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Molecular Targets for Biological Therapies of Severe Asthma
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Molecular Targets for Biological Therapies of Severe Asthma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 51494

Special Issue Editor

Prof. Dr. Girolamo Pelaia

E-Mail Website
Guest Editor
Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy
Interests: COPD; eosinophilic asthma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). Within this context, in recent years several molecular effectors and signalling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic antibodies currently allow one to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. In addition to pro-allergic immunoglobulin E (IgE), which chronologically represents the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed, today other targets are successfully being exploited by biological treatments of severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor. Moreover, dupilumab behaves as a dual receptor antagonist of pleiotropic interleukins 4 (IL-4) and 13 (IL-13). Besides these drugs, which are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing severe asthma management on a global level. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, which are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. Such tailored strategies are thus allowing one to successfully target the immune-inflammatory responses underlying uncontrolled T2-high asthma.

Prof. Dr. Girolamo Pelaia
Guest Editor

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Keywords

  • IgE
  • IL-5
  • IL-4
  • IL-13
  • cytokine receptors
  • TSLP
  • monoclonal antibodies
  • omalizumab
  • mepolizumab
  • reslizumab
  • benralizumab
  • dupilumab
  • tezepelumab

Published Papers (15 papers)

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Research

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10 pages, 456 KiB  
Article
Biologics in Severe Eosinophilic Asthma: Three-Year Follow-Up in a SANI Single Center
by Paolo Solidoro, Stefania Nicola, Irene Ridolfi, Giorgio Walter Canonica, Francesco Blasi, Pierluigi Paggiaro, Enrico Heffler, Diego Bagnasco, Filippo Patrucco, Fulvia Ribolla, Caterina Bucca, Giovanni Rolla, Carlo Albera and Luisa Brussino
Biomedicines 2022, 10(2), 200; https://doi.org/10.3390/biomedicines10020200 - 18 Jan 2022
Cited by 7 | Viewed by 2135
Abstract
Introduction: Biologic drugs have dramatically improved severe eosinophilic asthma (SEA) outcomes. Our aim was to evaluate the long-term efficacy of biological therapy in SEA in a real-life setting and to identify the predictors for switching to another biological drug in patients with poor [...] Read more.
Introduction: Biologic drugs have dramatically improved severe eosinophilic asthma (SEA) outcomes. Our aim was to evaluate the long-term efficacy of biological therapy in SEA in a real-life setting and to identify the predictors for switching to another biological drug in patients with poor asthma control. The outcomes for efficacy were decreased annual exacerbations (AE) and improved asthma control test (ACT). Methods: In 90 SEA patients being treated with a biological drug, clinical examination, ACT, blood eosinophils count and spirometry were assessed before (T0) and after 6 (T1), 12 (T2), 24 (T3) and 36 (T4) months from the start of biological therapy. Patients were considered responders (R) or non-responders (NR) to biologics depending on whether or not they had less than two AE and a 20% increase in the ACT after 12 months of treatment. Results: 75% of the patients were R, 25% NR. In R patients, biological therapy add-on was followed by significant improvement in AE and ACT throughout the whole follow-up period. The percentage of patients on oral corticosteroids (OCS) dropped from 40% to 12%. By contrast, the NR patients were shifted to another biological drug after 12 months of therapy, as they still had high AE and nearly unchanged ACT; 40% of them still needed OCS treatment. The predictors of switching to another biological drug were three or more AE, ACT below 17, nasal polyposis and former smoking (p < 0.05). In NR, the shift to another biological drug was followed by a significant decrease in AE and an increase in the ACT. Discussion: This real-life study confirms the long-term efficacy of biologics in most SEA patients and indicates that even in non-responders to a first biological drug, it is worth trying a second one. It is hoped that the availability of additional biologics with different targets will help improve the personalization of SEA therapy. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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14 pages, 1327 KiB  
Article
Switch from Omalizumab to Benralizumab in Allergic Patients with Severe Eosinophilic Asthma: A Real-Life Experience from Southern Italy
by Corrado Pelaia, Claudia Crimi, Santi Nolasco, Giovanna Elisiana Carpagnano, Raffaele Brancaccio, Enrico Buonamico, Raffaele Campisi, Claudia Gagliani, Vincenzo Patella, Girolamo Pelaia, Giuseppe Valenti and Nunzio Crimi
Biomedicines 2021, 9(12), 1822; https://doi.org/10.3390/biomedicines9121822 - 03 Dec 2021
Cited by 16 | Viewed by 2771
Abstract
Background. The wide availability of monoclonal antibodies for the add-on therapy of severe asthma currently allows for the personalization of biologic treatment by selecting the most appropriate drug for each patient. However, subjects with overlapping allergic and eosinophilic phenotypes can be often eligible [...] Read more.
