Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antagonist, decreases the inflammatory response

Abstract

IL-23 is part of the IL-12 family of cytokines and is composed of the p19 subunit specific to IL-23 and the p40 subunit shared with IL-12. IL-23 specifically contributes to the inflammatory process of multiple chronic inflammatory autoimmune disorders, including psoriasis, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. So far, one antibody targeting the shared p40 subunit of IL-12 and IL-23, Ustekinumab, is approved clinically to treat psoriasis. However, there are no treatments inhibiting specifically the IL-23 proinflammatory response. We have developed small IL-23R-specific antagonists by designing all D-peptides arising from flexible regions of IL-23R. Of these peptides, we selected 2305 (teeeqqly), since in addition to its soluble properties, it inhibited IL-23-induced STAT3 phosphorylation in spleen cells. Peptide 2305 specifically binds to IL-23R/IL-12Rβ1-expressing HEK-293 cells and not to cells devoid of the receptor. Peptide 2305 showed functional selectivity by modulating IL-23-induced gene expression in IL-23R/IL-12Rβ1-expressing cells and in Jurkat cells; 2305 does not inhibit IL-12-induced cytokine expression in IL-12Rβ-IL-12Rβ2-HEK-293 cells. Finally, compared with anti-p40 treatment, 2305 effectively and selectively inhibits IL-23-induced inflammation in three in vivo mouse models: IL-23-induced ear inflammation, anti-CD40-induced systemic inflammatory response, and collagen-induced arthritis. We, hereby, describe the discovery and characterization of a potent IL-23R small-peptide modulator, 2305 (teeeqqly), that is effective in vivo. 2305 may be more convenient, less cumbersome, less costly, and most importantly, more specific than current biologics for the treatment of inflammatory conditions, and conceivably complement the actual therapies for these chronic and debilitating inflammatory diseases.

Increased interleukin‐23 receptor (IL‐23R) expression is associated with disease severity in acute‐on‐chronic liver failure

“…These studies indicate critical involvement of IL‐23R in inflammation and injury which could be inhibited by blockade of IL‐23R. Specific targeting of IL‐23R decreases the inflammatory response by inhibiting IL‐23‐induced STAT3 phosphorylation . Another data revealed IL‐23R R381Q gene variant protects against immune‐mediated diseases via hampering IL‐23‐induced Th17 cell effector response .…”

IL23R (Interleukin 23 Receptor) Variants Protective against Inflammatory Bowel Diseases (IBD) Display Loss of Function due to Impaired Protein Stability and Intracellular Trafficking

“…As examples, competitors of IL2-IL2R␣ and BcL-2/ BcL-xL interactions have been identified using fragment based approach, and the compounds bind to a groove that locks the conformation of the protein and prevents its interaction with its natural partners (57). Alternatively, we have reported an allosteric peptide inhibitor of IL23R function that, in contrast to anti-p40 IL23 hormone subunit, selectively inhibits IL-23-induced inflammation in three in vivo mouse models (59). In addition, development of structure-specific synthetic antibodies could prove another alternative to developing functionally antagonistic or competitive inhibitors of IL23R function (60).…”

Cytokines in psoriasis

“…One of the key functions of IL-23 appears to be its ability to amplify and sustain Th17 T cells [97] and as such, is targeted by the anti-IL12p40 biologic ustekinumab (Fig. 3) as well as the more specific approach of targeting the IL-23p19 subunit (CNTO1959 currently in phase 2 trials for palmar plantar pustulosis) and the IL-23 receptor itself [99,100] as a means of targeting IL-17 activity upstream of Th17 cells.…”