Placental biology breakthrough could make biologic medicines safer during pregnancy
核心洞察
Researchers from the University of Oslo and Oslo University Hospital (搜索) discovered that the placenta selectively transports IgG (搜索) antibodies while largely excluding albumin, despite both binding the neonatal Fc receptor (FcRn (搜索)).
The study, published in Science Immunology, shows that fusing albumin to therapeutic IgG (搜索) antibodies yields biologics with long plasma half-life and substantially reduced placental transport.
An engineered albumin variant (QMP) with optimized FcRn (搜索) binding further reduced fetal exposure, validated in a mouse model of fetal and neonatal alloimmune thrombocytopenia (搜索) (FNAIT).
Researchers from the University of Oslo and Oslo University Hospital (搜索), 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.
Published in Science Immunology, the study demonstrates that although the neonatal Fc receptor (FcRn (搜索)) binds both IgG (搜索) 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. By contrast, FcRn expressed by endothelial cells lining blood vessels rescues both IgG and albumin from intracellular degradation, thereby providing 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 (搜索) binds both IgG (搜索) 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," said Professor Jan Terje Andersen, who led the study at the University of Oslo and Oslo University Hospital (搜索).
Uncovering the mechanism of selective transport
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 (搜索) antibodies were transferred efficiently, whereas albumin was not.
Engineering next-generation biologics
The researchers then leveraged the discovery to build a platform for engineering next-generation biologics. They found that fusion of albumin to therapeutic IgG (搜索) antibodies produced biologics with both FcRn (搜索)-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 (搜索) (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.
Addressing an unmet clinical need
The findings address a rapidly growing unmet need. While monoclonal IgG (搜索) 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 said.
"The placenta selectively transfers protective IgG (搜索) 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 concluded.
The research was financed through the Research Council of Norway, South-Eastern Norway Regional Health Authority, Norwegian Cancer Society, Novo Nordisk Foundation, North Norway Regional Health Authority, the Saudi Ministry of Education - King Abdullah Scholarship, and the Alliance for Lupus Research and NIH.