Breaking the COPD Bottleneck: IL-33/ST2/IL1RAP Breakthroughs and the Power of Humanized Models

The Unmet Clinical Need in COPD: Why Novel IL-33 Targeted Therapies Are Critical

COPD is currently the third leading cause of death worldwide, affecting nearly 400 million people. Even with standard-of-care dual or triple inhaler maintenance therapies, over 50% of patients still experience moderate-to-severe acute exacerbations. Alarmingly, following a first severe exacerbation, only half of the patients survive beyond 3.5 years [2-5]. Consequently, there is an urgent unmet clinical need to develop novel targeted therapies that can fundamentally suppress inflammatory pathways and reduce the frequency of acute exacerbations.

Figure 2. Global COPD disease burden statistics

Mechanistic Insights: IL-33/ST2/IL1RAP: An Upstream Switch in Inflammatory Signaling

As a member of the IL-1 family, IL-33 acts as a unique "alarmin." Upon mechanical tissue damage, viral infection, or allergen exposure, IL-33 is rapidly released from the nuclei of barrier tissue cells into the extracellular space. Its biological function is highly dependent on a heterodimeric receptor complex comprising ST2 (IL1RL1) and IL1RAP.

Figure 3. The critical role of the IL-33 signaling pathway in various pathological states^[6].

Upon binding to its primary receptor, ST2, IL-33 recruits the co-receptor IL1RAP to form a trimeric complex. This complex activates the MyD88-NF-κB and MAPK pathways, triggering the massive release of type 2 cytokines and acting as a critical upstream switch that bridges innate immunity and adaptive inflammation [6-7].

Figure 4. Structure of the IL-33/ST2/IL1RAP complex and downstream signaling^[7].

Evolving IL-33 Therapeutics: The Shift from Single-Target mAbs to Multi-Pathway Synergistic Blockade

Given the pivotal role of the IL-33/ST2/IL1RAP axis in type 2 immunity and inflammation, it has become a highly strategic target across respiratory, autoimmune, and oncological indications. Global pharmaceutical companies are rapidly evolving their pipelines from single ligand/receptor neutralizing mAbs to bispecific antibodies (e.g., IL-33×TSLP, IL-33×IL-4Rα) and multi-pathway synergistic inhibitors.

Figure 5. Key pipeline layout for IL-33/ST2 targets.

Taking Tozorakimab as a prime example, its unique competitive advantage lies in its ability to simultaneously inhibit both reduced and oxidized IL-33 signaling. It blocks the binding of reduced IL-33 (IL-33red) to ST2, inhibiting ST2-dependent inflammatory signals, while also preventing oxidized IL-33 (IL-33ox) from driving epithelial dysfunction via the RAGE/EGFR pathway. This dual mechanism provides a more comprehensive intervention into the COPD pathological cycle, yielding significant clinical benefits for patients with high exacerbation risks [8].

Figure 6. Dual inhibition mechanism of Tozorakimab.[8]

Beyond COPD: IL-33/ST2 in Autoimmunity, Immuno-Oncology, and Cardiovascular Disease Risk Stratification

Autoimmune Diseases: The IL-33/ST2 axis is significantly upregulated in rheumatoid arthritis, severe asthma, atopic dermatitis, and ulcerative colitis. Blocking this pathway has shown high potential for controlling acute exacerbations in clinical trials [9-10].

Tumor Immunology: This pathway plays a dual, context-dependent role in the tumor microenvironment (TME). While associated with a favorable prognosis in soft tissue sarcomas, it promotes T-cell exhaustion in acute myeloid leukemia (AML) [11-13].

Metabolic and Cardiovascular Diseases: Soluble ST2 (sST2) is FDA-approved for heart failure risk stratification (serum thresholds >35 ng/mL indicate significantly increased risk for adverse cardiovascular events) [14]. In the adipose tissue of obese and type 2 diabetes patients, IL-33/ST2 signaling improves insulin sensitivity; however, elevated circulating sST2 is independently correlated with the severity of metabolic syndrome [15].

Targeting IL1RAP (IL1R3): A Shared Co-Receptor Hub for Broad-Spectrum Anti-Inflammatory and Immuno-Oncology Strategies

As the shared co-receptor for three major inflammatory pathways (IL-1, IL-33, and IL-36), IL1RAP (IL1R3) is not only an essential component of IL-33 signaling but also a highly promising broad-spectrum therapeutic target. Upon forming a trimeric complex with primary receptors (IL1R1, ST2, IL-36R) and their respective ligands, it recruits MyD88/IRAK/TRAF6 via its TIR domain, activating NF-κB/MAPK pathways to drive inflammatory cascades and TME remodeling.

Immuno-Oncology: IL1RAP is significantly overexpressed in AML and various solid tumors (e.g., pancreatic cancer, NSCLC). ADCC-enhanced antibodies targeting IL1RAP (such as Nadunolimab) exhibit a dual mechanism: blocking the inflammatory TME while selectively depleting tumor cells, showing vast potential in both solid and hematological malignancies [16-19].

