Petr Maly
BIOCEV Research Center, Czech Republic
Title: Targeting IL-23/Th17 pro-inflammatory axis by novel non-immunoglobulin protein binders with an immunosuppressive potential
Biography
Biography: Petr Maly
Abstract
IL-23 receptor-mediated signaling has recently been closely associated with development of several chronic autoimmune diseases such as psoriasis, psoriatic arthritis, inflammatory bowel disease and multiple sclerosis. Recently we generated novel IL-23 receptor antagonists (called REX ligands) derived from scaffold of albumin-binding domain (ABD) that exhibited immunosuppressive control over IL-23-driven ex vivo expansion of primary human Th-17+ T-cells. Due to small size, excellent tissue penetration and self-refolding activity, these binders represent a valuable non-immunoglobulin alternative for development of topically-administrated anti-psoriatic biologicals. As the structure of IL-23/IL-23R complex is unavailable and a precise mode of interaction remains unknown, designing more efficient IL-23 inhibitors is cumbersome. Following our concept, we generated a novel class of binding proteins targeting p19 subunit of human IL-23 cytokine. These unique proteins, called ILP binders, were selected from high-complex ABD-derived combinatorial library in combination with ribosome display. From 214 clones analyzed by ELISA, Western blot and DNA sequencing, 53 provided 35 different sequence variants that were further characterized. Using in silico docking in combination with cell-surface competition binding assay we identified a group of inhibitory candidates that substantially diminished binding of recombinant p19 to the IL-23 receptor on human monocytic THP-1 cells. Several found p19-blocking variants inhibited IL-23-driven expansion of IL-17-producing primary human CD4+ T-cells. Thus, these novel binders represent unique IL-23-targeted probes useful for IL-23/IL-23R epitope mapping studies and could be used for designing novel p19/IL-23-targeted anti-inflammatory