What are the preclinical assets being developed for IL-36R?

Introduction to IL-36R
IL-36 receptor (IL-36R) is a member of the interleukin-1 receptor family that plays a central role in mediating inflammatory responses. In normal physiology, IL-36R transduces signals upon binding to its agonist ligands—IL-36α, IL-36β, and IL-36γ—while its activity is physiologically modulated by the antagonist IL-36Ra. Together, these ligands orchestrate critical immune responses by activating downstream signaling cascades such as NF-κB and MAP kinase pathways, leading to the transcription of pro-inflammatory genes. Fundamentally, IL-36R functions as a bridge between innate and adaptive immunity by inducing the production of cytokines, chemokines, and other inflammatory mediators in cells including keratinocytes, dendritic cells, and T cells.

IL-36R Biological Role
IL-36R is predominantly expressed on barrier tissues such as the skin and mucosal membranes, but it is also found in various other organs such as the kidney, thyroid, and liver. Its activation leads to the recruitment and activation of immune cells, notably neutrophils, T lymphocytes, and macrophages, which contribute to the localized inflammatory environment. The receptor‐ligand interaction involves the heterodimer formation of IL-36R with the co-receptor IL-1RAcP, which is necessary for signal transduction. The biology of IL-36R is further characterized by proteolytic activation of its ligands; neutrophil-derived proteases such as elastase promote the conversion of IL-36 cytokine precursors into their active forms, thereby amplifying the pro-inflammatory response.

IL-36R in Disease Pathophysiology
The deregulation of IL-36R signaling is implicated in a wide array of inflammatory and autoimmune diseases. In the skin, for instance, aberrant IL-36 signaling has been closely linked to the pathogenesis of generalized pustular psoriasis (GPP) and hidradenitis suppurativa (HS). The increased expression of IL-36 cytokines in such conditions leads to a cascade of inflammatory signals that contribute to keratinocyte activation, neutrophil recruitment, and an imbalanced immune response. Beyond dermatological disorders, IL-36R signaling also appears to play a role in the development of other inflammatory diseases, including inflammatory bowel disease (IBD) and even in influencing tissue repair mechanisms following injury. Evidence from both human and murine studies has underlined that the dysregulated IL-36 pathway can drive pathological inflammation, emphasizing its potential as a therapeutic target.

Preclinical Development Landscape
The current preclinical development landscape for IL-36R therapies is rich and varied, with multiple assets advancing through rigorous research and early development phases. The strategic focus in the preclinical arena is on developing molecules that specifically block IL-36R signaling to mitigate downstream inflammatory cascades.

Current Preclinical Assets
Among the preclinical assets being developed, monoclonal antibodies (mAbs) remain at the forefront, given their specificity and robust ability to interfere with IL-36R function.

• One of the notable preclinical candidates is IMG-008, a humanized long-acting anti-IL-36R monoclonal antibody originally generated by Maijin Biomedical Technology (Shanghai) Co., Ltd. and now being advanced by Huabo Biopharm Co Ltd. IMG-008 has demonstrated significant preclinical promise due to its potent binding affinity to human IL-36R, its extended half-life (over four times longer than that of a spesolimab analog), and enhanced exposure in preclinical monkey studies. Such features suggest that IMG-008 could reduce dosing frequency and potentially improve treatment efficacy for inflammatory diseases driven by IL-36R signaling.
• Another asset under preclinical investigation is exemplified by anti-IL-36R antibodies covered under various patents. For instance, patents related to anti-interleukin 36 receptor therapies for ichthyosis and for other inflammatory indications indicate that multiple therapeutic antibodies are in development, with potential applications not only in psoriasis but also in other IL-36 pathway–mediated diseases. These patent filings reveal design strategies that aim to block IL-36 ligand binding and subsequently prevent the receptor’s activation, thereby dampening the associated inflammatory response.
• In addition to full antibody formats, there is exploration of antibody fragments and novel binding compounds that can offer benefits such as improved tissue penetration, reduced immunogenicity, or modified pharmacokinetic properties while retaining high specificity against IL-36R.
• While monoclonal antibodies dominate the preclinical asset landscape, smaller molecule inhibitors or decoy receptors that can indirectly regulate IL-36R signaling have also been explored. Although these are not as prevalent as mAbs, the potential for small molecule inhibitors to modulate proteolytic activation of IL-36 ligands (for example by targeting elastase activity) has been demonstrated in other areas of IL-1 family cytokine research. Such approaches could offer alternative or complementary mechanisms to neutralize IL-36R pathway activity.

