that despite much similarity there are potentially important differences in diversity, genetics, and biology of antibody and of FcRs in macaques compared to humans which are mentioned below and in [29][30][31][32][33]. Thus, the extrapolation of FcγR-mediated antibody functions from these models to efficacy in humans should be made with caution.…”

Fc Receptors

“…They should be also of interest to tailor and to assess the efficacy of novel therapeutic antibodies for specific purposes. Indeed, nonhuman primates that are often viewed as the best animal models for preclinical vaccine trials, seem not to have the same FcRs as humans (Trist et al 2014).…”