Half-life extension through albumin fusion technologies

Thrombosis Research
Stefan Schulte

Abstract

Haemophilia B is characterized by a deficiency of coagulation factor IX (FIX), a protein that is important in the process of haemostasis and normal blood clotting. Recurrent bleeding into joints and soft tissues is the hallmark of severe haemophilia B. The goal of treatment is to prevent and manage haemorrhage and thereby reduce disabling joint and tissue damage, improve quality of life, and extend life expectancy. Current treatment with FIX replacement concentrates often requires repeated, frequent infusions, owing to the relatively short terminal half-life of FIX in the circulation. We have developed a unique technology for improving the biological characteristics of FIX in vivo. For this approach, recombinant FIX (rFIX) was genetically fused to albumin via a cleavable peptide linker. Constructs of the fusion protein were expressed in mammalian cells and characterized following purification. In vitro activation studies demonstrated that cleavage of the linker occurred in parallel with FIX activation. The molar specific clotting activity of the cleavable fusion protein (rIX-FP) was 10- to 30-fold greater than that of the fusion protein with non-cleavable linkers. In rats, rabbits, and FIX-deficient mice, the pharmacokinetics o...Continue Reading

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Citations

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