Companies and Research Institutions Involved
The preclinical asset development for IL-36R targets is a global effort that involves both specialized biopharmaceutical companies and academic research institutions.
• Huabo Biopharm Co Ltd. is actively involved, in collaboration with Maijin Biomedical Technology, in advancing IMG-008 to Phase I trials, underlining the commitment from Chinese companies to address inflammatory diseases using IL-36R antagonistic strategies.
• Inmagene Biopharmaceuticals is another significant player, having announced IND clearance for IMG-008. Inmagene leverages its proprietary QuadraTek® platform to create innovative IL-36R targeting antibodies with enhanced pharmacokinetic and pharmacodynamic profiles.
• Additionally, companies such as AnaptysBio are mentioned in related documents and prospectuses as developing IL-36R–targeting assets such as ANB019. Their strategic focus spans inflammatory conditions like generalized pustular psoriasis (GPP) and palmoplantar pustulosis (PPP), where excessive IL-36 signaling plays a pivotal role.
• Research institutions and academic collaborations, as evident from several patents, also contribute to the early-stage development of IL-36R inhibitors. These collaborations not only fuel the discovery of novel compounds but also refine mechanisms of action through in-depth preclinical studies.

Mechanisms of Action
Understanding the precise mechanisms by which IL-36R antagonists exert therapeutic effects is crucial for both refining current assets and optimizing clinical outcomes.

IL-36R Targeting Strategies
Therapeutic strategies targeting IL-36R aim to intercept the receptor–ligand interaction that triggers a cascade of pro-inflammatory signaling events.
• The principal mechanism involves blocking the extracellular domain of IL-36R to prevent binding of its activating ligands (IL-36α, β, and γ), thus inhibiting downstream signal transduction. Antibodies like IMG-008 achieve this by high-affinity binding to IL-36R, and in doing so, they obstruct the recruitment of the IL-1 receptor accessory protein (IL-1RAcP) necessary for signal transduction.
• Another strategy focuses on modifying the pharmacokinetic profile of the antibody to enhance its half-life and exposure. The long-acting design of IMG-008, for example, is engineered to prolong systemic circulation, potentially lowering the frequency and dosage required in patients.
• There are also studies exploring the use of decoy receptors or antibody fragments that specifically bind to IL-36 ligands. By sequestering these ligands, these decoy molecules indirectly reduce receptor activation. Although less common than mAbs, these approaches are part of the broader effort to capitalize on the IL-36 pathway for therapeutic benefit.
• In addition, some research investigates the modulation of protease activity responsible for the activation of IL-36 precursors. Inhibitors of neutrophil elastase, which plays a significant role in cleaving and activating IL-36 ligands, present an alternative pathway to reduce excessive IL-36R signaling.
• Overall, these targeting strategies are geared toward both neutralizing the receptor’s activity and fine-tuning the immune cascade that leads to pathological inflammation, thereby rendering them attractive for a variety of inflammatory disorders.

Potential Therapeutic Applications
Preclinical assets targeting IL-36R are being developed with a broad spectrum of indications in mind.
• The foremost therapeutic applications include inflammatory skin disorders. Generalized pustular psoriasis (GPP), a severe, life‐threatening form of psoriasis characterized by systemic inflammation and neutrophilic infiltration, has been a primary focus. Preclinical studies indicate that by blocking IL-36R, these agents can dramatically reduce inflammation and restore immune homeostasis in psoriatic lesions.
• Hidradenitis suppurativa (HS) is another inflammatory skin disorder in which IL-36R dysregulation is implicated. Given the chronic nature of HS and its association with recurrent flares and comorbidities such as obesity, long-acting IL-36R antagonists like IMG-008 have potential to provide sustained control with improved dosing convenience.
• Beyond dermatology, there is interest in applying IL-36R antagonists in inflammatory bowel disease (IBD), as preclinical colitis models have demonstrated that IL-36R signaling contributes to mucosal inflammation and impaired wound healing in the gastrointestinal tract.
• Recent research also suggests potential applications in other organ systems, including renal inflammation, lung injury, and even certain fibrotic conditions where overactivation of the IL-36 pathway has been implicated.
• The patents covering anti-IL-36R therapies for ichthyosis reveal yet another potential application: disorders of epidermal differentiation and barrier function, where disturbed IL-36 signaling might contribute to abnormal skin scaling and inflammation.
• Collectively, these therapeutic applications underscore the versatility of IL-36R–targeting agents with the potential to address both common and rare inflammatory diseases by modulating an upstream node in the inflammatory cascade.

Challenges and Future Directions
Despite the promising preclinical results with IL-36R targeted therapies, several challenges remain that must be addressed to optimize their clinical adoption.

