Asthma is a heterogeneous and complex chronic disease. Children with severe asthma often experience acute exacerbations, ultimately leading to impaired lung function and poor quality of life. In the past, asthma was simply categorized as atopic or non-atopic based on traditional concepts. However, with further research into the pathogenesis of asthma, asthma classifications based on different inflammatory pathways have emerged, namely type 2 (T2-high) asthma and non-type 2 (T2-low) asthma. Inflammation is crucial to the pathophysiology of type 2 asthma, and type 2 asthma can be accompanied by multiple comorbidities associated with type 2 inflammation, such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Although most asthma patients' symptoms can be effectively controlled with standardized treatment, there are still a small number of patients whose symptoms cannot be controlled or even further deteriorate, developing into refractory asthma. The application of biologics provides a new approach for precision treatment of patients with refractory asthma and can also address patients' comorbidities associated with type 2 inflammation. Currently, the biologics used in asthma treatment are mainly targeted at type 2 asthma.
The Mechanism of Type 2 Inflammation in Asthma
Type 2 inflammation serves as the pathophysiological basis of chronic inflammation in asthma. Type 2 asthma is primarily mediated by T-bet+CD4+ type 2 helper T cells (Th2), type 2 innate lymphoid cells (ILC2), and related cytokines. The type 2 immune response in the airways is primarily mediated by eosinophils, mast cells, basophils, Th2 cells, ILC2, and IgE-producing B cells. When exogenous environmental factors such as bacteria, viruses, fungi, pollutants, and allergens damage the airway epithelial barrier, the goblet cells in the injured epithelial cells undergo metaplasia, releasing alarm-like cytokines such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). These cytokines recruit dendritic cells (DC) to present antigens and work together to activate and induce the differentiation of T lymphocytes into Th2 cells. Additionally, alarm-like cytokines can also activate ILC2, leading to the secretion of type 2 inflammation-related cytokines such as IL-4, IL-5, and IL-13, which contribute to the vulnerability of the epithelial barrier. Furthermore, alarm-like cytokines are also chemoattractants for eosinophils and neutrophils, and the secretion of TSLP, IL-25, and IL-33 can further stimulate the secretion of key type 2 cytokines.
IL-4 and IL-13 stimulate B cells to produce allergen-specific IgE, which binds to the FcεRI receptors on mast cells and basophils. When exogenous environmental factors re-enter the body, they create an allergen-IgE-cell cross-linkage, activating mast cells and basophils to degranulate, releasing mediators such as prostaglandin D2 (PGD2), leukotrienes, and histamine. This promotes local vasodilation and increases vascular permeability, leading to the contraction of tracheal smooth muscles and triggering airway hyperreactivity. IL-13 acts on epithelial cells, damaging the epithelial barrier, increasing epithelial permeability, stimulating the secretion of IL-33, and causing goblet cell metaplasia. Additionally, IL-13 can directly act on airway smooth muscle cells, causing their contraction and proliferation. IL-13 also participates in airway remodeling by inducing fibroblast proliferation and promoting collagen synthesis. IL-5 is a key cytokine that regulates the maturation of eosinophils in the bone marrow, mobilizing and promoting the production, proliferation, and survival of eosinophils in the bone marrow and peripheral tissues. IL-5 also contributes to airway remodeling by promoting eosinophil infiltration in the airways.
In type 2 asthma, the expression of cytokines (IL-4, IL-5, IL-13, IL-25, IL-33, TSLP, etc.) is elevated. Biomarkers of type 2 cytokines include increased fractional exhaled nitric oxide (FeNO), total serum IgE, allergen-specific IgE, and elevated levels of eosinophils in blood and sputum. Regarding the immune mechanisms of type 2 inflammation in asthma, biological agents can precisely target the key processes involved.
The Research and Application of Biologics in Pediatric Asthma
1.Anti-IgE Antibodies
In 2003 and 2005, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) successively approved the use of omalizumab for moderate to severe persistent allergic asthma in patients aged 12 and above. Later, in 2009 and 2016, the approval was extended to patients aged 6 and above with moderate to severe allergic asthma. Omalizumab is a humanized recombinant immunoglobulin G1 (IgG1) monoclonal antibody, the earliest biologic agent used to treat pediatric asthma. In August 2017, the China Food and Drug Administration approved its use for children aged 12 and above with uncontrolled moderate to severe persistent allergic asthma, sensitized to at least one inhaled allergen or with elevated serum immunoglobulin E (IgE) levels, and insufficient control of symptoms with inhaled corticosteroids.
