Albumin is prevented from crossing the placenta – opening opportunities for design of long-acting biologic medicines

Biologic medicines have transformed the treatment of cancer, autoimmune diseases, migraine, inflammatory disorders and many other diseases. Yet, their growing use among women of reproductive age constitutes a major clinical challenge in that therapeutic IgG antibodies are actively transported across the placenta to the developing fetus. Evidence that supports safe use of such therapeutics during pregnancy remains limited.

Now, researchers from the University of Oslo and Oslo University Hospital, together with national and international collaborators, have uncovered that the placenta distinguishes between antibodies and albumin, a finding that may reshape the future design of biologic medicines with reduced fetal exposure.  

The placenta distinguishes between antibodies and albumin

Published in Science Immunology, the study demonstrates that although the neonatal Fc receptor (FcRn) binds both IgG antibodies and albumin - the two most abundant proteins in the bloodstream – FcRn expressed in the placenta selectively transports IgG to the fetus while largely excluding albumin. The discovery resolves a longstanding question in placental biology and inspires engineering of long-acting biologic medicines with minimal fetal exposure. On the other hand, FcRn, expressed by for instance endothelial cells lining blood vessels, rescues both IgG and albumin from intracellular degradation, and thus provides both with long plasma half-life.    

“This is first and foremost a discovery of how the placenta works. 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.”, says Professor Jan Terje Andersen, who led the study at the University of Oslo and Oslo University Hospital.

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.

Deliberate protein design

The researchers then took advantage of the discovery to make a platform for engineering of a 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. 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.

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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.

“Rather than asking whether existing biologic medicines are safe to use during pregnancy, our findings show that we can now design them differently”, Andersen says.

“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 design of better medicines.” Andersen concludes.