Nature Communications | CM326 targets TSLP for treating refractory nasal polyps in 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. Furthermore, TSLP emerges as a potential predictive biomarker for therapeutic response, offering new insights into precision medicine strategies.

 

Literature Overview
This study, 'An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial' published in Nature Communications, reviews the mechanism of action and clinical performance of CM326 in treating refractory CRSwNP. The research employs a randomized, double-blind, placebo-controlled clinical trial design to assess safety, pharmacodynamic (PD) profiles, 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 symptoms including nasal obstruction, rhinorrhea, headache, and olfactory dysfunction, significantly impairing quality of life. While current treatments (e.g., topical/systemic corticosteroids, surgery) are widely used, disease remains uncontrolled in certain patients. Studies reveal CRSwNP's heterogeneous inflammatory phenotypes: eosinophilic CRSwNP (ECRSwNP) correlates with elevated IL-4/IL-5 and tissue eosinophilia, whereas neutrophilic inflammation represents another subtype. This heterogeneity has intensified interest in phenotype-specific precision therapies.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine activated during inflammatory responses. It triggers dendritic cells, type 2 innate lymphoid cells (ILC2), and Th2 cells to secrete type 2 cytokines (IL-4, IL-5, IL-9, IL-13), amplifying type 2 immune responses. Previous studies demonstrate that anti-TSLP antibodies (tezepelumab) effectively reduce asthma exacerbations through Th2-independent mechanisms, suggesting broader therapeutic potential for TSLP inhibition.
CM326 is a humanized anti-TSLP monoclonal antibody showing favorable safety, linear pharmacokinetics, and low immunogenicity in phase 1 trials. The DUBHE trial extends these findings by evaluating CM326's safety and efficacy in CRSwNP patients while investigating TSLP's predictive value as a biomarker for therapeutic response.

 

 

Research Methods and Experiments
This multicenter, randomized, double-blind, placebo-controlled 1b/2a clinical trial enrolled 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) for 16 weeks, followed by 36-week open-label extension and 12-week follow-up. Primary endpoints assessed safety and NPS changes in ECRSwNP patients at week 16. Secondary endpoints evaluated NPS modifications in non-ECRSwNP patients and pharmacodynamic biomarker alterations.

Key Conclusions and Perspectives

• In the Q2W group, ECRSwNP patients showed significant NPS score reduction versus placebo (mean difference -1.2, 95% CI -2.3 to -0.1, P=0.04).
• Q4W dosing demonstrated non-significant NPS improvement in ECRSwNP patients (-1.1, P=0.24).
• Q2W CM326 effectively decreased peripheral and tissue eosinophils, along with plasma IL-5 and IL-13 levels, indicating type 2 inflammation suppression.
• Post-hoc analysis revealed greater NPS reduction (-1.75, 95% CI -3.06 to -0.44, P=0.01) in ECRSwNP patients with baseline TSLP >330 fg/mL, establishing TSLP as a predictive biomarker.
• Both dosing regimens showed good tolerability with no drug-related antibodies detected; all treatment-emergent adverse events (TEAEs) were mild to moderate.
• Q2W and Q4W groups maintained therapeutic effects during open-label and follow-up phases, with sustained NPS improvement 12 weeks post-treatment, demonstrating prolonged efficacy.
• CM326 demonstrates significant efficacy in ECRSwNP but limited effects in non-ECRSwNP, suggesting distinct TSLP pathway mechanisms across inflammatory phenotypes.

Research Significance and Prospects
This trial pioneers TSLP's role as a predictive biomarker in CRSwNP while validating CM326's therapeutic value for ECRSwNP. Future studies should expand patient cohorts to confirm efficacy and long-term safety across diverse populations. Further investigations are needed to determine TSLP's utility as an inflammatory subtype classifier and its broader applications in 2-type inflammatory diseases. As a next-generation anti-TSLP antibody, CM326's potential extends to allergic asthma, atopic dermatitis, and other type 2 immune-mediated conditions.

 

 

Conclusion
The DUBHE clinical trial systematically evaluated CM326's safety and efficacy in treating refractory chronic rhinosinusitis with nasal polyps. Biweekly administration demonstrated significant NPS score improvement and reduced type 2 inflammatory markers (IL-5, IL-13, eosinophils). This study identifies plasma TSLP >330 fg/mL as a novel predictive biomarker for therapeutic response. CM326 shows superior efficacy in ECRSwNP patients but limited benefits in non-ECRSwNP cases, highlighting its phenotype-specific advantages. With favorable tolerability and sustained effects, CM326 requires phase 3 trials to validate broader applicability. These findings establish TSLP-targeted therapy for CRSwNP and provide a framework for antibody treatments in 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.