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

• Published in: Scientific reports Vol. 14; no. 1; pp. 17515 - 12
• Main Authors: Fourie, Anne M., Cheng, Xiaoli, Chang, Leon, Greving, Carrie, Li, Xinyi, Knight, Beverly, Polidori, David, Patrick, Aaron, Bains, Trpta, Steele, Ruth, Allen, Samantha J., Patch, Raymond J., Sun, Chengzao, Somani, Sandeep, Bhandari, Ashok, Liu, David, Huie, Keith, Li, Shu, Rodriguez, Michael A., Xue, Xiaohua, Kannan, Arun, Kosoglou, Teddy, Sherlock, Jonathan P., Towne, Jennifer, Holland, M. Claire, Modi, Nishit B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/436/108; 631/250/127/1213; Administration, Oral; Animals; Blood; Colitis; Colitis - chemically induced; Colitis - drug therapy; Disease Models, Animal; Dosage; Female; Gastrointestinal tract; Humanities and Social Sciences; Humans; Inflammatory bowel diseases; Interleukin 23; Interleukin-23 - metabolism; Male; multidisciplinary; Peptides; Peptides - administration & dosage; Peptides - pharmacology; Pharmacodynamics; Psoriasis; Psoriasis - chemically induced; Psoriasis - drug therapy; Psoriatic arthritis; Rats; Rats, Sprague-Dawley; Receptors, Interleukin - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Skin diseases; Sulfonic acid; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-67371-5

The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (K D : 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC 50 : 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23–induced interferon (IFN)γ production in NK cells, and in blood from healthy donors and psoriasis patients (IC 50 : 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses ≥ 0.3 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–stimulated IL-17A production was observed. In an IL-23–induced rat skin inflammation model, JNJ-77242113 inhibited IL-23–induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23–stimulated IFNγ 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–driven immune-mediated diseases.