title: Mechanism-Based Competitive Binding Model to Investigate the Effect of Neonatal Fc Receptor Binding Affinity on the Pharmacokinetic of Humanized Anti-VEGF Monoclonal IgG1 Antibody in Cynomolgus Monkey.
abstract: The quantitative relationship between neonatal Fc receptor (FcRn) binding affinity at both acidic and physiological pH and the pharmacokinetics of protein engineered FcRn IgG1 variants has not yet been reported. Our objective was to develop a quantitatively mechanism-based competitive binding model to describe the effects of FcRn binding affinity at acidic and physiological pH on the pharmacokinetics of anti-VEGF IgG1 antibodies when both endogenous and exogenous antibodies are competing for the same FcRn. Pharmacokinetic (PK) and FcRn binding data from five Fc variants of humanized anti-VEGF IgG1 monoclonal antibodies with wide range of FcRn binding affinity were used for the analysis. Sixty-seven anti-VEGF IgG1 antibody-treated animals and 25 control animals with simulated endogenous IgG levels were used to develop the final model. A hybrid iterative two stages and Monte Carlo parametric expectation-maximization method was used to obtain the final model parameters estimates. The final model well described the observed PK data. Quantitative FcRn binding affinity-pharmacokinetics relationships was constructed to provide important biological insights in better understanding of the FcRn binding effect on pharmacokinetics of anti-VEGF IgG1 antibodies in cynomolgus monkeys and served as an important model-based drug discovery platform to guide the design and development of the future generation of anti-VEGF or other therapeutic IgG1 antibodies.
authors.affiliation: College of Pharmacy, University of Kentucky, BioPharm Building, Room 341, 789 S. Limestone, Lexington, Kentucky, 40536, USA. chee.ng@uky.edu.
authors.forename: Chee M
authors.initials: CM
authors.lastname: Ng
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000068258:Bevacizumab; D001667:Binding, Competitive; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D008252:Macaca fascicularis / Q000276:immunology*; D011485:Protein Binding; D011961:Receptors, Fc / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
keywords: FcRn; IgG; mechanism-based model; pharmacokinetics