Directed Evolution of a Soluble Human IL-17A Receptor for the Inhibition of Psoriasis Plaque Formation in a Mouse Model

SummaryInterleukin-17 (IL-17) is a T-cell-derived cytokine that promotes inflammatory pathology in autoimmune diseases. Blocking IL-17A interactions with its endogenous IL-17 receptor (IL-17RA) can constitute an important target for therapeutic intervention. Here, we utilized a directed evolution approach to generate soluble IL-17RA mutants that exhibit increased IL-17A binding affinity and thermostability, relative to the wild-type. Human fibroblast cell-based assay and in vivo analysis in mice indicated that two improved IL-17RA mutants efficiently inhibit the secretion of IL-17A-induced proinflammatory cytokines. Analysis of one of these mutants in a psoriasis mouse model showed its efficacy in promoting the recovery of psoriasis plaques. This mutant can be used as a promising drug candidate for the treatment of psoriasis and may be a therapeutic agent for various other autoimmune diseases.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (275 K)Download as PowerPoint slideHighlights► IL-17 is involved in many inflammatory diseases ► Directed evolution of IL-17A receptor results in improved IL-17A affinity ► The engineered receptors efficiently inhibit IL-17A induced cytokine secretion ► Engineered receptor promotes the recovery of psoriasis plaques in mouse model