What are the therapeutic candidates targeting IL-36R?

Introduction to IL-36R
The interleukin-36 receptor (IL-36R) is a member of the IL-1 receptor family that has gained considerable attention over the past decade as a central mediator of inflammation. IL-36R binds to a family of cytokines—IL-36α, IL-36β, and IL-36γ—which serve as potent activators of the inflammatory response, while its natural antagonist IL-36Ra (and potentially IL-38) modulate this activity by preventing receptor activation. The therapeutic interest in this receptor arises from its unique structure, its role in coupling extracellular inflammatory signals to intracellular pathways such as NF-κB and MAPK, and its tissue distribution, particularly in epithelial cells, keratinocytes, and immune cells.

Role of IL-36R in Human Physiology
IL-36R is expressed in multiple tissues including the skin, lung, intestine, and kidney, where it facilitates communication between stressed epithelial cells and the immune system. Under normal physiological conditions, the IL-36/IL-36R axis participates in host defense and tissue homeostasis. For example, in the skin, a low level of IL-36 cytokines is essential for maintaining barrier function and antimicrobial responses by stimulating keratinocyte activity and modulating dendritic cell maturation. In addition, IL-36R is involved in the regulation of wound healing responses; upon damage, its ligands are induced to promote re-epithelialization and repair. The receptor’s involvement in these processes depends on its ability to recruit the co-receptor IL-1 receptor accessory protein (IL-1RAcP), which then triggers downstream signaling events that lead to the production of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Thus, the IL-36 system stands as an important nexus between inflammation and tissue regeneration.

Importance of IL-36R in Inflammatory Diseases
Dysregulation of IL-36R signaling is strongly linked to a number of inflammatory diseases. Over-expression of IL-36 agonists—or a deficiency in the natural antagonist IL-36Ra—can lead to uncontrolled inflammatory responses, particularly evident in chronic skin disorders such as generalized pustular psoriasis (GPP) and other dermatological conditions including ichthyosis. In these contexts, mutations in IL36RN, the gene encoding IL-36Ra, can result in unrestrained signaling through IL-36R, culminating in severe skin inflammation and systemic immune disturbances. Beyond dermatological diseases, aberrant IL-36R activity has also been implicated in inflammatory bowel disease, lung inflammation during asthma or chronic obstructive pulmonary disease (COPD), and even in kidney injury situations such as tubulointerstitial lesions. The central role of IL-36R, particularly in neutrophil recruitment and T cell activation, offers a compelling rationale for targeting this receptor therapeutically in inflammatory conditions where conventional pathways fail to restore balance.

Current Therapeutic Candidates Targeting IL-36R
Many therapeutic strategies have emerged around the inhibition of the IL-36R signaling pathway. Given the strong body of evidence emerging from the synapse source—which includes detailed structured data from both clinical trials and patents—the current therapeutic candidates targeting IL-36R can be broadly categorized into approved therapies (where available) and candidate treatments under active clinical investigation.

Approved Therapies
At present, there are limited examples of fully approved therapies that directly target IL-36R for inflammatory indications. However, within some regulated regions there have been approvals for therapies designed for rare, life‐threatening autoinflammatory conditions. For instance, anti-IL-36R antibodies have been explored as effective treatments for GPP, a prototype inflammatory skin disease resulting from dysregulation of IL-36 signaling. Although full regulatory approval may still be in progress in some jurisdictions, these agents represent the most advanced clinical candidates and are demonstrating promising early results. In parallel, some formulations targeting IL-36R signaling for treating ichthyosis have emerged from patent filings, which indicate that these approaches are moving toward clinical application even if they are not yet fully approved for widespread use. These approvals or conditional authorizations underscore the potential of IL-36R inhibition in conditions where conventional anti-inflammatory drugs prove insufficient.

