Biologic medicines have transformed care for cancer, autoimmune disease, migraine, inflammatory disorders and numerous other conditions. Yet their expanding use among women of reproductive age has created a difficult clinical problem: many of these medicines are therapeutic immunoglobulin G (IgG) antibodies, and IgG can be actively transported across the placenta to the developing fetus. Because evidence on the safety of biologic treatment during pregnancy remains limited, clinicians and patients often face a difficult calculation between controlling potentially serious maternal disease and minimizing fetal drug exposure. A new study from the University of Oslo, Oslo University Hospital and collaborating institutions now identifies a previously unrecognized filtering function in the placenta that could guide the design of safer, long-acting medicines.
Published in Science Immunology, the research shows that the placenta can distinguish between IgG antibodies and albumin, despite both proteins binding to the same transport receptor, the neonatal Fc receptor, or FcRn. IgG is efficiently transferred from the maternal circulation to the fetus, while albumin is largely excluded. The finding helps resolve a longstanding question in placental biology and suggests that biologic medicines could be redesigned to retain the prolonged circulation time associated with FcRn while limiting their passage into fetal tissues. Such medicines could be particularly valuable for chronic diseases requiring treatment throughout pregnancy.
FcRn is best known for its ability to protect circulating proteins from destruction. After cells take up IgG or albumin through normal intracellular trafficking, FcRn can bind them in acidic compartments and return them to the bloodstream rather than allowing them to be delivered to lysosomes for degradation. This recycling process extends the plasma half-life of both proteins. In the placenta, however, the receptor appears to operate in a more selective context. Although FcRn recognizes IgG and albumin, the cellular architecture and trafficking pathways of placental cells favor the delivery of IgG across the placental barrier while preventing most albumin from reaching the fetal circulation.
“This is first and foremost a discovery of how the placenta works,” said Professor Jan Terje Andersen, who led the study at the University of Oslo and Oslo University Hospital. “For decades, we have known that FcRn binds both IgG and albumin, yet only IgG reaches the fetus by an FcRn-dependent mechanism. We show that the placenta has a remarkable ability to distinguish between these two soluble proteins, revealing a level of biological selectivity that was previously unrecognized.” The result indicates that receptor binding alone does not determine whether a protein crosses the placenta; the surrounding cellular environment and the route taken after binding are also decisive.
To investigate the mechanism, the researchers combined experiments in conventional mice with studies using genetically humanized mouse models. They also used an advanced ex vivo human placental perfusion system, in which placental tissue donated immediately after childbirth can be maintained under controlled conditions and exposed to proteins on the maternal and fetal sides. Across the different experimental platforms, the pattern was consistent. IgG antibodies were transported efficiently through the placental tissue, whereas albumin showed little movement into the fetal compartment. The agreement between animal models and human placental tissue strengthens the relevance of the findings for human pregnancy biology.
The researchers then used this biological distinction as a platform for protein engineering. They fused albumin to therapeutic IgG antibodies, creating hybrid biologics that retained FcRn-dependent persistence in the circulation but crossed the placenta far less efficiently than conventional IgG antibodies. The design takes advantage of albumin’s natural behavior in the placenta while preserving the half-life benefits conferred by FcRn engagement in other tissues. The team also generated antibody fragments linked to an engineered albumin variant known as QMP. This variant was optimized for interaction with human FcRn, allowing the investigators to tune both circulation time and placental transfer through rational molecular design.
The approach was tested in human placental tissue and in disease models, including fetal and neonatal alloimmune thrombocytopenia, or FNAIT. In this potentially life-threatening pregnancy complication, maternal antibodies recognize fetal platelet antigens and destroy fetal platelets, creating a risk of severe bleeding before or shortly after birth. In a mouse model of FNAIT, the engineered antibody formats produced substantially lower fetal exposure and reduced adverse effects in offspring compared with conventional antibody-based treatment. The experiments suggest that reducing placental transport may not simply alter drug distribution but could directly lessen the risk of antibody-mediated effects in the fetus.
The study does not mean that existing biologic medicines are automatically safe during pregnancy, nor does it eliminate the need for clinical studies assessing maternal and fetal outcomes. Placental transport can vary according to antibody structure, dose, gestational age and the properties of the disease being treated. In humans, IgG transfer generally increases as pregnancy progresses, with particularly active transport during later gestation. Nevertheless, the new findings provide a design principle that could be applied before a medicine reaches clinical testing: instead of accepting fetal exposure as an unavoidable consequence of using an IgG therapeutic, developers may be able to build molecules that maintain therapeutic activity in the mother while remaining largely outside the fetal circulation.
“Rather than asking whether existing biologic medicines are safe to use during pregnancy, our findings show that we can now design them differently,” Andersen said. He added that the placenta’s selective handling of IgG and albumin offers an opportunity to combine long-lasting efficacy with improved pregnancy safety. The work illustrates how a fundamental discovery about protein transport can become a practical strategy for drug development. If the engineered formats prove safe and effective in further preclinical and clinical studies, they could eventually expand treatment options for women who need continuous biologic therapy during pregnancy while reducing unnecessary exposure of the developing fetus.
The researchers’ findings also broaden understanding of FcRn biology beyond its established role as a molecular recycling system. In blood vessels and other tissues, FcRn can rescue both IgG and albumin from intracellular degradation, explaining why each protein remains in circulation for an extended period. In the placenta, the same receptor participates in a specialized transport system in which protein identity, cellular routing and tissue organization combine to produce selective transfer. The study therefore presents the placenta not as a passive barrier, but as an active biological filter capable of discriminating between closely related circulating proteins. That insight may influence the next generation of antibody therapeutics for pregnancy-associated disease, chronic inflammatory conditions and other settings in which prolonged activity is needed without broad tissue exposure.
Subject of Research: Placental transport of IgG antibodies and albumin, FcRn biology, and the engineering of long-acting biologic medicines with reduced fetal exposure.
Article Title: Fusion of IgG antibodies to albumin inhibits transport across the placenta
Web References: https://doi.org/10.1126/SCIIMMUNOL.AEE5151
References: Nilsen, J., Sand, K.M.K., Al-Khabbaz, H.J., van Ligtenberg, L., Mester, S., Mathiesen, L., Noordzij, H.T., Jensen, K.-R., Leitzinger, N., Ottersen, O., Benjakul, S., Herigstad, M.L., Ruso-Julve, F., Anthi, A.K., Moen, A., Nyquist-Andersen, M., Gjølberg, T.T., Bertelsen, E.L., Cameron, J., Foss, S., Christianson, G.J., Schlothauer, T., Stuge, T.B., Knudsen, L.E., Sandlie, I., Roopenian, D.C., Ahlen, M.T., and Andersen, J.T. “Fusion of IgG antibodies to albumin inhibits transport across the placenta.” Science Immunology (2026). DOI: 10.1126/SCIIMMUNOL.AEE5151.
Keywords: placenta, pregnancy, biologic medicines, monoclonal antibodies, IgG, albumin, neonatal Fc receptor, FcRn, fetal exposure, drug engineering, FNAIT, translational medicine
