Targeting receptor systems by competitive inhibition is the objective of various antibody 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. The results suggest that the microenvironment may have an influence on the success of drug treatment with competitive inhibitors, like therapeutic antibodies in cancer therapy.
|Title of host publication||Proceedings Foundations of Systems Biology and Engineering (FOSBE 2009)|
|Number of pages||4|
|Publication status||Published - 2009|