A quantitative view of strategies to engineer cell-selective ligand binding

A critical property of many therapies is their selective binding to specific target populations. Exceptional specificity can arise from high-affinity binding to unique cell surface targets. In many cases, however, therapeutic targets are only expressed at subtly different levels relative to off-target cells. More complex binding strategies have been developed to overcome this limitation, including multi-specific and multi-valent molecules, but these create a combinatorial explosion of design possibilities. Therefore, guiding strategies for developing cell-specific binding are critical to employ these tools. Here, we extend a multi-valent binding model to multi-ligand and multi-receptor interactions. Using this model, we explore a series of mechanisms to engineer cell selectivity, including mixtures of molecules, affinity adjustments, and valency changes. Each of these strategies maximizes selectivity in distinct cases, leading to synergistic improvements when used in combination. Finally, we identify situations in which selectivity cannot be derived through passive binding alone to highlight areas in need of new developments. In total, this work uses a quantitative model to unify a comprehensive set of design guidelines for engineering cell-specific therapies. Summary pointsO_LIAffinity, valency, and other alterations to target cell binding provide enhanced selectivity in specific situations. C_LIO_LIEvidence for the effectiveness and limitations of each strategy are abundant within the drug development literature. C_LIO_LICombining strategies can offer enhanced selectivity. C_LIO_LIA simple, multivalent ligand-receptor binding model can help to direct therapeutic engineering. C_LI