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FcRn, but not FcgRs, drives maternal-fetal transplacental transport of human IgG antibodies

By Sara Borghi, Stylianos Bournazos, Natalie K Thulin, Chao Li, Anna Gajewski, Robert Sherwood, Sheng Zheng, Eva Harris, Prasanna Jagannathan, Lai-Xi Wang, Jeffrey V. Ravetch, Taia T. Wang

Posted 25 Mar 2020
bioRxiv DOI: 10.1101/2020.03.22.999243 (published DOI: 10.1073/pnas.2004325117)

The IgG Fc domain has the capacity to interact with diverse types of receptors, including FcRn and FcγRs, which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as ADCC and phagocytosis are mediated by FcγRs, which upon crosslinking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and non-overlapping functional properties of FcRn and FcγRs, recent studies have suggested that FcγRs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of FcγRs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcγRIIIA or FcRn binding, half-life, or their ability to deplete target cells in FcγR/FcRn humanized mice. Modeling maternal/fetal transport in FcγR/FcRn humanized mice confirmed that only FcRn contributed to transplacental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing FcγRIIIA binding did not result in enhanced maternal/fetal transport. These results argue against a role for FcγRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to only enhance FcRn binding as a means to improve maternal/fetal transport of IgG.

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