The mechanism of omalizumab involves binding to IgE antibodies with high affinity, blocking their binding to IgE receptors on eosinophils, inhibiting their activation and degranulation after binding to high-affinity receptors FcεRI on mast cells and basophils. This reduces the allergic cascade reaction and affects the activation of inflammatory cells and the release of proinflammatory factors throughout the inflammatory process. Additionally, by binding to the low-affinity receptor CD23 on B cell surfaces, omalizumab affects their antigen-presenting function, thereby regulating the interaction between B and T cells and inducing downregulation of IgE receptors and rapid reduction of free IgE levels, thus blocking the amplification of Th2-mediated inflammatory responses. Omalizumab can also modulate the process of airway remodeling, effectively improving symptom control and delaying the progression of asthma. Clinical studies have shown that omalizumab can reduce the rate of asthma exacerbations, decrease corticosteroid usage, improve quality of life and asthma symptoms, as well as improve lung function and reduce the rate of disease progression.
2.Anti-IL-5/IL-5R Antibodies
Mepolizumab is a humanized monoclonal antibody targeting IL-5, approved by the FDA for use in children aged 6 and above. It was approved for marketing in China on November 19, 2021, for the treatment of eosinophilic asthma in children aged 12 or above. IL-5 is a cytokine released by Th2 cells that binds to IL-5Rα on eosinophils, promoting their production, activation, and survival. Mepolizumab specifically binds to free IL-5, blocking its binding to IL-5 receptors on the surface of eosinophils. This inhibits eosinophil proliferation, survival, differentiation, and promotes programmed cell death, reducing eosinophilic airway inflammation. Studies have shown that mepolizumab reduces severe persistent eosinophilic asthma exacerbations by approximately 50%, with improvements in lung function and health status. Among patients dependent on oral corticosteroids, mepolizumab reduced the need for oral corticosteroid therapy by 50% compared to placebo.
Anti-IL-5R monoclonal antibodies bind to the IL-5Rα subunit, reducing circulating eosinophils. Benralizumab is an anti-IL-5R monoclonal antibody that binds to the IL-5Rα subunit. By inducing eosinophil depletion and modulating eosinophil-related proteins, it blocks the production, maturation, and survival of eosinophils. Benralizumab can be used as an add-on treatment for patients aged over 12 with uncontrolled severe eosinophilic asthma (with blood eosinophils ≥ 150/μL).
3.Anti-IL-4Rα/IL-13
IL-4 and IL-13 are associated with tissue migration, smooth muscle contraction, basement membrane thickening, remodeling, mucus production, and B cell class switching. Dupilumab is a fully humanized monoclonal antibody against interleukin-4 receptor α (IL-4Rα), approved by the US FDA on October 21, 2021, for use in severe asthma patients aged 12 and above. By blocking IL-4 and IL-13 signaling, it downregulates B lymphocyte production and class switching to IgE, reduces inflammatory cell accumulation, and improves the forced expiratory volume in the first second (FEV1) of asthmatic patients. Dupilumab can be used as an add-on therapy for adult and adolescent patients with severe eosinophilic (blood eosinophils ≥ 150/μL) type 2 asthma or asthma requiring maintenance oral corticosteroid therapy, with a minimum age for use in children of 6 years. While ensuring asthma control, dupilumab can also improve lung function, reduce the risk of severe exacerbations, and decrease dependence on oral corticosteroids, with good safety. Additionally, dupilumab is the only biologic agent that covers all comorbidities associated with type 2 inflammation, making it the preferred choice for children with multiple comorbidities of type 2 inflammation.