Therapies in Clinical Trials
Multiple therapeutic candidates targeting IL-36R are currently in clinical trials. The leading candidates in this arena include:

• Spesolimab – A humanized anti-IL-36R monoclonal antibody that has undergone proof-of-principle clinical trials in patients with generalized pustular psoriasis. Early clinical data indicate rapid and significant improvements in skin lesions, which validates the concept of IL-36R inhibition in controlling severe inflammatory skin disorders.
• Imsidolimab – Another promising monoclonal antibody targeting IL-36R, currently under evaluation in clinical studies. Its mechanism is similar to that of spesolimab; however, there is evidence suggesting that imsidolimab might have complementary immunomodulatory effects in addition to its anti-inflammatory properties.

In addition to the antibody-based approaches, there are also developments in the realm of small molecule inhibitors that target IL-36R directly or inhibit its activation. For example, a small-molecule inhibitor identified as A-552 has been reported to block IL-36γ binding by interacting directly with key residues on the cytokine, thereby preventing the assembly of the active receptor complex. Although these small-molecule candidates are at earlier stages compared to monoclonal antibodies, they represent a strategic diversification in the IL-36R targeting platform and are being actively investigated in preclinical research.

Patent literature has also provided evidence of proprietary candidates. Multiple patents have been filed describing anti-IL-36R antibodies aimed at treating ichthyosis and related conditions, highlighting the competitive activity in this space and suggesting that diverse antibody formats (including full-length antibodies, antigen-binding fragments, or humanized variants) are in development.

The clinical landscape is further enriched by candidates designed to modulate IL-36R signaling indirectly via targeting upstream or downstream mediators. Agents that inhibit proteases responsible for activating pro-IL36 cytokines by proteolytic cleavage have also been reported. Although these are not direct IL-36R antagonists, they functionally reduce the receptor’s agonist stimulation and thus serve as alternative therapeutic candidates in the IL-36 pathway.

Collectively, the emphasis of the current clinical and preclinical research is on the use of monoclonal antibodies such as spesolimab and imsidolimab to neutralize IL-36R activation in inflammatory conditions. These agents are subjected to extensive clinical studies in various phases, with clinical trial data supporting the inhibition of IL-36-mediated inflammatory cascades.

Mechanisms of Action
Understanding the mechanisms of action for therapeutics targeting IL-36R is essential as it provides insight into their efficacy, safety profiles, and potential combinatorial strategies with other immunomodulators.

How Therapeutics Target IL-36R
Anti-IL-36R therapies principally function by binding to the extracellular domain of the IL-36 receptor and, by doing so, they prevent the binding of the agonist cytokines (IL-36α, β, and γ). This blockade of the receptor impedes the recruitment of IL-1RAcP—a critical co-receptor necessary for the initiation of downstream intracellular signaling. When monoclonal antibodies like spesolimab or imsidolimab bind IL-36R, they sterically hinder the assembly of the active ternary complex (IL-36R, IL-36 ligand, and IL-1RAcP). Without this complex formation, the receptor is unable to transduce a signal that would normally lead to the activation of NF-κB, MAPK, and other pro-inflammatory signaling cascades.

In the context of small molecule inhibitors, agents such as A-552 target specific residues on IL-36γ or IL-36R that are crucial for binding affinity in the receptor-ligand interaction. By forming hydrogen bonds with key amino acids—such as arginine 121 and lysine 123 on IL-36γ—the small molecules block the cytokine from engaging with IL-36R, thereby indirectly preventing receptor activation and subsequent inflammatory signaling. Additionally, peptide-based inhibitors have been developed as pseudo-substrates that interfere with proteolytic activation of IL-36 cytokines. Since the mature, active forms of IL-36 agonists require proteolytic cleavage at their N-terminus, the inhibition of this processing step represents a targetable mechanism to diminish the overall burden of receptor activation.

Furthermore, patent filings have described antibody formats that exhibit a dominant-negative effect. Overexpression of soluble ectodomains of IL-36R—or of its accessory proteins—can sequester the cytokines away from their cell-bound receptors, thereby reducing IL-36 signaling in a competitive manner. These approaches represent different molecular strategies that intercept the pathological IL-36/IL-36R interaction at distinct points along the activation cascade.

