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Fc-Fusion Protein Development

  • Overview of Fc-fusion Based Half-Life Extension

    IgG molecules of the IgG1, IgG2, and IgG4 subclasses exhibit exceptionally long half-lives due to FcRn-mediated recycling. Half-lives of up to 4 weeks have been described for therapeutic antibodies. The binding site for FcRn resides in the Fc region, which is formed by the CH2 and CH3 domains. Thus, fusion to an Fcγ region endows a therapeutic protein with the half-life extension properties (increased size, FcRn recycling) of immunoglobulins. Fc fusion represents one of the most clinically successful half-life extension strategies to date and has been used in the development of a major portion of the fusion proteins. A wide range of molecules, from small peptides to larger proteins, are suitable for fusion to the Fc region, suitable molecules include hormones, growth factors, blood proteins, and protein or peptide mimetics.

    Examples of Fc-fusion Application in Half-Life Extension

    • Most of the functional moieties in approved Fc fusion proteins are portions of the receptors, such as TNF receptor, IL- 1 receptor, VEGF receptor, and CTLA-4. The half-lives of these fusion proteins are in the range of 3–13 days in vivo.
    • Fc fusion was applied to extend the half-life of biologically active proteins such as blood proteins, growth factors, and hormones, or protein and peptide mimetics thereof.
    • Fc fusion technology was applied to coagulation factors, and a factor VIII-Fc fusion protein as well as a factor IX-Fc fusion protein were approved in 2014 for the treatment of hemophilia A and B, respectively.
    • The Fc-fusion protein development allows for mutations, which increase the affinity for FcRn and consequently further increase the half-life. Various mutations have been described to increase the half-life of IgGs. For example, mutations in three amino acids within the Fc region of an anti-respiratory syncytial virus IgG1 resulted in a 10-fold increased FcRn-binding and a 2- to 4-fold longer serum half-life in humans. Principally, mutations affecting FcRn binding should also be applicable to Fc fusion proteins.