Biological drugs have revolutionized the treatment of cancer, autoimmune diseases, migraine, inflammatory diseases and a range of other conditions.
At the same time, their growing use among women poses a major challenge when they want to become pregnant. Many such medications cross the placenta and reach the fetus. This raises concern when pregnant women are treated, because the fetus and newborn can be exposed to the drug.
In the worst case, this can harm the fetus.
Researchers at the University of Oslo and Oslo University Hospital have now made a discovery that could help solve this major challenge. They have shown that the placenta is more selective about what it lets through to the child than previously believed.
"This discovery could pave the way for more tailored drugs that still protect the mother, but that affect and potentially harm the fetus to a lesser degree," says Professor Jan Terje Andersen, who led the study, published in the journal Science Immunology. The study has also been covered in Nature.
Andersen is deputy director of PRIMA, a Centre of Excellence at UiO and Oslo University Hospital. He is also part of AFIRE, a new initiative on emerging technologies funded by the Norwegian Ministry of Education and Research.
The placenta protects the newborn
The placenta is the organ that connects mother and fetus during pregnancy. It transfers oxygen and nutrients from the mother to the child in the womb, carries away waste products and produces hormones essential to pregnancy.
The placenta also plays an important role in protecting the newborn against infections. Toward the end of pregnancy, large amounts of antibodies are transported from the mother across the placenta to the fetus.
"The antibodies protect the child against foreign invaders such as viruses and bacteria during the first weeks of life. At birth, the concentration of antibodies in the child can actually be higher than in the mother," says Andersen.
Antibodies with a uniquely long duration of action
The type of antibody that is transferred is called IgG. This is the most common type of antibody in our blood, and it is crucial for fighting infections.
The antibodies are carried across the placenta with the help of a receptor, a kind of gateway on cells, called FcRn. This receptor is also found in many other cells in the body, in both children and adults.
FcRn protects IgG antibodies so that they remain in the blood for several weeks. As such, they have a long plasma half-life. Long-acting protein-based drugs provide good protection over time and are a major advantage when the body needs to fight infections.
"Long-acting drugs can make a significant difference for people with chronic illnesses, where treatment is needed throughout life," says Jeannette Nilsen, postdoctoral researcher at PRIMA and first author of the study.
When drugs act for a long time, they can be taken less often as they will circulate in the blood for a long time.
This is one of the reasons why so many drugs are built on IgG antibodies.
"A number of antibody-based drugs have been developed to treat, among other things, chronic inflammatory diseases, autoimmune diseases and severe migraine. These are conditions that are common among women," Nilsen says.
The placenta is more selective than we thought
The researchers examined how the placenta transfers antibodies and other proteins from mother to child in the womb. Their study confirms that FcRn plays a key role when the mother's antibodies are transported across to the fetus.
At the same time, the study shows that the placenta is far more selective than previously assumed about what it lets through to the child.
The placenta clearly distinguishes between IgG antibodies and another protein called albumin. Albumin is a common protein that transports fatty acids, hormones, metals but also waste products in the blood.
The researchers found that IgG antibodies were efficiently transported across the placenta. Albumin, on the other hand, passed through only to a small extent and was largely retained in the mother's bloodstream.
"We see that the placenta has a remarkable ability to distinguish between IgG and albumin. This is interesting because both bind to FcRn, which is important for their long plasma half-life. Yet the placenta discriminates between them," Andersen says.
This knowledge is important for pregnant women who use biological drugs.
"Biologically, this makes sense," the professor explains:
"The mother produces antibodies that protect against serious infections. These antibodies are transferred to the fetus and protect the newborn during the first weeks of life. Since albumin also transports waste products, it makes sense that it is not actively transferred to the child," Andersen explains.
From biological discovery to new technology
Building on this new knowledge, the researchers have developed a new way of designing biological drugs.
By linking albumin to antibodies, they demonstrated that they retain a long plasma half-life. But as they are linked to albumin, they were to a lesser extent transported across the placenta.
The researchers also made use of a unique Norwegian developed technology, based on an engineered variant of human albumin. Using this technology, they developed long-acting proteins that reduced fetal exposure even further.
"Rather than simply asking whether existing biological drugs are safe enough during pregnancy, our research opens the door to developing potential long-acting drugs that are designed from the outset to limit transport to the fetus," says Andersen.
"This represents a new technological principle tailored for women who are planning a pregnancy or are already pregnant," Andersen adds.
Studied in both mice and placental tissue from women after birth
The published work builds on extensive international collaboration with researchers in Denmark, England, Germany, Saudi Arabia and the United States, and combines studies in mice with studies on human placental tissue, in which placentas are kept alive and functional outside the body after birth. The results were consistent across all the model systems.
"The study shows how an in-depth biological understanding can pave the way for new protein engineering strategies with translational impact," Andersen concludes.
The research was funded by the Research Council of Norway, the South-Eastern Norway Regional Health Authority, the Norwegian Cancer Society, the Novo Nordisk Foundation, the Northern Norway Regional Health Authority, the Saudi Arabian Ministry of Education through the King Abdullah Scholarship, the Alliance for Lupus Research, and the National Institutes of Health (NIH).
Reference
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). https://doi.org/10.1126/sciimmunol.aee5151
