What are the therapeutic candidates targeting IL-23p19?

Introduction to IL-23p19
IL-23 is a heterodimeric cytokine comprised of two subunits – a unique p19 subunit and a shared p40 subunit (with IL-12). The p19 subunit (commonly referred to as IL-23p19) is of particular interest because it is exclusively present in IL-23 and is responsible for many of the cytokine’s specific biological effects. Targeting IL-23p19 offers the potential to block IL-23‐driven pathogenic pathways without interfering with the IL-12 signalling that is critical for host defense. This selective inhibition can therefore offer an improved safety profile and specificity for treating autoimmune and inflammatory conditions.

Biological Role of IL-23p19
IL-23p19 is an essential mediator in the differentiation, expansion, and stabilization of T helper 17 (Th17) cells. Through binding to the IL-23 receptor—together with the common IL-12Rβ1 chain—IL-23 initiates downstream signalling cascades via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, especially activating STAT3. This signalling cascade ultimately leads to the upregulation of proinflammatory cytokines such as IL-17A, IL-17F, IL-22, and TNF-α, which are central to the pathogenesis of several inflammatory and autoimmune diseases. Further mechanistic studies have detailed that the blockade of IL-23p19 may disrupt the maintenance of Th17 cells and may induce a reduction in the production of these proinflammatory mediators, thereby curbing the inflammatory cascade responsible for the symptoms and tissue damage seen in these disorders.

Diseases Associated with IL-23p19
Dysregulation of the IL-23/Th17 axis has been implicated in many immune-mediated conditions. Elevated levels of IL-23 have been observed in diseases such as psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD), Crohn’s disease, and rheumatoid arthritis. In psoriasis, IL-23 drives the formation of psoriatic plaques by promoting keratinocyte hyperproliferation and sustaining chronic inflammation. In Crohn’s disease and ulcerative colitis, the IL-23/Th17 pathway plays a significant role in mucosal inflammation, making IL-23p19 a promising target for therapeutic intervention. Furthermore, preclinical and clinical data also suggest that IL-23p19 may be involved in other immune-mediated conditions, including multiple sclerosis and certain types of arthritis, further underscoring the importance of this target for next-generation therapies.

Current Therapeutic Candidates
There is an expanding portfolio of therapeutic candidates specifically targeting IL-23p19. Given the increasing evidence that selective IL-23p19 inhibition is both effective and has a favorable safety profile compared to broader inhibitors (such as the older IL-12/23 p40 blockers), several monoclonal antibodies and engineered protein constructs have been developed, which are now at various stages of preclinical and clinical evaluation.

Overview of Existing Therapies
The most extensively investigated therapeutic candidates targeting IL-23p19 are fully humanized monoclonal antibodies. Key examples include:

• Guselkumab – A monoclonal antibody that binds the IL-23p19 subunit to prevent its interaction with the IL-23 receptor. Guselkumab has been approved for the treatment of moderate-to-severe plaque psoriasis and is being further evaluated for psoriatic arthritis and Crohn’s disease.

• Risankizumab – This antibody also targets IL-23p19 with high specificity. Risankizumab has shown robust efficacy in phase III trials for psoriasis and is being studied in other conditions such as Crohn’s disease, where IL-23 plays a critical mechanistic role.

• Tildrakizumab – Another IL-23p19-specific monoclonal antibody, tildrakizumab has demonstrated significant improvements in clinical endpoints in psoriasis trials. It is similarly expected to provide beneficial effects in other IL-23-driven diseases.

In addition to these monoclonal antibodies that are already on the market or in late-stage clinical trials, there are several candidates in the earlier phases of development:

• Engineered anti-IL-23p19 antibodies – A number of engineered antibodies are under development that aim to improve upon the specificity and pharmacokinetic profiles of current molecules. Multiple patents from synapse sources detail novel constructs, including modifications that optimize Fc function and reduce immunogenicity.

