Abstract A critical property of many therapies is their selective binding to target populations. Exceptional specificity can arise from high-affinity binding to surface targets expressed exclusively on target cell types. 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 multivalent molecules, creating a combinatorial explosion of design possibilities. Guiding strategies for developing cell-specific binding are critical to employ these tools. Here, we employ a uniquely general multivalent binding model to dissect multi-ligand and multi-receptor interactions. This model allows us to analyze and explore a series of mechanisms to engineer cell selectivity, including mixtures of molecules, affinity adjustments, valency changes, multi-specific molecules and ligand competition. Each of these strategies can optimize selectivity in distinct cases, leading to enhanced selectivity when employed together. The proposed model, therefore, provides a comprehensive toolkit for the model-driven design of selectively binding therapies.

中文翻译：

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工程细胞选择性配体结合策略的定量观点

摘要 许多疗法的一个关键特性是它们对目标人群的选择性结合。与专门在靶细胞类型上表达的表面靶标的高亲和力结合可能会产生异常的特异性。然而，在许多情况下，治疗靶标的表达水平与脱靶细胞的表达水平略有不同。已经开发了更复杂的结合策略来克服这一限制，包括多特异性和多价分子，创造了设计可能性的组合爆炸。开发细胞特异性结合的指导策略对于使用这些工具至关重要。在这里，我们采用独特的通用多价结合模型来剖析多配体和多受体相互作用。该模型使我们能够分析和探索一系列机制来设计细胞选择性，包括分子混合物、亲和力调整、化合价变化、多特异性分子和配体竞争。这些策略中的每一个都可以在不同的情况下优化选择性，从而在一起使用时提高选择性。因此，所提出的模型为选择性结合疗法的模型驱动设计提供了一个综合工具包。