Biological Pathways Involved
Upon activation, IL-36R triggers several well-characterized intracellular signaling pathways. The primary pathway involves recruitment of the adaptor protein MyD88, which leads to the sequential activation of interleukin-1 receptor–associated kinases (IRAKs) and ultimately results in the phosphorylation and activation of transcription factors NF-κB and AP-1. These transcription factors drive the production of a variety of pro-inflammatory cytokines such as IL-6, IL-8, TNF-α, and several chemokines. This cascade is responsible for the amplification of inflammatory responses in tissues such as the skin, lungs, and intestines.

In keratinocytes, the IL-36R signaling pathway supports not only the recruitment of immune cells (notably neutrophils) but also stimulates the production of antimicrobial peptides and enhances the inflammatory milieu that leads to the clinical manifestations of psoriasis and related disorders. In dendritic cells and T lymphocytes, IL-36R signaling promotes the production of cytokines (for example, IL-12 and IFN-γ) that skew adaptive immunity toward a Th1 or Th17 phenotype, thereby reinforcing chronic inflammation.

Therapeutic candidates targeting IL-36R work by interrupting these signaling events. For instance, blocking IL-36R with a neutralizing antibody prevents the formation of the IL-36R/IL-1RAcP complex and the subsequent MyD88-dependent signaling cascade. This results in a reduction of downstream pro-inflammatory cytokine production, suppression of dendritic cell maturation, and decreased T cell activation—all of which contribute to the mitigation of pathological inflammation. Moreover, these agents have been shown in preclinical models to reduce markers such as phosphorylation of MAPKs (including p38, ERK, and JNK) and lower NF-κB activation, demonstrating the effectiveness of IL-36 blockade at the molecular level.

Challenges and Future Directions
Despite the encouraging progress in targeting IL-36R for inflammatory diseases, there are considerable challenges that remain. These difficulties span the translational, production, and mechanistic understanding phases.

Current Challenges in Targeting IL-36R
One of the most significant challenges is the complexity of the IL-36 signaling network itself. Because IL-36R is activated by a group of related cytokines and modulated by natural antagonists like IL-36Ra and possibly IL-38, precise manipulation of this pathway requires a careful balance. Over-inhibition of IL-36R could dampen beneficial host defense mechanisms, while insufficient inhibition may not adequately control pathological inflammation.

Clinical trials of anti-IL-36R antibodies such as spesolimab and imsidolimab are closely monitoring for adverse effects that arise from targeting a receptor that also has a role in normal tissue repair and homeostasis. Another challenge is achieving selective blockade in tissues where IL-36R is most detrimental. For example, while effective inhibition in psoriatic skin may be desirable, the same mechanism may inadvertently affect wound healing or immune responses in other organs.

In the case of small molecule inhibitors like A-552, issues regarding specificity and off-target effects are a major concern. The design of such molecules requires a deep understanding of the receptor-ligand interactions at the atomic level. Structural differences between the various IL-36 agonists can result in variable binding affinities and pharmacodynamics, making it challenging to develop a “one-size-fits-all” small molecule inhibitor. Furthermore, variability in patient response—due to genetic differences, comorbidities, or the microenvironmental context of inflammatory lesions—adds another layer of complexity to the clinical development process.

Manufacturing and delivery also pose challenges. Biologics such as monoclonal antibodies require highly controlled production processes and are associated with high cost, cold-chain storage, and parenteral administration. Moreover, immunogenicity remains a concern, as the formation of anti-drug antibodies could reduce therapeutic efficacy over time. Patent-related restrictions and competition also influence the pace and direction of new candidate development.

It is also important to mention that although early phase clinical trial data for IL-36R inhibitors are promising, long-term safety and the potential for effects on immune surveillance and infection control need further evaluation. Many of these studies are still in the early to mid-phase, and the long-term outcome regarding relapse rates, durability of response, and overall mortality remains to be determined.

Future Research and Development Opportunities
Looking forward, several research directions and development opportunities could help overcome these challenges. One promising area includes the integration of advanced structural biology techniques to precisely map the interaction between IL-36 cytokines and IL-36R. This level of detail can improve the design of both antibody-based and small molecule inhibitors to maximize efficacy and minimize off-target effects.

