2. Academic Validation
  3. 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

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

  • Sci Rep. 2024 Jul 30;14(1):17515. doi: 10.1038/s41598-024-67371-5.
Anne M Fourie 1,  Xiaoli Cheng 2,  Leon Chang 3,  Carrie Greving 3,  Xinyi Li 3,  Beverly Knight 3,  David Polidori 3,  Aaron Patrick 4,  Trpta Bains 4,  Ruth Steele 4,  Samantha J Allen 4,  Raymond J Patch 4,  Chengzao Sun 4,  Sandeep Somani 4,  Ashok Bhandari 2,  David Liu 2,  Keith Huie 2,  Shu Li 2,  Michael A Rodriguez 3,  Xiaohua Xue 3,  Arun Kannan 3,  Teddy Kosoglou 4,  Jonathan P Sherlock 4,  Jennifer Towne 3,  M Claire Holland 4,  Nishit B Modi 2
Affiliations

Affiliations

  • 1 Janssen Research & Development, LLC, La Jolla, CA, USA. afourie@its.jnj.com.
  • 2 Protagonist Therapeutics, Newark, CA, USA.
  • 3 Janssen Research & Development, LLC, La Jolla, CA, USA.
  • 4 Janssen Research & Development, LLC, Spring House, PA, USA.
PMID: 39080319 DOI: 10.1038/s41598-024-67371-5
Abstract

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 (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 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 (IC50: 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.

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