Research Progress on the Application of Biologics in Childhood Asthma.

Asthma is a heterogeneous, complex chronic disease. Children with severe asthma often experience acute exacerbations, leading to impaired lung function and poor quality of life. In the past, asthma was simply classified as either atopic or non-atopic. With deeper research into the mechanisms of asthma, asthma subtypes based on different inflammatory pathways have emerged, namely type 2 (T2-high) and non-type 2 (T2-low) asthma. Inflammation is crucial to the pathophysiology of T2 asthma, and T2 asthma can be accompanied by multiple T2 inflammatory comorbidities, such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Most asthma patients' symptoms can be effectively controlled with standardized treatment, but a small number of patients still have uncontrolled or even worsening symptoms, developing into refractory asthma. The application of biologics offers a new method for precise treatment of refractory asthma patients while also addressing their T2 inflammatory comorbidities. Currently, biologics used in the treatment of asthma mainly target T2 asthma.

Mechanisms of Type 2 Inflammation in Asthma

Type 2 inflammation is the pathological basis of chronic inflammation in asthma. Type 2 asthma is characterized by airway inflammation mediated primarily by T-bet+CD+4 1-type helper T cells (Th2), type 2 innate lymphoid cells (ILC2), and related cytokines. The type 2 immune response in the airways is mainly mediated by eosinophils, mast cells, basophils, Th2 cells, ILC2, and B cells that produce IgE. When external environmental factors such as bacteria, viruses, fungi, pollutants, and allergens disrupt the airway epithelial barrier, damaged epithelial cells undergo metaplasia into goblet cells, releasing cytokines such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) as warning-like cell factors. These factors recruit dendritic cells (DCs) to present antigens and act together to activate and induce the differentiation of T lymphocytes into Th2 cells. At the same time, warning-like cell factors can also activate ILC2, thereby secreting type 2 inflammation-related cytokines IL-4, IL-5, and IL-13, leading to the vulnerability of the epithelial barrier. Furthermore, warning-like cell factors are also chemoattractants for eosinophils and neutrophils. 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 external environmental factors re-enter the body, allergen-IgE-cell crosslinking occurs, activating mast cells and basophils to degranulate and release mediators such as prostaglandin D2 (PGD2), leukotrienes, and histamine, promoting local vasodilation and increased vascular permeability. This causes contraction of the bronchial smooth muscle and triggers airway hyperresponsiveness. IL-13 can act on epithelial cells, disrupting the epithelial barrier and increasing epithelial permeability. It induces the secretion of IL-33 and metaplasia of goblet cells. IL-13 can also directly act on airway smooth muscle cells, causing their contraction and proliferation. Additionally, IL-13 induces fibroblast proliferation and promotes collagen synthesis, contributing to airway remodeling. IL-5 is a key cytokine that regulates the maturation of eosinophils in the bone marrow. It mobilizes and promotes the production, proliferation, and survival of eosinophils in the bone marrow and peripheral tissues, leading to infiltration in the airways and involvement in airway remodeling.

In type 2 asthma, the expression of cytokines such as IL-4, IL-5, IL-13, IL-25, IL-33, and TSLP is increased. Biomarkers of type 2 cytokines include fractional exhaled nitric oxide (FeNO), serum total IgE, allergen-specific IgE, and elevated levels of eosinophils in blood and sputum. Biologic agents specifically target key components of the immune mechanisms underlying type 2 inflammation in asthma.

Research Application of Biological Agents in Pediatric Asthma

1.      Anti-IgE Antibodies

In 2003 and 2005, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved omalizumab for the treatment of moderate to severe persistent allergic asthma in individuals aged 12 years and older. In 2009 and 2016, it was also approved for use in children aged 6 years and older with moderate to severe allergic asthma. Omalizumab is a humanized recombinant immunoglobulin G1 (IgG1) monoclonal antibody and was one of the earliest biological agents used to treat pediatric asthma. In August 2017, the China Food and Drug Administration approved its use in children aged 12 years and older with uncontrolled moderate to severe persistent allergic asthma who are sensitized to at least one inhaled allergen or have elevated serum immunoglobulin E (IgE) levels and inadequate symptom control with inhaled corticosteroids. Its mechanism of action involves high-affinity binding to IgE antibodies, blocking their interaction with IgE receptor on eosinophils, mast cells, and basophils, inhibiting their activation and degranulation, reducing allergic cascade reactions, and decreasing the activation of inflammatory cells and release of pro-inflammatory mediators. Additionally, by binding to the low-affinity receptor CD23 on B cells, omalizumab affects antigen presentation, modulates interactions between B cells and T cells, induces downregulation of IgE receptors, and rapidly decreases free IgE levels, thereby blocking the amplification of Th2-induced inflammatory responses. Omalizumab can also modulate airway remodeling processes, effectively improving symptom control and delaying asthma progression. Clinical studies have shown that omalizumab can reduce asthma exacerbation rates, decrease the use of corticosteroids, improve quality of life and asthma symptoms, improve lung function, and reduce disease exacerbations.

2.      Anti-IL-5/IL-5R Antibodies

Reslizumab is a humanized monoclonal antibody targeting IL-5. It received FDA approval for use in children aged 6 years and older with eosinophilic asthma. IL-5 is a cytokine released by Th2 cells that binds to IL-5 receptor alpha (IL-5Rα) on eosinophils, promoting their production, activation, and survival. Reslizumab specifically binds to free IL-5, blocking its interaction with the IL-5 receptor on the surface of eosinophils, inhibiting eosinophil proliferation, survival, and differentiation, promoting apoptosis, and reducing eosinophilic airway inflammation. Studies have shown that reslizumab reduces severe exacerbations of persistent eosinophilic asthma by approximately 50% and improves lung function and overall health status. In patients dependent on oral corticosteroids, reslizumab reduces the need for oral corticosteroid therapy by 50%. Benralizumab, an anti-IL-5R monoclonal antibody, binds to the alpha subunit of IL-5R, depletes eosinophils, and regulates eosinophil-related proteins, thereby blocking the generation, maturation, and survival of eosinophils. Benralizumab can be used as an adjunctive therapy in patients aged >12 years with severe eosinophilic asthma (blood eosinophils ≥ 150/μL) that is inadequately controlled.

