An immune cell-selective interleukin 4 agonist

Interleukin 4 (IL-4) is a pleiotropic cytokine. Og the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4R alpha/IL-2R gamma (class I IL-4R), whereas endothelial cells express another type, IL4R alpha/IL-13R alpha (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. a series of IL-4 muteins were generated that were substituted its the region of IL-4 implicated in interactions with IL-2R gamma. These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding steadies indicated that IL-4/R121E retained physical interaction with IL-2R gamma bat not IL-13R alpha; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.