This article reviews recent advances in three novel targeted therapeutic strategies for severe asthma, revealing a new immunomodulatory mechanism of Charcot-Leyden crystals (CLC) and demonstrating the potential broad-spectrum efficacy of tezepelumab in T2-low phenotypes, offering new intervention avenues for refractory asthma.
Literature Overview
The article, 'Wiping Out Wheezing: Novel Therapeutic Targets for Patients with Severe Asthma,' published in the American Journal of Respiratory and Critical Care Medicine, reviews and summarizes recent research progress on three emerging therapeutic targets for severe type 2 inflammatory asthma: Charcot-Leyden crystals (CLC), thymic stromal lymphopoietin (TSLP), and CRTh2. The article highlights three pivotal studies by Persson et al., Corren et al., and Bateman et al., published in Science, New England Journal of Medicine, and European Respiratory Journal, respectively. It systematically analyzes the roles of these targets in asthma pathogenesis, clinical trial outcomes of related drugs, and their potential clinical value. This work not only expands our understanding of the molecular mechanisms of T2 inflammation but also provides new insights for future personalized therapies.Background Knowledge
Severe asthma is a highly heterogeneous and difficult-to-control chronic airway disease. The T2-high phenotype is characterized by eosinophilia, activation of the IL-4/5/13 pathway, and elevated IgE levels. Although biologics targeting IgE, IL-5/5R, and IL-4Rα have significantly improved outcomes for some patients, a substantial proportion remain unresponsive or develop resistance. Therefore, exploring upstream or non–cytokine-dependent therapeutic targets has become a research focus. Charcot-Leyden crystals (CLC), formed by crystallization of galectin-10 protein released from eosinophils, have traditionally been viewed as inflammatory byproducts, but recent studies suggest they actively drive T2 immune responses. TSLP, an epithelial-derived alarmin located upstream of the T2 inflammatory cascade, regulates the release of key cytokines such as IL-4, IL-5, and IL-13, offering a broader anti-inflammatory potential. CRTh2 is a receptor on Th2 cells and eosinophils that mediates the chemotactic effects of PGD2, making it an ideal target for small-molecule antagonists. This article focuses on these three targets, representing different mechanistic layers, to evaluate their potential for therapeutic intervention.
Research Methods and Experiments
Persson et al. used X-ray crystallography to resolve the structure of CLC, identifying key domains essential for self-crystallization, and developed specific antibodies to block crystal formation and dissolve existing crystals. In a humanized mouse model, they reconstituted the immune system using house dust mite-sensitized PBMCs to evaluate the effects of anti-CLC antibodies on airway inflammation, MUC5AC expression, bronchial hyperresponsiveness, and IgE levels.
Corren et al. conducted a phase II, randomized, double-blind, placebo-controlled trial involving 550 patients aged 18–75 with uncontrolled severe asthma, who were randomized to receive different doses of tezepelumab or placebo for 52 weeks. The primary endpoint was the annualized asthma exacerbation rate, with secondary endpoints including time to first exacerbation, FEV1, FeNO, blood eosinophil count, and total IgE levels, analyzed by baseline AEC strata.
Bateman et al. conducted a phase IIb randomized controlled trial involving 1,058 patients with allergic asthma, comparing once- or twice-daily fevipiprant, montelukast (positive control), and placebo over 12 weeks. The primary endpoint was change in pre-dose FEV1, with additional assessments of Asthma Control Questionnaire (ACQ) and asthma control diary scores.Key Conclusions and Perspectives
Research Significance and Prospects
CLC, as a newly identified immune activator, challenges the traditional view of it being merely an inflammatory byproduct, offering a novel therapeutic target for eosinophilic asthma. Anti-CLC antibody strategies may benefit patients with severe eosinophilic asthma exhibiting high CLC expression, especially those unresponsive to current biologics, warranting future clinical trials to confirm safety and efficacy.
Tezepelumab’s broad anti-inflammatory potential makes it one of the most promising biologics for asthma, particularly due to its efficacy in T2-low patients, potentially filling a critical treatment gap. Its phase III studies have confirmed clinical benefits, suggesting TSLP is a superior target compared to downstream cytokines, and may emerge as a 'pan-phenotype' treatment option.
The failure of fevipiprant underscores the challenges of small-molecule targeted therapies in asthma management, despite a well-defined target mechanism and limited clinical improvement. Nevertheless, the PGD2-CRTh2 pathway remains biologically significant, with other agents such as GB001 (a PGD2 blocker) still in development, indicating the pathway is worth further exploration through more precise patient stratification or combination strategies.
Conclusion
This article systematically reviews three novel therapeutic strategies for severe asthma, highlighting multidimensional advances from molecular mechanisms to clinical translation. First, Charcot-Leyden crystals have been shown not only to serve as inflammatory markers but also as functional immunomodulators. Antibodies targeting their formation demonstrate significant efficacy in mouse models, offering a new intervention strategy for eosinophil-associated diseases. Second, tezepelumab, a monoclonal antibody targeting the upstream mediator TSLP, exhibited strong clinical effects in phase II trials that were independent of eosinophil counts, suggesting potential applicability across a broader asthma population, including T2-low phenotypes, and positioning it as a potential broad-spectrum biologic. However, although the oral CRTh2 antagonist fevipiprant improved lung function, it failed to translate into significant clinical control benefits, and its phase III failure reminds us that target validation does not guarantee clinical success—small-molecule development requires more precise endpoint design and patient selection. Overall, these studies collectively advance asthma treatment from a 'phenotype-driven' to a 'mechanism-driven' paradigm, emphasizing the importance of upstream targets and novel pathological mechanisms, laying a solid foundation for future personalized and precision medicine strategies.