3.      Anti-IL-4Rα/IL-13

IL-4 and IL-13 are involved in tissue migration, smooth muscle contraction, basement membrane thickening, remodeling, mucus production, and B cell class switching. Dupilumab is a fully human monoclonal antibody targeting the interleukin-4 receptor alpha (IL-4Rα). It received FDA approval in October 2021 for use in individuals aged 12 years and older with severe asthma. By blocking IL-4 and IL-13 signaling, dupilumab downregulates B lymphocyte class switching to IgE, reduces the accumulation of inflammatory cells, and improves forced expiratory volume in 1 second (FEV1) in asthma patients. Dupilumab can be used as an adjunctive therapy for adults and adolescents with severe eosinophilic (blood eosinophils ≥ 150/μL) type 2 asthma or asthma patients who require oral corticosteroids, with a minimum age of 6 years for pediatric use. Dupilumab improves lung function, reduces the rate of severe exacerbations, decreases dependence on oral corticosteroids, and has a good safety profile. Additionally, dupilumab is the only biological agent that covers all comorbidities associated with type 2 inflammation, making it the preferred choice for children with multiple type 2 inflammatory comorbidities.

4. Anti-Thymic Stromal Lymphopoietin Antibodies

Thymic stromal lymphopoietin (TSLP) is an inflammatory mediator secreted by airway epithelial cells. It can activate dendritic cells (DCs) to induce the differentiation of naive lymphocytes into Th17 cells. Th17 cells, either directly or indirectly through the secretion of chemotactic factors, recruit neutrophils in the airways. Additionally, IL-17 cytokines upregulate the glucocorticoid receptor-beta (GRβ), leading to GRβ/GRα imbalance and glucocorticoid resistance. Tezepelumab is an anti-thymic stromal lymphopoietin antibody that blocks the action of TSLP. It was approved on December 17, 2021, as an add-on maintenance treatment for severe asthma patients aged 12 and older in the United States. Tezepelumab is the only biologic therapy approved for severe asthma without phenotype (e.g., eosinophilic or allergic) or biomarker restrictions. It is beneficial for asthma control, improvement of health-related quality of life, and lung function in 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, irrespective of blood eosinophil baseline levels or other type 2 inflammation biomarkers. Furthermore, Tezepelumab can reduce blood eosinophil counts, fractional exhaled nitric oxide (FeNO), and serum total IgE levels.

Other Potential Targets and Biologics

CRTH2 is a G protein-coupled receptor selectively expressed by type 2 T lymphocytes, basophils, eosinophils, and ILC2s. It plays a role in allergic reactions and may be a new favorable target for asthma treatment. Transcription factor GATA-3 plays a crucial role in the differentiation and activation of Th2 cells by controlling the production of Th2 cell cytokines (IL-4, IL-5, and IL-13). It is significantly increased in the airways of allergic inflammation, suggesting that GATA-3 may serve as a new target for asthma therapy. In multicenter clinical trial studies, GATA3-specific deoxyribozyme Hgd40 (inhaled formulation SB010) significantly alleviated early and late bronchoconstriction in asthma and reduced sputum eosinophil counts and blood IL-5 levels. CCR3 is a homologous receptor for human major eosinophil chemotactic substances expressed by eosinophils, playing an important role in eosinophil recruitment in the lungs. AXP1275 is a CCR3 receptor antagonist that has been evaluated for efficacy in human asthma allergen challenge models. After 2 weeks of oral treatment with the CCR3 antagonist in patients with mild allergic asthma, there was no significant reduction in airway eosinophils, but lung function improved.

Siglec-8, a sialic acid-binding immunoglobulin-like lectin on the surface of eosinophils and mast cells, is an inhibitory receptor that regulates eosinophil apoptosis. Lirentlimab/AK002, a monoclonal antibody targeting Siglec-8, induces eosinophil apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) and prevents systemic allergic reactions. Experimental studies on airway cells from asthma patients have shown increased expression of Siglec-8, which is associated with eosinophil and mast cell gene expression.

The research and application of biologics can precisely target intermediate steps in the immune response of inflammatory pathways, significantly improving the therapeutic effect of refractory asthma. However, due to the high cost and variety of biologics, clinical physicians need to select the most beneficial biologic therapy based on the patient's condition. Although an increasing number of biologics have undergone clinical trials or have been approved for the treatment of refractory asthma in children, there is still a relative lack of trial data for biologics in adolescents and children, especially in younger children. Therefore, future developments in targeted biologic therapies should include separate high-quality studies on children and the accumulation of clinical data to assess their effectiveness and safety. In addition, clinical physicians should continue to strive to find safer and more effective treatments for children and adolescent asthma patients.

References:

[1] Du, Y., Zhao, D. Application and research progress of biologics in the treatment of childhood asthma. Journal of Pediatric Pharmacy, 2023, 29(07), 58-63.

[2] Qin, F., Shu, C. Research progress on the application of biologics in the treatment of refractory asthma in children. Advances in Clinical Medicine, 2022, (Issue 6).

About the Author:

Xiaomichong is a researcher in drug quality, who has long been committed to the research of drug quality and the validation of drug analysis methods. Currently, Xiaomichong is employed by a large Chinese pharmaceutical research and development company, engaging in drug inspection and analysis as well as validation of analytical methods.