The gut might seem like an unlikely battleground, but in inflammatory bowel disease (IBD), it's where some of the body’s most intense immune conflicts take place.

IBD—primarily comprising Crohn’s disease and ulcerative colitis—arises from an exaggerated immune response to environmental triggers, such as gut microbiota, in genetically susceptible individuals. While TNF inhibitors have long been a mainstay of treatment, 10–30% of patients experience a primary non-response, and up to 46% require dose escalation within just 12 weeks—highlighting the need for more effective therapies (Roda et al., 2016).

Recent advances in our understanding of IBD’s immunological underpinnings are paving the way for more targeted treatment strategies. Among the most promising discoveries are the identification of the interleukin-23 (IL-23) receptor as a genetic risk factor, and the pivotal role of interleukin-12 (IL-12) family cytokines in promoting gut inflammation.

IL-12 and IL-23 in Autoimmune Disease Therapies

IL-12 and IL-23 are pivotal cytokines in immune regulation, both sharing the p40 subunit essential for receptor binding (Verstockt B et al., 2023).

• IL-12, composed of p40 and p35 subunits, signals through the IL-12Rβ1/IL-12Rβ2 receptor complex to promote Th1 cell differentiation and stimulate the production of interferon-gamma (IFN-γ)—critical for defense against intracellular pathogens and tumors (Wojino, Hunter, & Stumhofer, 2019).
• IL-23, consisting of p40 and p19 subunits, signals via the IL-12Rβ1/IL-23R complex to activate Th17 cell responses, sustaining inflammation through cytokines such as IL-17A/F, IL-6, IL-22, TNF-α, and GM-CSF (Krueger et al., 2024).​

Given their essential roles in immune regulation, IL-12 and IL-23 have become key targets for autoimmune disease therapies, including IBD.

• Risankizumab (Skyrizi^®) by AbbVie: Approved in June 2022 for moderately to severely active Crohn's disease, and in June 2024 for moderately to severely active ulcerative colitis. ​

• Guselkumab (Tremfya^®) by Janssen: Approved in 2017 for moderate-to-severe plaque psoriasis, with subsequent approvals for psoriatic arthritis (2020), ulcerative colitis (2024), and Crohn's disease (2025). ​

• Ustekinumab (Stelara^®) by Janssen: Targets the shared p40 subunit of IL-12 and IL-23; approved since 2009 for plaque psoriasis, with expanded indications for psoriatic arthritis (2013), Crohn's disease (2016), and ulcerative colitis (2019). ​

• Tildrakizumab (Ilumya™) by Sun Pharma : Approved in 2018 for moderate-to-severe plaque psoriasis. ​

Diagram of IL-12 and IL-23 Signaling Pathways. (Source: Teng et al., 2015)

What Biocytogen Offers

Biocytogen is leading the way in advancing IL-12/IL-23-targeted therapies through its robust portfolio of humanized mouse models targeting IL-12, IL-23, and their receptors. These cutting-edge models are accelerating preclinical drug discovery and offering a powerful platform for developing next-generation therapies for IBD and other immune-related diseases.

Case Study: B-hIL12RB1/hIL12RB2 Mice Ad

In vivo toxicity study of human IL-12 in B-hIL12RB1/hIL12RB2 mice ad

Human IL-12 or PBS was intravenously administered to C57BL/6JNifdc and homozygous B-hIL12RB1/hIL12RB2 mice ad. In B-hIL12RB1/hIL12RB2 mice ad, human IL-12 (A) increased liver and spleen weights (% of body weight), (B–C) induced IFN-γ production and elevated AST/ALT levels, and (D) induced pathological changes in the liver and spleen. Mean ± SEM.

Anti-tumor activity of human IL-12 in B-hIL12RB1/hIL12RB2 mice ad

(A) Human IL-12 inhibited MC38 tumor growth in B-hIL12RB1/hIL12RB2 mice ad, which were subcutaneously implanted with murine colon cancer MC38 cells. Treatment began when tumors reached ~100 mm³, with hIL-12 administered intravenously as indicated. (B) Body weight changes were monitored during treatment. Human IL-12 demonstrated dose-dependent tumor inhibition. Mean ± SEM.

Contact us today to explore how Biocytogen’s humanized models can advance your drug development pipeline!

Reference

Roda, Giulia, et al. "Loss of response to anti-TNFs: definition, epidemiology, and management." Clinical and translational gastroenterology 7.1 (2016): e135.

Verstockt, Bram, et al. "IL-12 and IL-23 pathway inhibition in inflammatory bowel disease." Nature Reviews Gastroenterology & Hepatology 20.7 (2023): 433-446.

Wojno, Elia D. Tait, Christopher A. Hunter, and Jason S. Stumhofer. "The immunobiology of the interleukin-12 family: room for discovery." Immunity 50.4 (2019): 851-870.

Krueger, James G., et al. "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy." Frontiers in Immunology 15 (2024): 1331217. ​

Teng, Michele W. L., et al. "IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases." Nature Medicine 21.7 (2015): 719-729. ​