Half-life extension through albumin fusion technologies.
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 of rIX-FP were significantly improved compared with rFIX. Using the tail-clip bleeding model in FIX-deficient mice, rIX-FP effectively corrected the bleeding time and blood loss. These findings suggest that rIX-FP may be a promising therapy for the treatment of patients with haemophilia B.
Schulte
Stefan
S
CSL Behring GmbH, Marburg, Germany. Stefan.schulte@cslbehring.com
D000418:Albumins / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005164:Factor IX / Q000235:genetics / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D002836:Hemophilia B / Q000188:drug therapy*; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D051379:Mice; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D000418:Albumins; D011993:Recombinant Fusion Proteins; D005164:Factor IX