Engineered albumin carrier extends protein drug half-life and enables needle-free mucosal delivery

Protein-based medicines have transformed the treatment of many diseases, yet they carry a persistent practical limitation: because they are rapidly cleared from the bloodstream, they must be injected, often repeatedly. For patients who depend on long-term or lifelong therapy, the burden of frequent injections weighs heavily on everyday life. Researchers at the University of Oslo and Oslo University Hospital, working with international collaborators, now report an approach that addresses both sides of this problem at once.

The team chose human erythropoietin, or EPO, as their model therapeutic protein. EPO is a hormone that stimulates the production of red blood cells and is widely used to treat anemia, making it a clinically relevant test case. The researchers fused EPO to an engineered variant of human albumin designated QMP, carrying the mutations E505Q, T527M and K573P. This variant had been characterized in previous work and was shown to interact more efficiently with human FcRn, the neonatal Fc receptor.

The logic behind the design rests on fundamental albumin biology. Albumin normally circulates in the blood for around three weeks because it binds to FcRn. Inside cells, FcRn rescues albumin from degradation and returns it to the circulation through a pH-dependent mechanism, effectively recycling the protein and protecting it from being broken down. In the new study, EPO was genetically fused to the engineered albumin to determine whether these natural recycling and transport functions could be exploited to improve the properties of a therapeutic protein.

The results were striking. When administered intravenously to mice engineered to express human FcRn, EPO fused to the engineered albumin showed a plasma half-life of 5.7 days, compared with 1.1 days when EPO was fused to normal human albumin. That represents a more than fivefold improvement in circulatory persistence. The engineered fusion could be detected in the bloodstream for up to 27 days, whereas the corresponding fusion with normal albumin was no longer detectable after 10 days.

Crucially, prolonging the molecule’s stay in the body did not come at the cost of its therapeutic function. The engineered fusion bound the EPO receptor with similar strength to a commercially available long-acting EPO product and efficiently stimulated the production of red blood cells. Following a single intravenous dose, both molecules initially increased red blood cell numbers. However, the effect of the commercial EPO product subsequently declined, while animals receiving the engineered EPO-albumin fusion maintained elevated levels for longer.

The second half of the study explored an even more ambitious question: could engineered albumin act as a molecular carrier to transport EPO across mucosal barriers? Protein medicines are normally injected precisely because they do not readily cross the body’s selective biological barriers. When the fusion proteins were administered non-invasively through the nose in humanized mice, five times more of the QMP-containing EPO fusion reached the blood than the corresponding fusion containing normal albumin. Most importantly, the protein remained functional after crossing the mucosal barrier, producing a stronger and more prolonged increase in red blood cells than a commercially available EPO product used for comparison.

Professor Jan Terje Andersen, who led the study at the University of Oslo and Oslo University Hospital, emphasized the conceptual shift underlying the work. “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,” he said. Rather than modifying the therapeutic protein itself, the team engineered its carrier, gaining independent control over how long the fusion protein remains in the circulation and how effectively it traverses selective biological barriers.

Andersen highlighted the combination of the two achievements as particularly exciting. “The combination of long circulatory half-life and improved ability to cross mucosal barriers is particularly exciting. Protein medicines are normally injected because they do not readily cross the body’s barriers. Our results show that we can use QMP and its receptor, FcRn, as a transport system. This could potentially contribute to protein-based medicines that can be given less frequently – and perhaps, for some applications, without needles,” he said.

The work remains at the preclinical stage, with results demonstrated in humanized mice rather than patients, and the EPO system served as a model rather than an immediate product candidate. If the approach translates to clinical settings, patients relying on injected protein therapies could one day benefit from treatments that are both longer-acting and, for some applications, needle-free.

Subject of Research: Engineering albumin-based fusion proteins for long-acting and mucosally deliverable protein therapeutics

Article Title: Fusion to engineered albumin makes protein-based therapeutics long-acting and gives them the ability to cross mucosal barriers

Article References: Fusion to engineered albumin makes protein-based therapeutics long-acting and gives them the ability to cross mucosal barriers. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: albumin, FcRn, erythropoietin, protein therapeutics, mucosal delivery, half-life extension, biologics, drug delivery, University of Oslo, preclinical study, humanized mice, needle-free