Krippendorff, Ben-Fillippo and Oyarzun, Diego and Huisinga, Wilhelm
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.
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.
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