Broad-Spectrum Autoimmune Suppression: Fc-silenced antagonistic mAbs targeting IL1RAP (such as SAR445399, CAN10) have validated the broad-spectrum suppressive potential and favorable safety profiles across multiple inflammatory pathways in conditions like plaque psoriasis and hidradenitis suppurativa [20-21].

Figure 7: IL1RAP as a shared co-receptor for IL-1, IL-33, and IL-36 pathways.^[17]

Figure 8. Important IL1RAP-targeted antibody drug pipelines.

Cyagen’s IL-33/ST2/IL1RAP Humanized Mouse Models: Empowering Next-Gen Immunotherapy R&D

Cyagen’s IL-33/ST2/IL1RAP Humanized Mouse Models: Empowering Next-Gen Immunotherapy R&D

To comprehensively empower the preclinical validation of therapeutics targeting the IL-33/ST2/IL1RAP pathway, Cyagen has developed a robust suite of humanized mouse models covering these three core targets.

hIL33 Mouse Model (Product No.: C001722)

Figure 9. Detection of human/murine IL33 gene and protein expression in vivo

huIL1RL1 (IL33R/ST2) Mouse Model (Product No.: C001632)

Figure 10. Detection of human/murine IL1RL1 gene and protein expression in vivo.

hIL1RAP Mouse Model (Product No.: C001631)

Figure 11. Detection of human/murine IL1RAP gene and protein expression across tissues

Cyagen Help You Accelerating Clinical Translation

From IL-33 driving the COPD inflammatory cycle to the ST2 and IL1RAP complexes mediating microenvironment remodeling, this critical signaling axis is profoundly reshaping the R&D landscape for respiratory diseases, autoimmunity, and oncology.

As continuous breakthroughs from multinational pharmaceutical companies validate the clinical druggability of the IL-33 pathway, Cyagen remains aligned with preclinical needs. By ensuring high-fidelity, stable expression of human genes and proteins, our IL33, ST2, and IL1RAP humanized models achieve exceptional translational value. These models not only provide comprehensive support for the pharmacodynamic evaluation of antagonistic mAbs in respiratory diseases like COPD and asthma but also facilitate deep mechanistic exploration in immuno-oncology (e.g., AML, PDAC), effectively eliminating key technical bottlenecks in the leap from early target validation to clinical translation.

As the IL-33 pathway advances in late-stage clinical development, robust humanized model systems will be essential for de-risking early discovery and supporting the next generation of inflammation-targeted and immuno-oncology therapeutics.

Explore Cyagen’s IL33, IL1RL1/ST2, and IL1RAP humanized mouse models to support your next translational research program.

References

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[10] Mok MY et al. (2010) Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology. 49(3):520-527.

[11] Kang BH et al. (2025) Unlocking IL-33: new insights into tumor immunity. Immune Netw. 25(5):e36.

[12] Che K et al. (2025) IL-33 in cancer immunotherapy: pleiotropic functions and biological strategies. Cytokine Growth Factor Rev. 85:81-92.

[13] Chen H et al. (2018) Integrated expression profiles analysis reveals correlations between the IL-33/ST2 axis and CD8+ T cells, regulatory T cells, and myeloid-derived suppressor cells in soft tissue sarcoma. Front Immunol. 9:1179.

[14] Chen J et al. (2022) Growth stimulation expressed gene 2 (ST2): clinical research and application in cardiovascular related diseases. Front Cardiovasc Med. 9:1007450.

[15] Missous G et al. (2024) Circulating interleukin-33 levels in obesity and type 2 diabetes: a systematic review and meta-analysis. Am J Physiol Endocrinol Metab. 327(6):E686-E699.

[16] Garlanda C et al. (2025) IL-1 family cytokines in inflammation and immunity. Cell Mol Immunol. 22(11):1345-1362.

[17] Frenay J et al. (2022) IL-1RAP, a key therapeutic target in cancer. Int J Mol Sci. 23(23):14918.

[18] Zarezadeh Mehrabadi A et al. (2024) Interleukin-1 receptor accessory protein (IL-1RAP): a magic bullet candidate for immunotherapy of human malignancies. Crit Rev Oncol Hematol. 193:104200.

[19] Rydberg Millrud C et al. (2023) Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy. Cancer Immunol Immunother. 72(3):667-678.

[20] Fields JK et al. (2024) Antibodies targeting the shared cytokine receptor IL-1 receptor accessory protein invoke distinct mechanisms to block all cytokine signaling. Cell Rep. 43(5):114099.

[21] Meijs A et al. (2025) The novel, first-in-class IL-1R3 antagonist SAR445399 reduces skin inflammation in an innovative proof-of-mechanism study with dual immune challenge models and comparator drugs. Sanofi Medical Congress.