Extended half-life (EHL) blood clotting factors have several advantages, including reduced injection frequency, increased adherence to treatment by patients, and improved clinical outcomes.
One of the approaches by which the half-life of clotting factors (or the time the body takes to reduce the amount of clotting factor by half) can be extended is to fuse them to the Fc fragment of antibodies.
Fc fusion technology
The fragment crystallizable (Fc) region is the tail portion of antibody molecules called IgG1 (immunoglobulin G1) that binds to receptors on the surface of various cell types, thereby mediating their physiological effects.
Fc fusion is an established technology. The Fc domain of antibodies has been previously fused to various molecules such as cytokines (a type of cell signaling molecule), growth factors, or other proteins to be used as research tools or therapeutic agents. It has also been used to prolong the half-life of several drugs licensed for the long-term treatment of a number of chronic diseases, such as rheumatoid arthritis (RA).
Clotting factors regulate the blood clotting process. Afterward, they are broken down and removed from circulation. Fusion with Fc fragment prolongs the half-life of clotting factors through a biological process known as Fc receptor-mediated recycling.
Using Fc fusion technology, recombinant factor VIII Fc (rFVIIIFc) and recombinant factor IX Fc (rFIXFc) were developed for the treatment of hemophilia A and B respectively, by fusing a single molecule of rFVIII or rFIX to the Fc domain of IgG1.
Both drugs are produced by recombinant DNA technology in human embryonic kidney 293 cells. Preclinical and clinical studies of rFVIIIFc and rFIXFc have shown improved pharmacokinetics (the way a drug is processed in the body) over currently available products.
Bioverativ‘s FDA-approved Eloctate is the first Fc-fused recombinant clotting factor VIII therapy for the treatment of hemophilia A, designed to stay in the body for a prolonged time. It involves fusing a single molecule of B domain-deleted factor VIII (B-domain is not essential for blood clotting function) to the Fc portion of IgG1.
A problem for some patients taking the therapy is that their bodies produce antibodies against Eloctate, called inhibitors, which prevent the drug from working properly. The most frequent side effects of Eloctate are headaches, rashes, joint pain, muscle pain, and general discomfort.
Bioverativ’s Alprolix is the first recombinant clotting factor IX therapy with prolonged circulation in the body. It was also developed using Fc fusion technology, but to treat people with hemophilia B. Common side effects of Alprolix include headaches and an abnormal sensation in the mouth.
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