Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. An increased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn’s disease and ulcerative colitis.
IL-12 and IL-23, which are members of the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation, including in inflammatory bowel disease.
Multiple IL-12- and/or IL-23-neutralizing antibodies have been tested in immune-mediated diseases, including Crohn’s disease and ulcerative colitis.
In addition to demonstrated efficacy for clinical, endoscopic and histological outcomes, targeting IL-12 and/or IL-23 is a safe treatment strategy.
The exact positioning of such antibodies in current treatment algorithms will be influenced by ongoing head-to-head trials and evaluation of predictive molecular markers.
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The authors would like to thank L. M. Shackelton and S. Donegan for critical technical review and editing. B.V. is supported by the Clinical Research Fund (KOOR) at the University Hospitals Leuven and the Research Council at KU Leuven. N.V.C. is supported in part by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515).
Alimentiv Inc. is an academic gastrointestinal contract research organization (CRO), operating under the Alimentiv Health Trust. Alimentiv Inc. provides comprehensive clinical trial services, precision medicine offerings, and centralized imaging solutions for endoscopy, histopathology, and other imaging modalities. The beneficiaries of the Alimentiv Health Trust are the employees of the enterprises it holds. None of the authors is a beneficiary of the Alimentiv Health Trust. B.V., N.V.C., G.D’H., B.G.F., V.J., C.M., W.J.S. and A.S. are consultants to Alimentiv Inc. and have a primary academic appointment; they do not hold equity positions or shares in Alimentiv Inc. B.V. reports research support from AbbVie, Biora Therapeutics, Pfizer, Sossei Heptares and Takeda; speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris; and consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Inotrem, Inotrem, Ipsos, Janssen, Mylan, Progenity, Sandoz, Sosei Heptares, Takeda Tillots Pharma and Viatris. A.S. reports research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Alimentiv Inc, Boehringer Ingelheim and Origo Biopharma; consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Origo Biopharma and Boxer Capital. B.E.S. reports research grants from Takeda, Pfizer, Theravance Biopharma R&D and Janssen; consulting fees from 4D Pharma, Abivax, Abbvie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Bacainn Therapeutics, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Capella Bioscience, Celgene, Celltrion Healthcare, ClostraBio, Enthera, F.Hoffmann-La Roche, Ferring, Galapagos, Gilead, GlaxoSmithKline, GossamerBio, Immunic, Index Pharmaceuticals, Innovation Pharmaceuticals, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, MiroBio, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Redhill Biopharma, Rheos Medicines, Salix Pharmaceuticals, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva Branded Pharmaceutical Products R&D, Thelium, Theravance Biopharma R&D, TLL Pharma, USWM Enterprises, Ventyx Biosciences, Viela Bio, Vivante Health and Vivelix Pharmaceuticals; and holds stock in Vivante Health and Ventyx Biosciences. M.F.N. reports consulting fees from MSD Sharp & Dohme GmbH, PPM Services, IFM Therapeutics, Sterna Biologicals, Boehringer Ingleheim GmbH and Co. KG, Janssen Cilag GmbH, Pentax Europe GmbH, Takeda, Amgen GmbH, Pfizer Pharma, Falk Foundation e.v., Abbvie and Celgene. N.V.C. reports research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from Alimentiv, Inc (formerly Robarts Clinical Trials, Inc), Celltrion and Prometheus. These activities were all outside the submitted work. C.A. and H.L. declare no competing interests. The competing interests of the Alimentiv Translational Research Consortium Member Authors are listed in Supplementary Box 1.
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Verstockt, B., Salas, A., Sands, B.E. et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 20, 433–446 (2023). https://doi.org/10.1038/s41575-023-00768-1