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Comparative Study
. 2012 Apr;39(2):125-39.
doi: 10.1007/s10928-012-9243-7. Epub 2012 Mar 8.

Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Ben-Fillippo Krippendorff  1 , Diego A Oyarzún, Wilhelm Huisinga
Affiliations
Comparative Study

Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Ben-Fillippo Krippendorff et al. J Pharmacokinet Pharmacodyn. 2012 Apr.

Abstract

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.

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Figures

Fig. 1
Fig. 1
Schematic illustration of the pharmacokinetic model and the kinetic cell-level model. a Semi-mechanistic pharmacokinetic compartment model describing the pharmacokinetics of the the mAb zalutumumab in monkeys developed by Lammerts van Bueren et al. [6]. b Canonical model of ligand-receptor activation and trafficking [19, 29, 20]
Fig. 2
Fig. 2
Schematic illustration of the cell-level PK/PD model for analyzing the inhibitory effect on receptor activation of anti-EGFR antibodies. a Cell-level receptor model of receptor activation and inhibition. The cellular model describes the transient inhibitory effect of a therapeutic antibody by competitively binding the targeted receptor and thereby decreasing the active ligand-receptor complexes. b Cell-level PK/PD model used to study the trajectory of the drug concentration and the impact of biophysical properties of anti-EGFR antibodies. c Three different transient measures of the reduction in the number of active receptors: the integral, the peak, and the duration of inhibition. d Extended cell-level PK/PD model including tumor cells with elevated EGFR levels due to alteration of receptor dynamics used to compare the inhibitory effect of therapeutic antibodies on tumor cells and normal cells to optimize tumor specificity
Fig. 3
Fig. 3
Pharmacokinetics of zalutumumab in cynomolgus monkeys and prediction of the inhibitory effect on a cellular level using themodel depicted in Fig. 2b. a Predicted plasma concentration of zalutumumab by the cell-level PK/PD model (solid line) and the compartment PK model of Lammerts van Bueren et al. [6] (dashed line) for a high, medium and low dose of 40, 20 and 2 mg/kg. The experimental data for zalutumumab in cynomolgus monkeys are marked with circles (40 mg/kg), squares (20 mg/kg) and diamonds (2 mg/kg). Experimental data courtesy of Wim Bleeker, Genmab, Utrecht, The Netherlands. b Predictions of the residual EGFR activation per cell based on the cell-level pharmacokinetic model (Fig. 2b) for the high dose (dashed dotted line), the medium dose (solid line) and the low dose (dashed line). The inset depicts the corresponding receptor saturation according to Eq. 25
Fig. 4
Fig. 4
F(ab)-mediated inhibitory effect of different antibodies using the cell-level PK/PD model shown in Fig. 2b. a Predicted transient inhibitory effects of five anti-EGFR antibodies on the market or in clinical development with different affinities (see Table 3) for a 20 mg/kg dose (solid line) and a 2 mg/kg dose (dashed line). The different mAbs show a similar transient inhibitory effect despite their affinities vary 20-fold. b–d Inhibitory effect resulting from different affinities (KD = 1/affinity = koffC/konC) and downregulation rates (kdegRC). The F(ab)-mediated effect is quantified by three different measures: b the integral of inhibition, c the peak inhibition, and d the duration of inhibition, for the 20 mg/kg dose (solid line) and 2 mg/kg dose (dashed line). The shaded area indicates the affinity range of the five considered antibodies
Fig. 5
Fig. 5
The mechanism underlying increased receptor levels influences tumor specificity of mAbs. a Predicted transient inhibition based on the extended cell-level pharmacokinetic model shown in Fig. 2d for normal cells, tumor cells with a 10-fold increased receptor expression, and tumor cells with a 10-fold decreased internalization of the free and bound receptor. Profiles are shown for the 20 mg/kg (solid line) and 2 mg/kg (dashed line) dose. Both scenarios show similar steady-state activation levels of the receptor, but their response to drug treatment is substantially different. b Antibody specificity as defined in Eq. 29. Cells with a decreased receptor internalization have a much longer duration of inhibition and therefore a higher integral of inhibition than tumor cells with an increased receptor expression
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