4.Anti-TSLP (Thymic Stromal Lymphopoietin) Antibody
TSLP is an inflammatory mediator secreted by airway epithelial cells that activates dendritic cells (DCs) to induce the differentiation of naïve lymphocytes into Th17 cells. Th17 cells directly or indirectly secrete chemokines that recruit neutrophils to the airways. Meanwhile, the IL-17 cytokine can upregulate Glucocorticoid Receptor-β (GRβ), leading to GRβ/GRα imbalance and resulting in glucocorticoid resistance. Tezepelumab is an anti-TSLP antibody that blocks TSLP. It was first approved on December 17, 2021, in the US as an add-on maintenance therapy for severe asthma in patients aged 12 and above. It is the only biological agent approved for severe asthma without phenotypic (such as eosinophilic or allergic) or biomarker restrictions. Tezepelumab aids in asthma control, improves health-related quality of life, and lung function. For patients aged 12 and above, the use of tezepelumab significantly reduces the rate of severe exacerbations and has a significant preventive effect against asthma worsening, regardless of baseline blood eosinophil counts or other type 2 inflammation biomarker levels. Additionally, tezepelumab can reduce blood eosinophil counts, FeNO, and serum total IgE levels.
5.Other Potential Targets and Biologics
CRTH2 (Chemoattractant Receptor-Homologous Molecule expressed on Th2 cells) is a G protein-coupled receptor selectively expressed by type 2 T lymphocytes, basophils, eosinophils, and ILC2s (Innate Lymphoid Cells 2). CRTH2 can synergistically participate in allergic reactions through different processes, making it a potentially beneficial new target for asthma treatment.
The transcription factor GATA-3 plays a pivotal role in the differentiation and activation of Th2 cells by controlling the production of Th2 cytokines (IL-4, IL-5, and IL-13). GATA-3 exerts its function in the potential immune pathways of allergic inflammation, and its expression is significantly increased in the airways of asthmatic patients, suggesting that GATA-3 can serve as a new target for asthma treatment. In multicenter clinical trials, the GATA3-specific deoxyribozyme Hgd40 (inhaled formulation SB010) significantly reduced bronchoconstriction in both early and late stages of asthma, while also lowering sputum eosinophil counts and blood IL-5 levels.
CCR3 is a homologous receptor for major human eosinophil chemotactic substances, expressed by eosinophils, and plays an important role in the recruitment of eosinophils in the lungs. AXP1275 is a CCR3 receptor antagonist that has been evaluated for its efficacy in human asthma allergen challenge models. After 2 weeks of oral CCR3 antagonist treatment in patients with mild allergic asthma, there was no significant reduction in airway eosinophils, but lung function improved.
Siglec-8, a regulatory sialic acid-binding immunoglobulin-like lectin that modulates eosinophil apoptosis, is a cell surface inhibitory receptor selectively expressed on human eosinophils and mast cells. The monoclonal antibody of Siglec-8 (Lirentlimab/AK002) can induce eosinophil apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC), preventing systemic allergic reactions. Experiments on airway cells from asthmatic patients have shown that the gene expression of Siglec-8 is increased in asthmatic patients, correlating with the gene expression of eosinophils and mast cells.
The research and application of biologics can precisely target the intermediate steps of immune response in inflammatory pathways, significantly improving the treatment outcomes for refractory asthma. However, due to the high cost and diverse types of biologics, clinicians need to select the most beneficial ones for patients based on their specific conditions. While more and more biologics have undergone clinical trials or have been approved for the treatment of refractory asthma in children, there is still a relative lack of experimental data on biologics in adolescents and children, especially in younger children. Therefore, the future development of targeted therapy with biologics should include conducting separate high-quality studies on children and accumulating clinical data to assess their effectiveness and safety. Additionally, clinicians should continue to strive to find safer and more effective treatment methods for children and adolescents with asthma.
References
[1] Du Yi, Zhao Deyu. Application and Research Progress of Biologics in the Treatment of Pediatric Asthma [J]. Journal of Pediatric Pharmacy, 2023, 29(07): 58-63.
[2] Qin Fengyuan, Shu Chang. Research Progress on the Application of Biologics in Pediatric Refractory Asthma [J]. Advances in Clinical Medicine, 2022, (Issue 6).
Author Introduction
Xiaomichong is a researcher in drug quality, who has long been committed to drug quality research and drug analysis method validation. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection analysis and analysis method validation.
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