IL-23 Inhibitors: Breakthroughs in Modern Immunotherapy

Immune system dysregulation plays a central role in many chronic inflammatory diseases, driving researchers to develop targeted therapies that can modulate specific immune pathways. IL-23 inhibitors have transformed treatment for conditions like psoriasis and inflammatory bowel disease by selectively blocking key inflammatory signals.

These inhibitors continue to improve patient outcomes with fewer side effects than traditional immunosuppressants. Understanding their role, mechanisms, and clinical applications provides insight into how they are reshaping modern immunotherapy.

Role Of IL-23 In Immune Processes

Interleukin-23 (IL-23) is a cytokine that regulates immune responses, particularly in chronic inflammation and autoimmune conditions. Produced by dendritic cells and macrophages in response to microbial stimuli, IL-23 consists of p19 and p40 subunits, the latter also shared with IL-12. Unlike IL-12, which drives Th1 responses, IL-23 promotes Th17 cell differentiation and expansion, leading to the production of pro-inflammatory cytokines such as IL-17 and IL-22.

The IL-23/Th17 axis plays a key role in mucosal immunity and defense against extracellular pathogens, but its dysregulation is linked to chronic inflammatory diseases. Elevated IL-23 levels correlate with disease severity in psoriasis, Crohn’s disease, and ankylosing spondylitis. Research in The Lancet found increased IL-23 expression in psoriasis patients, contributing to keratinocyte hyperproliferation and inflammation. Similarly, Gastroenterology studies indicate IL-23 disrupts the intestinal barrier in inflammatory bowel disease by enhancing Th17-driven inflammation.

Beyond Th17 cells, IL-23 influences innate immunity by acting on innate lymphoid cells (ILC3s), which contribute to tissue-specific inflammation. In the gut, IL-23-driven ILC3 activation worsens colitis by increasing IL-22 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production. It also modulates neutrophil recruitment, amplifying inflammatory cascades. These findings underscore its central role in chronic inflammation.

Classes Of IL-23 Inhibitors

IL-23 inhibitors selectively target and neutralize IL-23 activity, reducing inflammation in chronic conditions. These therapies primarily consist of monoclonal antibodies binding to the p19 subunit, preventing IL-23 receptor interaction. Alternative biological approaches are also being explored.

Therapeutic Monoclonal Antibodies

Monoclonal antibodies targeting IL-23 are widely used, offering greater specificity than earlier IL-12/23 inhibitors that targeted the shared p40 subunit. By selectively blocking IL-23, these therapies reduce inflammation while preserving IL-12’s role in immune regulation. Approved treatments include guselkumab, tildrakizumab, and risankizumab for moderate-to-severe plaque psoriasis.

Clinical trials, such as VOYAGE 1 and 2 in The New England Journal of Medicine, demonstrated guselkumab’s efficacy in psoriasis, surpassing placebo and adalimumab. Risankizumab also showed superior results in the IMMhance and UltIMMa trials, with higher rates of long-term remission. These antibodies are being studied for other inflammatory conditions like Crohn’s disease and psoriatic arthritis, with promising phase III trial results.

Other Biological Approaches

Alternative strategies to inhibit IL-23 signaling include small molecule inhibitors, RNA-based therapies, and gene-editing technologies. Selective TYK2 inhibitors like deucravacitinib disrupt IL-23 receptor signaling with a more targeted approach than broader JAK inhibitors. RNA-based therapies, such as antisense oligonucleotides and small interfering RNAs (siRNAs), aim to reduce IL-23 production at the transcriptional level. Gene-editing technologies like CRISPR are being explored for tissue-specific modulation of IL-23 expression, though these remain in preclinical stages.

Mechanisms Of Action

IL-23 inhibitors block the p19 subunit, preventing IL-23 from binding its receptor complex (IL-23R/IL-12Rβ1). This halts downstream signaling, suppressing STAT3 phosphorylation, a key driver of inflammatory gene expression.

By reducing IL-23 activity, these inhibitors limit Th17 cell survival and proliferation, decreasing IL-17 and IL-22 secretion, which contribute to tissue damage. They also shift immune cell populations toward a less inflammatory phenotype, increasing regulatory T cells (Tregs) that restore immune balance.

Beyond adaptive immunity, IL-23 inhibitors affect innate responses by modulating ILC3s and neutrophils. IL-23 signaling enhances ILC3 activity, which contributes to epithelial barrier dysfunction in inflammatory diseases. Blocking IL-23 reduces ILC3-driven epithelial damage, aiding tissue repair. Additionally, IL-23 inhibition decreases neutrophil infiltration, reducing chemokine-driven inflammation in conditions like hidradenitis suppurativa and ulcerative colitis.

Common Indications

IL-23 inhibitors effectively treat chronic inflammatory diseases where IL-23-driven pathways contribute to pathology. Plaque psoriasis is the most well-documented indication, with multiple clinical trials confirming their efficacy in achieving sustained skin clearance.

The FDA has approved guselkumab, risankizumab, and tildrakizumab for moderate-to-severe psoriasis in patients requiring systemic therapy or phototherapy. These biologics outperform older treatments, with over 80% of patients achieving a Psoriasis Area and Severity Index (PASI) 90 response within a year.

IL-23 inhibitors are also widely used in gastroenterology, particularly for Crohn’s disease. Unlike traditional immunosuppressants, which broadly suppress immune function, these therapies provide targeted control of intestinal inflammation with fewer systemic side effects. Risankizumab has shown superior efficacy in maintaining remission compared to placebo, leading to FDA approval. Long-term studies indicate many patients remain in remission for years without needing corticosteroids or additional immunomodulators.

Administration Methods

IL-23 inhibitors are administered via subcutaneous injection, balancing efficacy with convenience. Dosing schedules vary, typically involving an initial loading phase followed by maintenance doses at extended intervals. Guselkumab is given at weeks 0 and 4, then every 8 weeks, while risankizumab transitions to every 12 weeks after induction. These extended intervals distinguish IL-23 inhibitors from older biologics like TNF inhibitors, which require more frequent administration.

Self-administration allows patients to inject the medication at home using prefilled syringes or autoinjectors. Healthcare providers train patients on proper techniques, including site rotation to minimize reactions. Studies show that adherence improves with self-administration, as frequent clinic visits can be a barrier to long-term treatment.

Research is exploring alternative formulations, including oral and intranasal delivery systems, to further improve accessibility. These innovations may benefit patients who experience injection-site discomfort or difficulty with self-administration.

Potential Side Effects

IL-23 inhibitors are generally well tolerated compared to traditional immunosuppressants, but they carry some risks. The most common side effects are injection-site reactions, mild upper respiratory infections, and headaches, which typically resolve without intervention. Unlike TNF inhibitors, which increase the risk of opportunistic infections, IL-23 inhibitors have a more targeted mechanism that preserves broader immune function. However, infections remain a concern, particularly in immunocompromised patients. Clinical trials indicate serious infections occur at a low incidence, similar to placebo, but long-term monitoring continues.

There have been concerns about potential links between IL-23 inhibition and malignancy due to IL-23’s role in immune surveillance. However, long-term studies have not shown a significant increase in cancer risk, though post-marketing surveillance remains ongoing. While IL-23 inhibitors do not appear to significantly impact lipid metabolism or cardiovascular health, some studies suggest mild liver enzyme elevations, necessitating monitoring in patients with preexisting hepatic conditions. Real-world data will further clarify their long-term safety profile.