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Ligand accumulation counteracts therapeutic inhibition of receptor systems

Krippendorff, Ben-Fillippo and Oyarzun, Diego and Huisinga, Wilhelm (2009) Ligand accumulation counteracts therapeutic inhibition of receptor systems. In: Third International Conference on Foundations of Systems Biology in Engineering (FOSBE 2009), August 9-12 2009, Denver, Colorado. (Unpublished)

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Abstract

Targeting receptor systems by competitive inhibition is the objective of various protein drugs in development and on the market. A variety of receptor systems also constitute a degradation mechanism for ligand and drug via endocytosis and therefore influence the microenvironment of the cell. A thorough understanding of the complex interplay between ligand kinetics, drug pharmacokinetics, and the drug effect arising from the inhibition of the receptor by competing with the natural ligand is largely missing. Based on a mathematical model of the drug-ligand-receptor dynamics we show that receptor inhibition may lead to accumulation of the natural ligand in the microenvironment of the cell, with counteracting impact on the inhibitory effect of the drug. In the absence of receptor-independent ligand degradation, we prove analytically that this counteracting effect cannot be eliminated by changing the structural properties of the drug, like the affinity, nor by changing drug dosage. It is a structural property of the type of receptor system under study that is due to the fact that inhibition influences the ligand concentration in the microenvironment. The results suggest that the microenvironment may have an influence on the success of drug treatment with competitive inhibitors, e.g., for therapeutic proteins in cancer therapy.

Item Type: Conference or Workshop Item (Paper)
Additional Information: B.-F. K. and W. H. acknowledge fruitful discussions with Charlotte Kloft (Clinical Phar- macy, MLU Halle-Wittenberg, Germany).
Keywords: therapeutic proteins; cell surface receptors; receptor inhibition;
Subjects: Science & Engineering > Hamilton Institute
Item ID: 2401
Depositing User: Hamilton Editor
Date Deposited: 26 Jan 2011 15:05
Refereed: No
URI:

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