Researchers at the University of Oslo and Oslo University Hospital, together with national and international collaborators, have reported on the results of preclinical research that could reshape the future design of biologic medicines that can be delivered during pregnancy with limited fetal exposure.
Led by Jan Terje Andersen, PhD, at the University of Oslo and Oslo University Hospital, the team’s studies in mice and in ex vivo human tissues found that the placenta distinguishes between antibodies and albumin. The scientists showed that although the neonatal Fc receptor binds both immunoglobulin G (IgG) antibodies and albumin, FcRn expressed in the placenta selectively transports IgG to the fetus, while largely excluding albumin. Their experiments demonstrated that fusing IgG antibodies to albumin minimized their transport across the placenta and prevented adverse effects in offspring in mice.
The findings address a rapidly growing unmet need. While monoclonal IgG antibodies are increasingly used to treat chronic diseases that affect women during their reproductive years, decisions concerning treatment during pregnancy often involve balancing the benefits of disease control against risks to the developing fetus.
Andersen said, “Rather than asking whether existing biologic medicines are safe to use during pregnancy, our findings show that we can now design them differently. The placenta selectively transfers protective IgG antibodies while preventing albumin from crossing. By understanding this, we now have the opportunity to develop a new generation of biologic medicines that combine long-lasting efficacy with improved safety during pregnancy. This study shows how fundamental discoveries in biology can directly inspire the design of better medicines.”
Andersen is corresponding author of the team’s published paper in Science Immunology, titled “Fusion of IgG antibodies to albumin inhibits transport across the placenta,” in which they concluded, “These findings identify albumin as an attractive fusion partner for biologics intended to minimize fetal exposure during pregnancy.”
Albumin and IgG antibodies are the most prevalent soluble proteins in blood, the team explained. “Whereas IgG is pivotal in the fight against infectious diseases, albumin transports a plethora of insoluble ligands, such as fatty acids, hormones, and waste products, for delivery to tissues and organs.”
IgG-based monoclonal antibodies are among the fastest-growing class of biologics that are being used to treat a range of acute and chronic diseases, the team noted, and are effective therapies for cancer, autoimmune diseases, and migraine. “However, they are actively transported across the placenta by the neonatal Fc receptor (FcRn), limiting their use during pregnancy.” Evidence that supports safe use of such therapeutics during pregnancy remains limited.
For their studies, the team focused on albumin, a transport protein that also has a long half-life and binds FcRn at a different site to IgG. The researchers showed that FcRn transferred maternal IgG, but not albumin, across the placenta and into fetal pups in mice. To uncover the mechanism, the researchers combined studies in conventional and genetically humanized mouse models with an advanced ex vivo human placental perfusion system using placentas donated immediately after childbirth. Across all models, the findings were strikingly consistent: IgG antibodies were transferred efficiently, whereas albumin was not.
The researchers then took advantage of the discovery to make a platform for engineering next-generation biologics. They found that fusion of albumin to therapeutic IgG antibodies produced biologics with both FcRn-mediated long plasma half-life and substantially reduced placental transport. An even greater effect was achieved by fusing antibody fragments to an engineered albumin variant (QMP) with optimized human FcRn binding, demonstrating that both reduced placental transfer and long plasma half-life can be tuned through rational protein design.
The concept was validated in human placental tissue and disease models. In a mouse model of fetal and neonatal alloimmune thrombocytopenia (FNAIT)—a potentially life-threatening pregnancy complication in which maternal antibodies attack fetal platelets—the engineered antibodies resulted in substantially reduced fetal exposure and associated adverse effects in the offspring.
“This is first and foremost a discovery of how the placenta works,” Andersen said. “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 findings address a rapidly growing unmet need. While monoclonal IgG antibodies are increasingly used to treat chronic diseases that affect women during their reproductive years, decisions concerning treatment during pregnancy often involve balancing the benefits of disease control against risks to the developing fetus. The authors propose that further research is needed to understand the mechanisms that restrict albumin transport, which could inform more tailored therapeutics with varied fetal exposure profiles.
