title: pH-dependent binding engineering reveals an FcRn affinity threshold that governs IgG recycling.
abstract: The Fc domain of IgG has been the target of multiple mutational studies aimed at altering the pH-dependent IgG/FcRn interaction to modulate IgG pharmacokinetics. These studies have yielded antibody variants with disparate pharmacokinetic characteristics, ranging from extended in vivo half-life to those exhibiting extremely rapid clearance. To better understand pH-dependent binding parameters that govern these outcomes and limit FcRn-mediated half-life extension, we generated a panel of novel Fc variants with high affinity binding at acidic pH that vary in pH 7.4 affinities and assessed pharmacokinetic outcomes. Pharmacokinetic studies in human FcRn transgenic mice and cynomolgus monkeys showed that multiple variants with increased FcRn affinities at acidic pH exhibited extended serum half-lives relative to the parental IgG. Importantly, the results reveal an underappreciated affinity threshold of neutral pH binding that determines IgG recycling efficiency. Variants with pH 7.4 FcRn affinities below this threshold recycle efficiently and can exhibit increased serum persistence. Increasing neutral pH FcRn affinity beyond this threshold reduced serum persistence by offsetting the benefits of increased pH 6.0 binding. Ultra-high affinity binding to FcRn at both acidic and neutral pH leads to rapid serum clearance.
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: M Jack
authors.initials: MJ
authors.lastname: Borrok
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Nurten
authors.initials: N
authors.lastname: Beyaz
authors.affiliation: Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, MedImmune, Inc., Gaithersburg, Maryland 20878.
authors.forename: Xiang-Qing
authors.initials: XQ
authors.lastname: Yu
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Vaheh
authors.initials: V
authors.lastname: Oganesyan
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and dallacquaw@medimmune.com.
authors.forename: William F
authors.initials: WF
authors.lastname: Dall'Acqua
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and tsuip@medimmune.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Tsui
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D000915:Antibody Affinity; D001435:Bacteriophages; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000502:physiology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D011961:Receptors, Fc / Q000502:physiology*; D020349:Surface Plasmon Resonance; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D010446:Peptide Fragments; D019151:Peptide Library; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
keywords: Antibody Engineering; Fc Receptor; FcRn; Monoclonal Antibody; Phage Display; Pharmacokinetics