IL-12 and IL-23 Therapeutic Targets Reviewed

Two cytokines, interleukin-12 (IL-12) and interleukin-23 (IL-23), play a central role in T cell–mediated responses in inflammation. Researchers have clarified the relative contribution of these two cytokines in immune regulation. Recently, the monoclonal antibody ustekinumab, which targets both cytokines, was approved to treat psoriasis and psoriatic arthritis. In a review article, published in the July 2015 issue of Nature Medicine, authors discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders. Currently, at least 10 therapeutic agents targeting IL-12, IL-23 or IL-17A are under clinical investigation for more than 17 immune-mediated diseases and inflammatory disorders. The authors noted that data from preclinical disease models, familial genetic studies, large-scale genome-wide association studies and next-generation sequencing approaches have indicated where IL-23 may contribute to inflammatory disease risk. The inflammatory role of IL-12, revealed in the mid-1990s, provided the rationale to develop the human IL-12–neutralizing antibodies, including ustekinumab, briakinumab and the 'SMART anti-IL-12 antibody'. They noted that cytokines induced by IL-12 (such as IFN-γ) and IL-23 (such as IL-17A, IL-17F and IL-22) are elevated in psoriatic arthritis plaques. In psoriasis, ustekinumab was evaluated in two phase 3 studies after subcutaneous dosing of 45 mg or 90 mg at week 0, week 4 and every 12 weeks afterward. From two-thirds to three-quarters of patients who took ustekinumab showed 75% moderate to severe disease reduction in the baseline Psoriasis Area and Severity Index (PASI-75). The placebo group placebo showed only 3–4% response. In two phase 3 trials of ustekinumab for psoriatic arthritis, the percentage of patients achieving an American College of Rheumatology score (ACR 20 response) at week 24 was twice as high with the monoclonal antibody (42.4-49.5%) as compared to placebo (20.2–22.8%), leading to its approval for psoriatic arthritis. Other inflammatory diseases with alterations in the IL-23 pathway include, ankylosing spondylitis, Crohn’s disease and multiple sclerosis, they added. In conclusion, the authors stated that clinical testing of IL-23 and IL-17A inhibitors have confirmed the initial hypotheses that these cytokines promote immune-mediated diseases, and agents targeting their pathways work particularly well in specific disease settings. Some questions still need to be answered, for example, why IL-17A and IL-17RA antagonists work well for psoriasis but exacerbate Crohn's disease. “It appears that different classes of inhibitor targeting IL-23 and IL-17 pathways may have unique non-overlapping attributes in different clinical settings,” they noted. “Investigators are still learning where the overlap occurs and what the differences are between targeting IL-23 and targeting other related pathway cytokines.” 

References:

Teng MW, et al. “IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases.” Nature Medicine 2015 Jul;21(7):719-29. doi: 10.1038/nm.3895. Epub 2015 Jun 29