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Published on: September 15, 2023
An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial
Mu Xian1,2,3, Feng Lan1,2,3, Bing Yan1,2,3
1Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
Abstract:
To explore the therapeutic potential of blocking thymic stromal lymphopoietin (TSLP) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), we conducted a phase 1b/2a, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of CM326, a monoclonal antibody against TSLP. We enrolled 84 eligible patients with uncontrolled CRSwNP and stratified them based on baseline tissue eosinophil count. Patients are assigned to receive CM326 220 mg (n = 40) or placebo (n = 20) every 2 weeks (Q2W) and CM326 220 mg (n = 20) or placebo (n = 4) every 4 weeks (Q4W) for 16 weeks. Subsequently, all patients continue on CM326 220 mg Q2W or Q4W for an additional 36 weeks, followed by a 12-week follow up. Primary endpoints are safety of CM326 and change from baseline in NPS at week 16 in patients with eosinophilic CRSwNP (ECRSwNP). Main secondary endpoints include the change from baseline in NPS at week 16 in non-eosinophilic CRSwNP (nonECRwNP) and pharmacodynamic markers. Throughout the 64-week study, all treatment-emergent adverse events (TEAEs) are mild or moderate. CM326 Q2W improves NPS in patients with ECRSwNP compared with placebo at week 16 (mean difference [95% CI], -1.2 [-2.3 to -0.1], P = 0.04), with sustained benefits during the open-label and follow-up periods. Notably, peripheral blood and tissue eosinophil counts and concentrations of plasma IL-13 and IL-5 are reduced by week 16 with the treatment of CM326 Q2W versus placebo. A post-hoc analysis demonstrates that all participants with baseline TSLP > 330 fg/mL achieve a substantial reduction in NPS by week 16 with the treatment of CM326 Q2W (mean difference vs. placebo: -1.75 [95%CI, -3.06 to -0.44], P = 0.01). Overall, CM326 is well tolerated and effective in patients with uncontrolled ECRSwNP. A baseline plasma TSLP level of 330 fg/mL may serve as a predictive marker for treatment efficacy of CM326. ClinicalTrials.gov Identifier: NCT05324137.
Insights
This study shows that CM326, a thymic stromal lymphopoietin (TSLP) inhibitor, effectively reduces nasal polyp size in patients with eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). Higher baseline TSLP levels predict a better treatment response.
Area of Science:
- Immunology
- Otolaryngology
- Clinical Pharmacology
Background:
- Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory upper airway disease.
- Thymic stromal lymphopoietin (TSLP) is a key cytokine implicated in Type 2 inflammation driving CRSwNP pathogenesis.
- Targeting TSLP presents a potential therapeutic strategy for CRSwNP, particularly eosinophilic phenotypes.
Purpose of the Study:
- To evaluate the safety and efficacy of CM326, a monoclonal antibody targeting TSLP, in patients with uncontrolled CRSwNP.
- To assess the impact of CM326 on nasal polyp size (NPS) and relevant biomarkers in CRSwNP patients.
- To identify potential predictive markers for CM326 treatment response.
Main Methods:
- A phase 1b/2a, randomized, double-blind, placebo-controlled trial involving 84 patients with uncontrolled CRSwNP.
- Patients received CM326 (220 mg) or placebo every 2 or 4 weeks for 16 weeks, followed by an extended open-label treatment period.
- Primary endpoints included safety and change in NPS at week 16 in eosinophilic CRSwNP (ECRSwNP) patients.
Main Results:
- CM326 administered every 2 weeks (Q2W) significantly improved NPS in ECRSwNP patients compared to placebo at week 16 (mean difference: -1.2; P=0.04).
- Treatment with CM326 Q2W led to reductions in peripheral blood and tissue eosinophil counts, and plasma IL-5 and IL-13 levels.
- A post-hoc analysis indicated that patients with baseline TSLP > 330 fg/mL experienced substantial NPS reduction with CM326 Q2W (mean difference vs. placebo: -1.75; P=0.01).
Conclusions:
- CM326 is well-tolerated and demonstrates efficacy in improving NPS in patients with uncontrolled ECRSwNP.
- The study suggests that CM326 Q2W is a promising therapeutic option for ECRSwNP.
- A baseline plasma TSLP level of 330 fg/mL may serve as a predictive biomarker for CM326 treatment efficacy.
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