Relationship between the dose of therapeutic antibodies and the inhibition of cytoplasmic and nuclear growth factor signalling
Ben-Fillippo Krippendorff (1), Diego A. Oyarzún (2), Jo Bramhall (1), Fernando López-Caamal (3), Aurélie Courtin (1), Wilhelm Huisinga (4), Frances Richards (1), Duncan Jodrell (1)
(1) University of Cambridge, Department of Oncology, Pharmacology & Drug Development Group (2) Imperial College London, Centre for Synthetic Biology and Innovation, Department of Bioengineering (3) National University of Ireland Maynooth, Hamilton Institute (4) University of Potsdam, Institute of Mathematics, Computational Physiology Group
Objectives: Inhibition of growth factor signalling is a promising strategy in cancer treatment because of the importance of such signals for proliferation, survival and resistance to chemotherapy. We have investigated how different physiological processes contribute to the relationship between the dose of a therapeutic antibody and the inhibition of cellular signalling. We therefore built a multi-level PK/PD model to relate the dose of an intravenously administered anti-EGFR antibody to the inhibition of intracellular growth factor signalling in cancer cells.
Methods: First, we built a pharmacokinetic model for different therapeutic antibodies on the market targeting the EGFR. The model follows the idea of target mediated drug disposition (TMDD), but we extended the concept by including intracellular receptor trafficking and the competition of the drug with endogenous receptor ligands. The final model allows the translation of a dose of administered antibody into the percentage of receptor molecules inhibited during the time of the treatment. Second, we built a cellular model to follow the effect of changes in EGFR activity from the cell surface to ERK in the nucleus. ERK is a key protein, downstream of the EGFR, controlling the expression of genes involved in proliferation and survival.
Results: To evaluate the multi-level PK/PD model, we compared our model predictions with experimental data of zalutumumab (2F8), an IgG1 antibody against the EGFR that inhibits tumor growth in xenograft models and has shown promising results in phase I/II clinical trials. The predicted time-courses of the drug concentrations showed a good agreement for high, medium and low doses (40 mg/kg, 20 mg/kg and 2 mg/kg). We then validated the cellular part of the model by using an imaging cytometer to quantify phosphorylated epidermal growth factor receptor (EGFR) and double phosphorylated Erk1/2 in individual cancer cells.
The decomposition of the different levels of drug treatment suggests that the overall response to a therapeutic antibody against the EGFR can be described by (i) a nonlinear relationship between the dose and receptor inhibition (ii) a nonlinear processing of the receptor signal by the MAPK cascade, and (iii) linear signal amplification by nuclear import processes of Erk.
Conclusions: Extending pharmacokinetic models to the cellular level by incorporating in vivo and in vitro data allows the prediction of the cellular effect of different drug doses.
References:
[1] Krippendorff, B.-F., Oyarzún, D. A., & Huisinga, W. (2012). Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling. Journal of pharmacokinetics and pharmacodynamics. doi:10.1007/s10928-012-9243-7
[2] Krippendorff, B.-F., Kuester, K., Kloft, C., & Huisinga, W. (2009). Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis. Journal of pharmacokinetics and pharmacodynamics, 36(3), 239–260. doi:10.1007/s10928-009-9120-1
[3] Chen, W. W., Schoeberl, B., Jasper, P. J., Niepel, M., Nielsen, U. B., Lauffenburger, D. A., & Sorger, P. K. (2009). Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data. Molecular Systems Biology, 5(1), doi:doi:10.1038/msb.2008.74