title: Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding.
abstract: 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 3 weeks because of 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 12-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 the C-terminal end. The engineered albumin variants may be attractive for improving the serum half-life of biopharmaceuticals.
authors.affiliation: From the Centre for Immune Regulation and Department of Biosciences, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.forename: Dorthe
authors.initials: D
authors.lastname: Viuff
authors.forename: Birgitte Thue
authors.initials: BT
authors.lastname: Ravn
authors.forename: Kristin Støen
authors.initials: KS
authors.lastname: Gunnarsen
authors.forename: Andrew
authors.initials: A
authors.lastname: Plumridge
authors.forename: Karen
authors.initials: K
authors.lastname: Bunting
authors.forename: Filipa
authors.initials: F
authors.lastname: Antunes
authors.forename: Rebecca
authors.initials: R
authors.lastname: Williamson
authors.forename: Steven
authors.initials: S
authors.lastname: Athwal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Allan
authors.forename: Leslie
authors.initials: L
authors.lastname: Evans
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.forename: Søren
authors.initials: S
authors.lastname: Kjærulff
authors.forename: Darrell
authors.initials: D
authors.lastname: Sleep
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Jason
authors.initials: J
authors.lastname: Cameron
mesh_terms: D000418:Albumins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D020125:Mutation, Missense; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000418:Albumins; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal
keywords: Albumin; Animal Models; Antibody Engineering; Biodegradation; Bioengineering; FC Receptors; Pharmacokinetics; pH Regulation