Another opportunity is the exploration of combination therapies. By combining IL-36R inhibitors with other immunomodulatory agents (for example, targeting IL-17, IL-23, or TNF-α), it may be possible to achieve a more robust and sustained therapeutic response, particularly in patients with complex or refractory inflammatory conditions. Such combination regimens could allow for lower doses of each component, thereby reducing side effects while achieving synergistic outcomes.

Biomarker discovery is another key facet for future research. There is a pressing need to identify reliable biomarkers that can predict patient responses to IL-36R-targeting therapies. This could facilitate more individualized treatments, ensuring that patients most likely to benefit from IL-36R inhibition are selected for therapy. Studies have suggested that genetic mutations in IL36RN and the expression levels of IL-36 agonists could serve as potential biomarkers, and further research is warranted to validate these markers in larger patient cohorts.

Furthermore, alternative delivery systems may provide future benefits. Advances in nanotechnology and drug delivery systems—such as liposomal carriers or biodegradable nanoparticles—could improve the targeting of IL-36R inhibitors to specific tissues, reduce systemic exposure, and enhance patient compliance by allowing for non-invasive administration routes. These approaches are particularly important for biologics, where targeted delivery can also help mitigate immunogenicity issues.

Understanding the interplay between IL-36R signaling and other inflammatory pathways presents another promising avenue. Detailed mapping of downstream signaling networks, including cross-talk with toll-like receptors (TLRs) and other cytokine receptors, could reveal new intervention points. This broader understanding might lead to the development of multi-target agents or rational design of combination therapies that more comprehensively address inflammatory dysregulation.

Additionally, preclinical models that better mimic human inflammatory conditions will be essential in testing these therapeutic candidates. The development of transgenic and humanized mouse models, as well as organ-on-a-chip systems, could accelerate the translation of promising preclinical agents into clinical trials by providing more reliable data on efficacy and safety in a human-like physiological environment.

Finally, regulatory frameworks and patent landscapes are likely to evolve in response to these emerging therapies. Collaboration between academic institutions, biotech companies, and pharmaceutical giants will be crucial in overcoming both scientific and logistical hurdles in the development of IL-36R inhibitors. Through such collaboration, iterative improvements based on clinical feedback can be made, ensuring that future therapies are both effective and accessible to patients suffering from debilitating inflammatory diseases.

Conclusion
In summary, the IL-36R has emerged as a critical therapeutic target due to its central role in mediating inflammatory responses across multiple organ systems, especially in conditions such as generalized pustular psoriasis and ichthyosis. The receptor’s involvement in both normal physiological processes like wound healing and in pathological states of uncontrolled inflammation has spurred a range of therapeutic interventions.

Currently, the therapeutic candidates targeting IL-36R predominantly consist of monoclonal antibodies such as spesolimab and imsidolimab, which have demonstrated promising clinical results and represent the forefront of this field. Small molecule inhibitors like A-552 also offer potential, although they are in earlier stages of development. Patent literature from synapse indicates multiple proprietary approaches aiming to treat conditions like ichthyosis by inhibiting IL-36R-mediated signaling. These candidates work primarily by binding to the receptor and preventing its association with IL-36 agonists and coreceptors, which in turn blocks essential pro-inflammatory pathways including NF-κB and MAPK.

Despite the successes seen thus far, there remain significant challenges. These include ensuring selectivity without compromising protective host defense functions, overcoming manufacturing and delivery hurdles for biologics, and the imperative to identify predictive biomarkers that can facilitate personalized therapy. Future research opportunities lie in leveraging advanced structural analyses, combination therapies, novel drug delivery systems, and deeper mechanistic studies to refine therapeutic strategies against IL-36R.

Overall, while the clinical translation of IL-36R inhibitors is still evolving, current evidence supports the potential of these agents to address unmet medical needs in a range of inflammatory diseases. With further research and collaboration, it is anticipated that more robust, safe, and effective IL-36R-targeting strategies will be developed, ultimately leading to improved patient outcomes in diseases where inflammation is a driving factor.