For Research Use Only. Not for Clinical Use.

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 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.

Fig.1 FcRn has an MHC-class I-like structure and binds the CH2-CH3 hinge region of IgG. (Roopenian, 2007)

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 was approved in 2014 for the treatment of hemophilia A and B, respectively.
• The Fc fusion technology allows implementing mutations, which increases the affinity for FcRn and consequently further increases 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.

Fig.2 Overview of pH-dependent FcRn-mediated recycling. (Tan, 2018)

References

1. Roopenian, D. C. and Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007, 7(9): 715-25.
2. Tan, H.; et al. Recent Advances in Half-life Extension Strategies for Therapeutic Peptides and Proteins. Curr Pharm Des. 2018, 24(41): 4932-4946.