Nature Communications | CM326 Targeting TSLP for Refractory Nasal Polyp-Type Chronic Rhinosinusitis

This study evaluates CM326, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), for its safety and efficacy in patients with refractory chronic rhinosinusitis with nasal polyps (CRSwNP). Results demonstrate that CM326 significantly improves nasal polyp scores (NPS) after 16 weeks of treatment, particularly in patients with baseline TSLP levels exceeding 330 fg/mL. Additionally, TSLP levels may serve as a potential predictive biomarker for therapeutic response, offering new insights into precision medicine.

 

Literature Overview
This article, "An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial", published in Nature Communications, reviews the mechanism and clinical performance of CM326 in treating refractory CRSwNP. The study employs a randomized, double-blind, placebo-controlled trial design to assess CM326's safety, pharmacodynamic (PD) profile, and efficacy, providing critical data support for TSLP-targeted therapies.

Background Knowledge
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease affecting 2%-4% of the global population. It presents with nasal congestion, rhinorrhea, headache, and olfactory dysfunction, severely impacting quality of life. While current treatments (e.g., topical or systemic corticosteroids, surgery) are widely used, some patients remain unresponsive. Research indicates that CRSwNP exhibits heterogeneous inflammatory phenotypes: eosinophilic CRSwNP (ECRSwNP) correlates with elevated IL-4/IL-5 and tissue eosinophilia, while neutrophilic inflammation represents another subtype. This heterogeneity has driven interest in precision therapies targeting distinct inflammatory mechanisms.
Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial cells during inflammation, activates dendritic cells, type 2 innate lymphoid cells (ILC2), and Th2 cells, promoting secretion of type 2 cytokines (e.g., IL-4, IL-5, IL-9, IL-13) and amplifying type 2 immune responses. Studies show that tezepelumab, an anti-TSLP antibody, effectively reduces asthma exacerbations independent of Th2 phenotypes, highlighting TSLP inhibition as a promising therapeutic strategy.
CM326 is a humanized monoclonal antibody against TSLP. Phase 1 trials demonstrated its favorable safety profile, linear pharmacokinetics, and low immunogenicity, supporting progression to Phase 2 trials. The DUBHE trial further evaluates CM326's safety and efficacy in CRSwNP patients and explores TSLP as a predictive biomarker, aiming to expand the clinical application of TSLP-targeted therapies.

 

 

Research Methods and Experimental Design
This was a multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a trial enrolling 84 patients with refractory CRSwNP, stratified by baseline tissue eosinophil levels. Participants were randomized to biweekly (Q2W) CM326 220mg or placebo (40 vs. 20 cases) and monthly (Q4W) CM326 220mg or placebo (20 vs. 4 cases). The treatment period lasted 16 weeks, followed by a 36-week open-label extension and 12-week follow-up. Primary endpoints included safety and changes in NPS scores in ECRSwNP patients at week 16. Secondary endpoints assessed NPS changes in nonECRSwNP patients and PD biomarkers.

Key Conclusions and Perspectives

• In the Q2W dosing group, ECRSwNP patients showed a significant reduction in NPS scores compared to placebo at week 16 (mean difference -1.2, 95% CI -2.3 to -0.1, P=0.04).
• The Q4W dosing group observed an NPS score reduction of -1.1 in ECRSwNP patients, but it was not statistically significant (P=0.24).
• Q2W CM326 treatment effectively reduced peripheral and tissue eosinophil counts, along with plasma IL-5 and IL-13 levels, indicating suppression of type 2 inflammation.
• Post-hoc analysis revealed that ECRSwNP patients with baseline TSLP >330 fg/mL achieved a greater NPS reduction (-1.75, 95% CI -3.06 to -0.44, P=0.01) at week 16, suggesting TSLP as a predictive biomarker.
• CM326 demonstrated good tolerability in both dosing regimens, with all treatment-emergent adverse events (TEAEs) being mild or moderate and no anti-drug antibodies (ADA) detected.
• Both Q2W and Q4W groups maintained therapeutic effects during the open-label and follow-up phases, with sustained NPS improvement 12 weeks post-treatment, indicating prolonged efficacy.
• CM326 showed robust efficacy in ECRSwNP but limited benefits in nonECRSwNP, implying distinct TSLP mechanisms across inflammatory subtypes.

Research Significance and Prospects
This study is the first to explore TSLP as a predictive biomarker in CRSwNP patients and validate CM326's therapeutic value in ECRSwNP. Future studies should expand sample sizes to confirm efficacy and long-term safety in diverse populations. Further investigation is needed to establish TSLP as a reliable indicator for inflammation subtyping and its utility across treatment regimens. As a next-generation anti-TSLP antibody, CM326's potential applications extend to other type 2 inflammation-related diseases, such as allergic asthma and atopic dermatitis.

 

 

Conclusion
Through the DUBHE clinical trial, this study systematically evaluated CM326's safety and efficacy in treating refractory CRSwNP. CM326 demonstrated significant NPS improvement under Q2W dosing and reduced type 2 inflammation markers, including IL-5, IL-13, and eosinophils. Notably, this study identifies plasma TSLP >330 fg/mL as a novel predictive biomarker for therapeutic response, enabling personalized treatment strategies. CM326 showed marked efficacy in ECRSwNP but limited benefits in nonECRSwNP, suggesting subtype-specific mechanisms. Overall, CM326 exhibits favorable tolerability and sustained effects, warranting further multi-center, large-scale Phase 3 trials to validate its broader clinical utility. This research establishes a foundation for TSLP-targeted therapies in CRSwNP and opens new avenues for antibody treatments in other type 2 inflammatory diseases.

 

Mu Xian, Feng Lan, Bing Yan, Chengshuo Wang, and Luo Zhang. An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial. Nature Communications.