• ILP protein blockers – Innovative strategies have been explored to generate non-antibody protein blockers. For instance, one approach involves the use of ILP binding proteins (such as ILP030, ILP317, and ILP323) that have been expressed on engineered bacteria like Lactococcus lactis, for direct secretion within the gut. This strategy may be particularly useful for indications such as Crohn’s disease where localized delivery to the gastrointestinal tract is desired.

• Bispecific and multispecific molecules – Researchers are also investigating bispecific antibodies that can simultaneously target IL-23p19 along with other cytokines involved in the proinflammatory cascade (for example, simultaneous blockade of other members of the IL-12 or IL-23 families), thereby potentially increasing efficacy while offering the opportunity to modulate nuanced immune responses.

These candidates collectively form the basis of a pipeline that emphasizes not only the direct inhibition of the IL-23p19 subunit but also improved pharmacodynamic characteristics, optimized dosing regimens, and potentially lower risks of adverse events compared to broader-spectrum cytokine inhibitors.

Mechanisms of Action
The principal mechanism of action for therapeutic candidates targeting IL-23p19 is based on the high-affinity binding of these agents to the unique p19 subunit of IL-23. By binding IL-23p19, these agents prevent IL-23 from engaging the IL-23 receptor complex on target immune cells, primarily Th17 cells. This blockade suppresses the downstream activation of the JAK–STAT signalling pathway and the subsequent production of proinflammatory cytokines such as IL-17A, IL-17F, IL-22, and TNF-α.

A detailed mechanistic understanding reveals that selective binding to IL-23p19 allows preservation of IL-12 activity, which is essential for host defense and antitumor responses. In contrast, earlier therapies that targeted the shared p40 subunit (e.g., ustekinumab) inhibited both IL-12 and IL-23, potentially compromising protective Th1 responses while achieving clinical efficacy. The explicit blockade of IL-23p19 by these newer candidates translates to a more directed modulation of the inflammatory circuit and is believed to reduce the risk of certain adverse events, such as increased susceptibility to infections.

Moreover, engineered antibody formats may also incorporate modifications in the Fc region that further enhance their ability to induce antibody-dependent cellular cytotoxicity (ADCC) or prolong their half-life, thus contributing to more sustained receptor occupancy and durable clinical outcomes. The bispecific designs, if combined with additional immune modulatory targets, provide the opportunity to counteract compensatory inflammatory pathways that might limit the efficacy of IL-23 blockade alone.

Evaluation of Therapeutic Candidates
Rigorous evaluation of the available therapeutic candidates targeting IL-23p19 has been carried out across preclinical studies and clinical trials with an emphasis on efficacy, safety, pharmacokinetics, and long-term outcomes.

Preclinical Studies
Preclinical research has established a strong foundation for IL-23p19 as a therapeutic target. Animal models have been used extensively to demonstrate that inhibition of IL-23p19 can reduce the production of IL-17 and related cytokines, leading to a pronounced decrease in inflammatory markers and tissue pathology. In murine models of psoriasis-like inflammation and colitis, administration of IL-23p19 inhibitors resulted in significant improvement in skin lesion severity and intestinal inflammation, respectively.

In one study, anti-IL-23p19 treatment was shown to reduce IL-17A levels and the infiltration of inflammatory cells into affected tissues. Additional in vitro studies have confirmed that blocking IL-23p19 in cultures of human peripheral blood mononuclear cells decreases the differentiation of naïve T cells into Th17 cells. These preclinical findings underscore the role of IL-23p19 in driving pathological immune responses and justify the progression of IL-23p19 inhibitors into clinical trials.

Moreover, engineered constructs—such as those delivered via genetically modified bacteria—have shown promising results in localized models of gut inflammation. For instance, Lactococcus lactis engineered to express ILP binding proteins targeting IL-23p19 has effectively bound the cytokine and reduced downstream inflammatory signals in ex vivo models, suggesting that local inhibition of IL-23 may be feasible with innovative delivery approaches. This strategy is particularly intriguing in the context of gastrointestinal diseases, where systemic exposure is limited and localized therapy could provide enhanced efficacy with minimal systemic effects.

