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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

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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.

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Authors and Affiliations

  1. College of Pharmacy, University of Kentucky, BioPharm Building, Room 341, 789 S. Limestone, Lexington, Kentucky, 40536, USA

    Chee M. Ng

  2. Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, USA

    Paul J. Fielder, Jin Jin & Rong Deng

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  1. Chee M. Ng
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Correspondence to Chee M. Ng.

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Supplementary Figure 1

Observed and model predicted binding of anti-VEGF IgG1 WT antibody and its variants to cynomolgus monkey FcRn at physiological pH. A) WT, B) N434H, C) T307Q/N434A, D) T307Q/N434, E) T307Q/E380A/N434A, and D) V308P/N434A. Open circle—observed values; solid line—model prediction (DOCX 78 kb)

Supplementary Figure 2

Individual serum endogenous IgG concentration-time profiles and model prediction from four animals without anti-VEGF IgG1 antibody treatment. For comparison purpose, the observed anti-VEGF IgG1 concentration-time profiles from two representative animals received either anti-VEGF IgG1 WT or FcRn variant with the highest FcRn binding affinity (V308P/N434A) were included in the plots. Open circle—observed anti-VEGF FcRn variant (V308P/N434A) IgG concentrations, open diamond—observed anti-VEGF IgG1 WT concentrations, solid line—model prediction (DOCX 31 kb)

Supplementary Figure 3

Schematic representation of mechanism-based competitive binding model for anti-VEGF IgG1 and endogenous IgG antibodies which assumed endosomal compartment was nested in peripheral compartment. (DOCX 36 kb)

Supplementary Figure 4

Inter-subject variance of CL by different anti-VEGF IgG1 and FcRn binding affinity (K D) at pH7 for the A) model without in vitro in vivo correlation (IVIVC) between the KD used in the model and the Biacore binding study and B) final model. Dashed line—LOESS smoothing line (DOCX 17 kb)

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Ng, C.M., Fielder, P.J., Jin, J. et al. 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. AAPS J 18, 948–959 (2016). https://doi.org/10.1208/s12248-016-9911-4

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  • DOI: https://doi.org/10.1208/s12248-016-9911-4

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