Extending Serum Half-life of Albumin by Engineering FcRn Binding [Immunology]

March 20th, 2014 by Andersen, J. T., Dalhus, B., Viuff, D., Thue Ravn, B., Gunnarsen, K. S., Plumridge, A., Bunting, K., Antunes, F., Williamson, R., Athwal, S., Allan, E., Evans, L., Bȷoras, M., Kȷarulff, S., Sleep, D., Sandlie, I., Cameron, J.

A major challenge for the therapeutic use of many peptides and proteins is their short circulatory half-life. Albumin has an extended serum half-life of three weeks due to its size and FcRn-mediated recycling that prevents intracellular degradation, properties shared with IgG antibodies. Engineering the strictly pH dependent IgG-FcRn interaction is known to extend IgG half-life. However, this principle has not been extensively explored for albumin. We have engineered human albumin by introducing single point mutations in the C-terminal end that generated a panel of variants with greatly improved affinities for FcRn. One variant (K573P) with 11-fold improved affinity showed extended serum half-life in normal mice, mice transgenic for human FcRn and cynomolgus monkeys. Importantly, favorable binding to FcRn was maintained when a single-chain fragment variable antibody was genetically fused to either the N- or C-terminal end. The engineered albumin variants may be attractive for improving the serum half-life of biopharmaceuticals.