Clinical Trials
Clinical evaluation of IL-23p19 inhibitors has rapidly advanced over the past several years as the efficacy and safety profiles of these agents have been demonstrated through phase II and phase III studies. In patients with moderate-to-severe plaque psoriasis, clinical trials evaluating guselkumab, risankizumab, and tildrakizumab have consistently shown high rates of skin clearance, measured by improvements in the Psoriasis Area and Severity Index (PASI). For example, risankizumab has achieved PASI 90 or PASI 100 responses in a significant proportion of patients, far surpassing the outcomes observed with traditional p40 inhibitors.

Clinical endpoints in these trials not only included improvements in skin lesions but also changes in inflammatory biomarkers and immunologic profiles, which confirmed the effective suppression of the IL-23/Th17 axis. Data from phase III trials have also highlighted the durability of the clinical effects, with many patients maintaining significant improvement even after treatment withdrawal.

Beyond dermatological indications, IL-23p19 inhibitors have entered clinical trials for inflammatory bowel disease. Early-phase studies in Crohn’s disease have demonstrated that selective inhibition of IL-23p19 leads to significant clinical remission rates and improved endoscopic outcomes when compared with placebo. These trials employ rigorous endpoints such as clinical remission scores, endoscopic healing rates, and safety assessments over extended time periods, providing evidence that targeting IL-23p19 may offer a robust therapeutic alternative for patients who have failed other biologic therapy.

In addition, clinical trials are investigating the role of IL-23p19 inhibitors in psoriatic arthritis and potentially other immune-mediated arthropathies. These studies have focused particularly on joint inflammation and structural damage, evaluating both symptomatic improvement and radiographic progression. Overall, the clinical data support that selective IL-23p19 blockade effectively modulates pathogenic inflammation while preserving the beneficial immune functions mediated by IL-12. The emerging evidence continues to build a compelling case for the expanded use of these candidates in a broader range of inflammatory conditions.

Future Directions and Challenges
Given the successful results in both preclinical and clinical settings, the field is now focused on refining and expanding the therapeutic potential of IL-23p19 inhibitors while addressing remaining challenges to optimize their clinical application.

Emerging Therapies
Ongoing research is aimed at not only refining the current generation of IL-23p19 monoclonal antibodies but also exploring novel strategies and delivery mechanisms. Emerging therapies include:

• Next-generation engineered antibodies – Researchers are developing IL-23p19 inhibitors with optimized Fc modifications that enhance half-life, reduce immunogenicity, and improve tissue penetration. These engineered antibodies aim to combine high specificity with favorable pharmacokinetics, thereby reducing dosing frequency and improving patient adherence.

• Bispecific and multispecific antibodies – New constructs that simultaneously target IL-23p19 and additional inflammatory mediators (or receptors) could provide a dual or even polypharmacological approach to suppressing the inflammatory cascade more effectively. These agents may block compensatory pathways that can undermine the efficacy of single-target therapies.

• Non-antibody protein inhibitors – Innovative approaches are being explored, such as the development of ILP binding proteins that can be produced by engineered probiotic bacteria. This strategy may allow for localized delivery of IL-23 inhibitors directly in the gastrointestinal tract, which is particularly useful for inflammatory bowel diseases. It represents a new frontier in drug delivery that leverages living microorganisms to provide a sustained release of therapeutic proteins at the disease site.

• Oligonucleotide and small molecule inhibitors – Although most current therapies are antibody-based, there is growing interest in developing oligonucleotide therapeutics or small molecules that can downregulate the expression or function of IL-23p19. These compounds could offer advantages in terms of manufacturing, stability, and potentially lower costs. Early preclinical studies are exploring these avenues, though they remain at a more experimental stage compared to the antibody therapies.

