Multivalent Binding Model Explains Immune Cell Responses to Engineered γ-chain Cytokine Muteins

The common γ-chain cytokines are promising immune therapies due to their central role in coordinating the abundance and activity of immune cell populations. One of these cytokines, interleukin (IL)-2, is an approved therapy for metastatic melanoma but is limited in effectiveness due to its induction of non-specific proliferation of off-target immune cell types. IL-2 muteins with altered receptor-ligand binding kinetics improve the cell type selectivity of the signaling response. Furthermore, muteins that are made dimeric through antibody Fc fusion have exhibited desirable pharmacokinetic benefits. Here, we analyze the response of four key immune cell types to a panel of muteins in both monomeric and dimeric Fc formats. We used a structured dimensionality reduction scheme to decompose the mean responses of each cell population to each ligand, and show that dimeric muteins are uniquely specific for regulatory T cells (Tregs) cells at intermediate ligand concentrations. To dissect the mechanism of enhanced Treg specificity in dimeric ligands, we used a simple multivalent binding model to determine whether the changes in signaling could be explained by binding avidity on its own, and found that our model was able to translate between cell surface binding and cellular response with high accuracy.