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Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (K<jats:sub>D<\/jats:sub>: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC<jats:sub>50<\/jats:sub>: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23\u2013induced interferon (IFN)\u03b3 production in NK cells, and in\u00a0blood from healthy donors and psoriasis patients (IC<jats:sub>50<\/jats:sub>: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses\u2009\u2265\u20090.3 mg\/kg\/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23\u2013stimulated IL-17A production was observed. In an IL-23\u2013induced rat skin inflammation model, JNJ-77242113 inhibited IL-23\u2013induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23\u2013stimulated IFN\u03b3 production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23\u2013driven immune-mediated diseases.<\/jats:p>","DOI":"10.1038\/s41598-024-67371-5","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T18:18:15Z","timestamp":1722363495000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["JNJ-77242113, a highly potent, selective peptide targeting the IL-23 receptor, provides robust IL-23 pathway inhibition upon oral dosing in rats and humans"],"prefix":"10.1038","volume":"14","author":[{"given":"Anne M.","family":"Fourie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie","family":"Greving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly","family":"Knight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Polidori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Patrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trpta","family":"Bains","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Steele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond J.","family":"Patch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengzao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Somani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Bhandari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Huie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Kannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teddy","family":"Kosoglou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Sherlock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Towne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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