Challenges in Targeting IL-23p19
Despite impressive advances, several challenges remain in the development and clinical deployment of IL-23p19 inhibitors:

• Long-term safety and tolerability – Although clinical trials have demonstrated a favorable safety profile over relatively short observation periods, the long-term effects of selectively blocking IL-23p19 still need to be fully elucidated. Questions remain regarding the risk of infections, malignancies, and other immune-related adverse events over extended treatment durations.

• Immunogenicity and drug resistance – As with any biologic therapy, there is a potential for anti-drug antibody formation that could neutralize the therapeutic effect of IL-23p19 inhibitors. Future research must continue to optimize antibody design to minimize immunogenicity without compromising efficacy.

• Variability in patient response – Even within clinical trials, there is significant heterogeneity in how patients respond to IL-23p19 inhibition. Biomarkers that reliably predict response remain an area of active investigation. Understanding the molecular and genetic factors that influence treatment response will be critical for personalized medicine approaches.

• Combination therapies – There is growing recognition that inhibition of IL-23p19 alone may not be sufficient for patients with highly refractory disease. The inflammatory network is complex and redundant; therefore, combination therapies that target multiple nodes within the IL-23/Th17 axis or other complementary inflammatory pathways are likely to be necessary. Designing such regimens while avoiding overlapping toxicities presents a considerable challenge.

• Route of administration and dosing strategies – Optimizing the route of administration and dosing frequency remains crucial. For systemic diseases such as psoriasis and psoriatic arthritis, intravenous or subcutaneous injections have been the norm. However, for localized conditions like Crohn’s disease, targeted delivery systems (for example, engineered probiotics) may improve local drug concentrations and reduce systemic exposure, thereby mitigating side effects.

• Cost and accessibility – Biologic therapies are associated with high production costs and may not be accessible to all patients, particularly in resource-limited settings. The future development of small molecule inhibitors or biosimilars may provide a more cost-effective alternative to monoclonal antibodies.

Conclusion
In summary, therapeutic candidates targeting IL-23p19 represent a vital frontier in the treatment of chronic inflammatory and autoimmune diseases, with a specific focus on modulating the IL-23/Th17 axis without adversely compromising the protective functions of IL-12. The biological role of IL-23p19 in promoting Th17 cell differentiation and maintenance links it directly to the pathogenesis of conditions such as psoriasis, Crohn’s disease, and psoriatic arthritis. Selective inhibition of IL-23p19—demonstrated by therapeutics like guselkumab, risankizumab, and tildrakizumab—has shown remarkable efficacy in reducing disease activity, as evidenced by robust clinical trial outcomes and corroborated by extensive preclinical studies.

The current therapeutic candidates, encompassing fully humanized monoclonal antibodies and novel engineered constructs, exert their effects by binding to the IL-23p19 subunit and disrupting the downstream JAK–STAT mediated inflammatory cascade. In preclinical models, these inhibitors have reliably reduced proinflammatory cytokine production and inflammatory cell infiltration, paving the way for their evaluation in clinical settings. Clinical trials have validated the therapeutic promise of these agents, achieving significant improvements in clinical endpoints and sustained remission, particularly in dermatologic and gastrointestinal indications.

Emerging therapies, including bispecific antibodies, non-antibody protein blockers expressed by engineered bacteria, and small molecule inhibitors, represent exciting new avenues for intervention. However, challenges such as long-term safety, potential immunogenicity, patient variability in drug response, the need for combination regimens, and optimizing administration routes must be addressed. Furthermore, cost considerations and access to treatment remain critical obstacles to widespread adoption.

Ultimately, the future of IL-23p19 targeting is promising, with ongoing research expected to refine these therapies, mitigate challenges, and broaden their application across multiple disease indications. The development of more sophisticated biological agents, combined with personalized treatment strategies that leverage predictive biomarkers, is anticipated to further improve patient outcomes and provide durable remission with fewer side effects. Continued advances in both preclinical modelling and clinical trial design will be essential for translating these promising therapeutic candidates from the laboratory to routine clinical practice, ensuring that patients with debilitating inflammatory and autoimmune diseases benefit from these targeted interventions.