Targeting drugs to combinations of receptors: A modeling analysis of potential specificity

Targeting drugs to specific cells by conjugating the drug to an antibody or ligand for a cell surface receptor currently requires that the receptor be uniquely over-expressed by the target cell (the target cell over-expresses a particular receptor in comparison with untargeted cells, which do display this receptor type but a lesser number of them). Here we develop a mathematical model to predict the behavior of multivalent ligand-drug constructs containing two different ligands for two different receptors, which would allow targeting cells that do not uniquely over-express any receptor. In this model, target cells express both receptors at a high level; whereas, untargeted cells express one receptor type at the high level but the other at a lower level. The model predicts that these heterovalent conjugates (containing two different types of ligands) can achieve specificity even when the target cell does not uniquely over-express any one receptor type. Using the current approach, constructs in which only one ligand type is used will bind as much to untargeted cells as to the target cells. Therefore, this combination strategy can enormously expand the number of applications for which cell surface receptor targeting of drugs is an appropriate option.