Evidence for the Role of a Second Fc-Binding Receptor in Placental IgG Transfer in Nonhuman Primates

• Published in: mBio Vol. 14; no. 2; p. e0034123
• Main Authors: Rosenberg, Yvonne J, Ordonez, Tracy, Khanwalkar, Urjeet S, Barnette, Philip, Pandey, Shilpi, Backes, Iara M, Otero, Claire E, Goldberg, Benjamin S, Crowley, Andrew R, Leib, David A, Shapiro, Mariya B, Jiang, Xiaoming, Urban, Lori A, Lees, Jonathan, Hessell, Ann J, Permar, Sallie, Haigwood, Nancy L, Ackerman, Margaret E
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 25.04.2023
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Editor's Pick; FcRn; FcγR; Female; Histocompatibility Antigens Class I; HIV Infections - metabolism; Humans; Immunoglobulin G; Immunology; Macaca mulatta; Mammals - metabolism; Maternal-Fetal Exchange; Mice; Placenta; placental transfer; plant and mammalian antibodies; Pregnancy; primates; Receptors, Fc - metabolism; Research Article; mouse models; placental transfer; primates; Fcγ receptors; plant and mammalian antibodies; nonhuman primate models; mice; placental immunology; plant production of antibodies; FcRn; human immunodeficiency virus; FcγR; human monoclonal antibodies
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.00341-23

Transplacental transfer of maternal antibodies provides the fetus and newborn with passive protection against infectious diseases. While the role of the highly conserved neonatal Fc receptor (FcRn) in transfer of IgG in mammals is undisputed, recent reports have suggested that a second receptor may contribute to transport in humans. We report poor transfer efficiency of plant-expressed recombinant HIV-specific antibodies, including engineered variants with high FcRn affinity, following subcutaneous infusion into rhesus macaques close to parturition. Unexpectedly, unlike those derived from mammalian tissue culture, plant-derived antibodies were essentially unable to cross macaque placentas. This defect was associated with poor Fcγ receptor binding and altered Fc glycans and was not recapitulated in mice. These results suggest that maternal-fetal transfer of IgG across the three-layer primate placenta may require a second receptor and suggest a means of providing maternal antibody treatments during pregnancy while avoiding fetal harm. This study compared the ability of several human HIV envelope-directed monoclonal antibodies produced in plants with the same antibodies produced in mammalian cells for their ability to cross monkey and mouse placentas. We found that the two types of antibodies have comparable transfer efficiencies in mice, but they are differentially transferred across macaque placentas, consistent with a two-receptor IgG transport model in primates. Importantly, plant-produced monoclonal antibodies have excellent binding characteristics for human FcRn receptors, permitting desirable pharmacokinetics in humans. The lack of efficient transfer across the primate placenta suggests that therapeutic plant-based antibody treatments against autoimmune diseases and cancer could be provided to the mother while avoiding transfer and preventing harm to the fetus.