A PHARMACOKINETIC APPROACH FOR EVALUATING CYTOKINE BINDING MACROMOLECULES AS ANTAGONISTS

Purpose. Cytokine binding macromolecules such as antibodies and solubl e receptors sometimes produce undesirable agonist-like activities inst ead of the expected antagonist-like effects when the cytokine binding macromolecule extends the half-life of a short-lived cytokine. The pur pose of this paper is to identify the pharmacokinetic and physicochemi cal properties that can cause these agonist-like activities. Methods. A simple pharmacokinetic model was used to determine whether a given c ytokine binding macromolecule will function effectively as an antagoni st in therapeutic situations in which cytokine is released chronically . Results. The model proposed satisfactorily fits experimental data fo r soluble interleukin-4 receptor and for an anti-interleukin-4 monoclo nal antibody under conditions in which agonist-like and antagonist act ivity are observed. Conclusions. We show that the unexpected agonist-l ike activities result only when there is nonlinearity in the cytokine- cytokine receptor interaction and the cytokine binding macromolecule p rolongs the half-life of the cytokine.