This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Protein-based medicines have transformed the treatment of many diseases, but they often come with a limitation: they must be injected, sometimes repeatedly, because they are rapidly cleared from the bloodstream. For patients who depend on long-term or lifelong treatment, frequent injections place a considerable burden on everyday life.
Now, researchers from the University of Oslo and Oslo University Hospital, together with international collaborators, have developed an approach to make a therapeutic protein last longer in the body while also opening the possibility of delivering it across mucosal surfaces without the use of needles. The work is published in Nature Communications. The researchers used human erythropoietin (EPO), a hormone that stimulates the production of red blood cells and is widely used to treat anemia, as a relevant model therapeutic protein.
By genetically fusing EPO to an engineered form of human albumin, they designed a long-acting molecule that remained biologically active and showed improved persistence in circulation. The engineered EPO-albumin fusion protein could also be transported across mucosal barriers following noninvasive administration through the nose in humanized mice. "This study shows how an understanding of the fundamental biology that regulates albumin homeostasis can be used to design engineered albumin-fused biologics with tailored transport properties," says Professor Jan Terje Andersen, who led the study at the University of Oslo and Oslo University Hospital.
"Instead of only focusing on the therapeutic protein itself, we have engineered its carrier. By doing so, we can control how long the fusion protein stays in the circulation and, at the same time, improve its ability to cross selective biological barriers," he adds. Albumin normally circulates for around three weeks because it binds to a receptor called the neonatal Fc receptor, or FcRn.
Inside cells, FcRn rescues albumin from degradation and returns it to the circulation via a pH-dependent mechanism. The researchers have previously reported on the characterization of an engineered human albumin variant (E505Q/T527M/K573P; QMP), which interacts more efficiently with human FcRn. Fusion to QMP limits antibody fragments from crossing the placenta during pregnancy.
In the new study, EPO was genetically fused to this engineered albumin to determine whether the natural recycling and transport functions of FcRn could be exploited to improve the properties of the therapeutic protein. When administered intravenously to mice engineered to express human FcRn, EPO fused to engineered albumin showed a plasma half-life of 5.7 days, compared with 1.1 days when EPO was fused to normal human albumin—a more than fivefold improvement. The engineered EPO-albumin fusion could be detected in the circulation for up to 27 days, whereas the corresponding fusion with normal albumin was no longer detectable after 10 days.
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