Patrick D. Mitchell

Emerging monoclonal antibodies as targeted innovative therapeutic approaches to asthma

Asthma is characterized by discordant responses among cells of the adaptive and innate immune systems. This interplay involves a complex pattern of cytokine‐driven processes resulting in cell migration and recruitment, inflammation, and proliferative states. The significant majority of asthmatic patients respond well to conventional inhaled treatments. However, about 5% of asthmatics have severe refractory asthma and account for 50% of the health expenditure on asthma. Human(ized) monoclonal antibodies (hMabs) targeting inflammatory pathways are promising therapeutic agents in asthma management. The anti‐IgE hMab omalizumab was the first biologic treatment approved for the treatment of allergic asthma. Potential future strategies and targets include interleukin (IL)‐5, IL‐4, and IL‐13, anti‐TSLP, IL‐25, and IL‐33. hMabs targeting IL‐5 have shown great promise in severe refractory asthma with a persisting eosinophilia, and clinical trials with hMabs against IL‐13 and IL4Rα have also shown clinical benefit. Studies of hMabs against other cytokines in severe asthma are under way.

Epithelial Derived Cytokines in Asthma.

&NA; The interaction between the airway epithelium and the inhaled environment is crucial to understanding the pathobiology of asthma. Several studies have identified an important role of airway epithelial‐derived cytokines, IL‐25, IL‐33, and thymic stromal lymphopoietin (TSLP) in asthma pathogenesis. These cytokines have been described as epithelial‐derived alarmins that activate and potentiate the innate and humoral arms of the immune system in the presence of actual or perceived damage. Each of the three epithelial‐derived alarmins has been implicated in the pathobiology of inhaled allergen‐induced airway responses. The best evidence to date exists for TSLP, in that a human monoclonal antibody, which binds TSLP and prevents its engagement with its receptor, resolves airway inflammation in patients with allergic asthma and attenuates allergen‐induced airway responses. Better understanding the roles that the epithelial‐derived alarmins play and how they influence airway immune response may allow the development of novel therapeutics for asthma treatment.

Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma

ABSTRACT Asthma is a chronic airway inflammatory disorder with characteristic symptoms of dyspnea, wheeze, chest tightness and cough, and physiological abnormalities of variable airway obstruction, airway hyperresponsiveness, and in some patients with chronic long standing disease reduced lung function. The physiological abnormalities are due to chronic airway inflammation and underlying structural changes to the airway wall. The interaction between the airway epithelium and the environment is crucial to the pathobiology of asthma. Several recent discoveries have highlighted a crucial role of airway epithelial derived cytokines such as interleukin (IL)‐25, IL‐33 and thymic stromal lymphopoietin (TSLP). These cytokines are collectively known as epithelial “alarmins”, which act solely or in concert to activate and potentiate the innate and humoral arms of the immune system in the presence of actual or perceive damage. Understanding the role of alarmins and how they are activated and released may allow the development of novel new therapeutics to treat asthma. This review describes the interactions between inhaled air, the pulmonary microbiome, airway epithelial cell layer and the alarmins, IL‐25, IL‐33 and TSLP. There is already compelling evidence for a role of TSLP in the airway responses to environmental allergens in allergic asthmatics, as well as in maintaining airway eosinophilic inflammation in these subjects. Further work is required to develop human monoclonal antibodies (hMabs) directed against IL‐25 and IL‐33 or their receptors, to help understand their role in the initiation and/or persistence of asthma.

Therapeutic interventions in severe asthma

The present paper addresses severe asthma which is limited to 5-10% of the overall population of asthmatics. However, it accounts for 50% or more of socials costs of the disease, as it is responsible for hospitalizations and Emergency Department accesses as well as expensive treatments.The recent identification of different endotypes of asthma, based on the inflammatory pattern, has led to the development of tailored treatments that target different inflammatory mediators. These are major achievements in the perspective of Precision Medicine: a leading approach to the modern treatment strategy.Omalizumab, an anti-IgE antibody, has been the only biologic treatment available on the market for severe asthma during the last decade. It prevents the linkage of the IgE and the receptors, thereby inhibiting mast cell degranulation. In clinical practice omalizumab significantly reduced the asthma exacerbations as well as the concomitant use of oral glucocorticoids.In the “Th2-high asthma” phenotype, the hallmarks are increased levels of eosinophils and other markers (such as periostin). Because anti-IL-5 in this condition plays a crucial role in driving eosinophil inflammation, this cytokine or its receptors on the eosinophil surface has been studied as a potential target for therapy.Two different anti-IL-5 humanized monoclonal antibodies, mepolizumab and reslizumab, have been proven effective in this phenotype of asthma (recently they both came on the market in the United States), as well as an anti-IL-5 receptor alpha (IL5Rα), benralizumab.Other monoclonal antibodies, targeting different cytokines (IL-13, IL-4, IL-17 and TSLP) are still under evaluation, though the preliminary results are encouraging.Finally, AIT, Allergen Immunotherapy, a prototype of Precision Medicine, is considered, also in light of the recent evidences of Sublingual Immunotherapy (SLIT) tablet efficacy and safety in mite allergic asthma patients.Given the high costs of these therapies, however, there is an urgent need to identify biomarkers that can predict the clinical responders.

