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

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

Experimental investigation of liquid jet injection into Mach 6 hypersonic crossflow

The injection of a liquid jet into a crossing Mach 6 air flow is investigated. Experiments were conducted on a sharp leading edge flat plate with flush mounted injectors. Water jets were introduced through different nozzle shapes at relevant jet-to-air momentum-flux ratios. Sufficient temporal resolution to capture small scale effects was obtained by high-speed recording, while directional illumination allowed variation in field of view. Shock pattern and flow topology were visualized by Schlieren-technique. Correlations are proposed on relating water jet penetration height and lateral extension with the injection ratio and orifice diameter for circular injector jets. Penetration height and lateral extension are compared for different injector shapes at relevant jet-to-air momentum-flux ratios showing that penetration height and lateral extension decrease and increase, respectively, with injector's aspect ratio. Probability density function analysis has shown that the mixing of the jet with the crossflow is completed at a distance of x/d (j) similar to 40, independent of the momentum-flux ratio. Mean velocity profiles related with the liquid jet have been extracted by means of an ensemble correlation PIV algorithm. Finally, frequency analyses of the jet breakup and fluctuating shock pattern are performed using a Fast Fourier algorithm and characteristic Strouhal numbers of St = 0.18 for the liquid jet breakup and of St = 0.011 for the separation shock fluctuation are obtainedAerospace Engineerin