Preclinical Development Challenges
The development of IL-36R–targeting agents is not without its hurdles.
• One significant challenge is achieving a balance between efficacy and safety. Given that IL-36R is an important mediator of immune response in barrier tissues, complete or prolonged inhibition may compromise protective inflammatory responses, potentially increasing the risk of infections or impairing wound healing.
• Immunogenicity is also a concern for biologic therapies. Even humanized antibodies such as IMG-008 must be carefully evaluated for anti-drug antibody responses that could diminish therapeutic benefit or cause adverse reactions.
• Another technical challenge involves refining the pharmacokinetic properties of the therapeutic candidates. While assets like IMG-008 have been engineered for extended half-life and improved exposure, optimizing these properties across diverse patient populations remains critical. Variability in receptor expression and the local tissue microenvironment may influence how these drugs perform in vivo.
• Furthermore, ensuring consistent manufacturing processes, quality control, and scalable production of complex biologics are non-trivial challenges that companies must overcome in the transition from preclinical to clinical stages.
• Lastly, patient stratification based on IL-36 pathway activation levels poses a challenge at the clinical trial design phase. With IL-36 dysregulation being a feature in several diseases but not uniformly expressed across all patients, biomarkers that reliably indicate pathway activation are needed to ensure appropriate patient selection in trials.

Future Prospects and Research Directions
Looking forward, the prospects for IL-36R targeted therapies remain bright, with several areas ripe for further research and development.
• There is an ongoing emphasis on improving antibody engineering techniques to further enhance the pharmacokinetic and pharmacodynamic profiles of these agents. Enhanced antibody formats, such as bispecific antibodies or engineered fragments, may offer opportunities for improved tissue penetration and target engagement while mitigating adverse effects.
• Future studies may also explore combination therapies that integrate IL-36R antagonists with other immunomodulatory strategies. For instance, combining IL-36R blockade with TNF inhibitors or IL-6-targeting agents may provide synergistic anti-inflammatory effects in refractory conditions where multiple cytokine pathways are at play.
• Advances in biomarker discovery will be crucial. Ongoing research into specific genetic, proteomic, or imaging markers that reflect IL-36 pathway activation will enhance patient selection for clinical trials and eventually enable personalized therapeutic approaches. This will not only maximize efficacy but also minimize unnecessary exposure in patients less likely to benefit.
• Moreover, the exploration of small molecule inhibitors that indirectly modulate IL-36R signaling—for example, through inhibition of proteases like neutrophil elastase—represents another promising avenue that could complement antibody-based approaches.
• There is also the potential for repurposing or re-engineering modalities originally developed for other cytokine pathways. Innovations in areas such as nanocarriers, antibody-drug conjugates (ADCs), and RNA-interference technologies might be adapted for targeting IL-36R, thus broadening the therapeutic arsenal available for inflammatory diseases.
• On the regulatory side, continuous dialogue with agencies and the accumulation of robust preclinical data will be vital to streamline subsequent clinical trials. Strategic partnerships and collaborations between industry leaders, such as Inmagene, Huabo Biopharm, and AnaptysBio, alongside academic institutions, will be central to overcoming current challenges and accelerating the translation of these assets from bench to bedside.
• In parallel, future research will help delineate the full spectrum of IL-36R’s role in health and disease. A deeper understanding of how IL-36 signaling interplays with other components of the immune system may uncover novel indications and reveal previously hidden therapeutic opportunities.

In summary, the preclinical development landscape for IL-36R comprises a diverse portfolio mainly dominated by innovative monoclonal antibodies such as IMG-008, along with other therapeutic formats like antibody fragments, decoy receptors, and potentially small molecule inhibitors that target the proteolytic activation of IL-36 ligands. Multiple companies and academic institutions, including Huabo Biopharm, Maijin Biomedical Technology, Inmagene Biopharmaceuticals, and AnaptysBio, are actively involved in advancing these assets toward clinical evaluation. Their mechanisms of action primarily center on the blockade of IL-36 ligand binding, inhibition of downstream NF-κB and MAPK signaling, and modulation of the inflammatory cascade, thereby offering therapeutic potential in a wide range of diseases—from inflammatory skin conditions such as generalized pustular psoriasis and hidradenitis suppurativa to gastrointestinal inflammation and beyond.

However, several preclinical challenges remain to be solved, including ensuring the safety of these agents without compromising necessary immune function, refining their pharmacokinetic properties, and establishing reliable biomarkers for patient selection. The future directions in this field involve not only optimizing current antibody architectures but also exploring combination therapies and alternative molecular approaches to broaden the therapeutic impact of IL-36R inhibition. Collaborative efforts between industry and academia will be key to overcoming these hurdles, ultimately paving the way for personalized and effective treatments against IL-36R–driven inflammatory diseases.

Ultimately, the convergence of advanced antibody engineering, improved understanding of immune signaling pathways, and innovative drug delivery systems holds the promise of transforming IL-36R from a well-characterized inflammatory mediator into a validated therapeutic target with substantial clinical benefit. With a robust early preclinical portfolio and dynamic global research collaborations, the development of IL-36R antagonists is poised to significantly impact the treatment paradigm for a variety of immune-mediated diseases, offering new hope for patients who currently have limited therapeutic options.