Allergen-induced Changes in Bone Marrow and Airway Dendritic Cells in Subjects with Asthma

RATIONALE Dendritic cells (DCs) are antigen-presenting cells essential for the initiation of T-cell responses. Allergen inhalation increases the number of airway DCs and the release of epithelial-derived cytokines, such as IL-33 and thymic stromal lymphopoietin (TSLP), that activate DCs. OBJECTIVES To examine the effects of inhaled allergen on bone marrow production of DCs and their trafficking into the airways in subjects with allergic asthma, and to examine IL-33 and TSPL receptor expression on DCs. METHODS Bone marrow, peripheral blood, bronchoalveolar lavage (BAL), and bronchial biopsies were obtained before and after inhalation of diluent and allergen from subjects with asthma that develop allergen-induced dual responses. Classical DCs (cDCs) were cultured from bone marrow CD34(+) cells. cDC1s, cDC2s, and plasmacytoid DCs were measured in bone marrow aspirates, peripheral blood, and BAL by flow cytometry, and cDCs were quantified in bronchial biopsies by immunofluorescence staining. MEASUREMENTS AND MAIN RESULTS Inhaled allergen increased the number of cDCs grown from bone marrow progenitors, and cDCs and plasmacytoid DCs in bone marrow aspirates 24 hours after allergen. Allergen also increased the expression of the TSLP receptor, but not the IL-33 receptor, on bone marrow DCs. Finally, inhaled allergen increased the percentage of cDC1s and cDC2s in BAL but only cDC2s in bronchial tissues. CONCLUSIONS Inhaled allergen increases DCs in bone marrow and trafficking of DCs into the airway, which is associated with the development airway inflammation in subjects with allergic asthma. Inhaled allergen challenge also increases expression of TSLP, but not IL-33, receptors on bone marrow DCs.

Allergen-Induced Increases in Interleukin-25 and Interleukin-25 Receptor Expression in Mature Eosinophils from Atopic Asthmatics

Background: Interleukin (IL)-25 plays a pivotal role in type 2 immune responses. In a baseline cross-sectional study, we previously showed that IL-25 plasma levels and IL-25 receptor (IL-25R: IL-17RA, IL-17RB, and IL-17RA/RB) expression on mature blood eosinophils are increased in atopic asthmatics compared to normal nonatopic controls. This study investigated allergen-induced changes in IL-25 and IL-25R expression in eosinophils from asthmatics. Methods: Dual responder atopic asthmatics (n = 14) were enrolled in this randomized diluent-controlled crossover allergen challenge study. Blood was collected before and 24 h after the challenge. The surface expression of IL-25R was evaluated by flow cytometry on eosinophils and Th2 memory cells. In addition, plasma levels of IL-25 were measured by ELISA, and functional responses to IL-25 including type 2 cytokine expression, degranulation, and the migrational responsiveness of eosinophils were evaluated in vitro. Results: Following the allergen but not the diluent inhalation challenge, significant increases in the expression of IL-17RB and IL-17RA/B were found on eosinophils but not on Th2 memory cells. IL-25 plasma levels and the number of eosinophils but not of Th2 memory cells expressing intracellular IL-25 increased significantly in response to the allergen but not the diluent challenge. Stimulation with physiologically relevant concentrations of IL-25 in vitro caused (i) degranulation of eosinophils (measured by eosinophil peroxidase release), (ii) enhanced intracellular expression of IL-5 and IL-13, and (iii) priming of eosinophil migration to eotaxin. IL-25 stimulated intracellular cytokine expression, and the migration of eosinophils was blocked in the presence of a neutralizing IL-25 antibody. Conclusions: Our findings suggest that the IL-25/IL-25R axis may play an important role in promoting the recruitment and proinflammatory function of eosinophils in allergic asthma.

Toll‐like receptor‐induced expression of epithelial cytokine receptors on haemopoietic progenitors is altered in allergic asthma

Haemopoietic progenitor cells (HPC) migrate to sites of allergic inflammation where, upon stimulation with epithelial cytokines, they produce Th2 cytokines and differentiate into mature eosinophils and basophils. They also express Toll‐like receptors (TLR) involved in antimicrobial responses.

Anti-IgE and Biologic Approaches for the Treatment of Asthma

Current asthma treatments are effective for the majority of patients with mild-to-moderate disease. However, in those with more severe refractory asthma, agents other than inhaled corticosteroids and beta-agonists are needed both to better manage this group of patients and to avoid the side effects of high-dose corticosteroids and the social and personal hardship endured. Several biological pathways have been targeted over the last 20 years, and this research has resulted in pharmacological approaches to attempt to better treat patients with severe refractory asthma. The flagship of the biologics, the anti-IgE monoclonal antibody, omalizumab, has proven efficacious in selected subgroups of asthma patients. Tailoring asthma treatments to suit specific subtypes of asthma patients is in keeping with ideals of personalized medicine. Research in the complex interplay of allergens, epithelial host defenses, cytokines, and innate and adaptive immunity interactions has allowed better understanding of the mechanics of allergy and inflammation in asthma. As a result, new biologic treatments have been developed that target several different phenotypes and endotypes in asthma. As knowledge of the efficacy of these biological agents in asthma emerges, as well as the type of patients in whom they are most beneficial, the movement toward personalized asthma treatment will follow.