Background. The wide availability of monoclonal antibodies for the add-on therapy of severe asthma currently allows for the personalization of biologic treatment by selecting the most appropriate drug for each patient. However, subjects with overlapping allergic and eosinophilic phenotypes can be often eligible to more than one biologic, so that the first pharmacologic choice can be quite challenging for clinicians. Within such a context, the aim of our real-life investigation was to verify whether allergic patients with severe eosinophilic asthma, not adequately controlled by an initial biologic treatment with omalizumab, could experience better therapeutic results from a pharmacologic shift to benralizumab. Patients and methods. Twenty allergic patients with severe eosinophilic asthma, unsuccessfully treated with omalizumab and then switched to benralizumab, were assessed for at least 1 year in order to detect eventual changes in disease exacerbations, symptom control, oral corticosteroid intake, lung function, and blood eosinophils. Results. In comparison to the previous omalizumab therapy, after 1 year of treatment with benralizumab our patients experienced significant improvements in asthma exacerbation rate (p < 0.01), rescue medication need (p < 0.001), asthma control test (ACT) score (p < 0.05), forced expiratory volume in the first second (FEV1) (p < 0.05), and blood eosinophil count (p < 0.0001). Furthermore, with respect to the end of omalizumab treatment, the score of sino-nasal outcome test-22 (SNOT-22) significantly decreased after therapy with benralizumab (p < 0.05). Conclusion. The results of this real-life study suggest that the pharmacologic shift from omalizumab to benralizumab can be a valuable therapeutic approach for allergic patients with severe eosinophilic asthma, not adequately controlled by anti-IgE treatment. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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15 pages, 2809 KiB  
Article
Real-Life Effectiveness of Mepolizumab on Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity in Patients with Severe Eosinophilic Asthma
by Angelantonio Maglio, Carolina Vitale, Simona Pellegrino, Cecilia Calabrese, Maria D’Amato, Antonio Molino, Corrado Pelaia, Massimo Triggiani, Girolamo Pelaia, Cristiana Stellato and Alessandro Vatrella
Biomedicines 2021, 9(11), 1550; https://doi.org/10.3390/biomedicines9111550 - 27 Oct 2021
Cited by 12 | Viewed by 2024
Abstract
Severe eosinophilic asthma (SEA) is associated with high peripheral blood and airway eosinophilia, recurrent disease exacerbations and severe airflow limitation. Eosinophilic inflammation is also responsible for small airway disease (SAD) development. SEA patients experience poor disease control and response to standard therapy and [...] Read more.
Severe eosinophilic asthma (SEA) is associated with high peripheral blood and airway eosinophilia, recurrent disease exacerbations and severe airflow limitation. Eosinophilic inflammation is also responsible for small airway disease (SAD) development. SEA patients experience poor disease control and response to standard therapy and are prime candidates for anti-IL5 biologicals, such as mepolizumab, but the effect of treatment on SAD is unclear. We investigated the effect of mepolizumab on lung function in SEA patients, focusing on SAD parameters, and searched for an association between patients’ phenotypic characteristics and changes in small airways function. In this real-life study, data from 105 patients with SEA were collected at baseline and after 6, 12 and 18 months of mepolizumab treatment. Along with expected improvements in clinical and lung function parameters brought by Mepolizumab treatment, FEF2525-75% values showed a highly significant, gradual and persistent increase (from 32.7 ± 18.2% at baseline to 48.6 ± 18.4% after 18 months) and correlated with ACT scores at 18 months (r = 0.566; p ≤ 0.0001). A patient subgroup analysis showed that changes in FEF25-75% values were higher in patients with a baseline peripheral blood eosinophil count ≥400 cells/μL and oral corticosteroid use. Mepolizumab significantly improves small airway function. This effect correlates with clinical benefits and may represent an accessible parameter through which to evaluate therapeutic response. This study provides novel insights into the phenotypic characteristics associated with the improved functional outcome provided by mepolizumab treatment. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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11 pages, 1742 KiB  
Article
Omalizumab Restores Response to Corticosteroids in Patients with Eosinophilic Chronic Rhinosinusitis and Severe Asthma
by Yoshiki Kobayashi, Akira Kanda, Dan Van Bui, Yasutaka Yun, Linh Manh Nguyen, Hanh Hong Chu, Akitoshi Mitani, Kensuke Suzuki, Mikiya Asako and Hiroshi Iwai
Biomedicines 2021, 9(7), 787; https://doi.org/10.3390/biomedicines9070787 - 07 Jul 2021
Cited by 10 | Viewed by 2430
Abstract
Eosinophilic chronic rhinosinusitis (ECRS), which is a subgroup of chronic rhinosinusitis with nasal polyps, is characterized by eosinophilic airway inflammation extending across both the upper and lower airways. Some severe cases are refractory even after endoscopic sinus surgery, likely because of local steroid [...] Read more.
Eosinophilic chronic rhinosinusitis (ECRS), which is a subgroup of chronic rhinosinusitis with nasal polyps, is characterized by eosinophilic airway inflammation extending across both the upper and lower airways. Some severe cases are refractory even after endoscopic sinus surgery, likely because of local steroid insensitivity. Although real-life studies indicate that treatment with omalizumab for severe allergic asthma improves the outcome of coexistent ECRS, the underlying mechanisms of omalizumab in eosinophilic airway inflammation have not been fully elucidated. Twenty-five patients with ECRS and severe asthma who were refractory to conventional treatments and who received omalizumab were evaluated. Nineteen of twenty-five patients were responsive to omalizumab according to physician-assessed global evaluation of treatment effectiveness. In the responders, the levels of peripheral blood eosinophils and fractionated exhaled nitric oxide (a marker of eosinophilic inflammation) and of CCL4 and soluble CD69 (markers of eosinophil activation) were reduced concomitantly with the restoration of corticosteroid sensitivity. Omalizumab restored the eosinophil-peroxidase-mediated PP2A inactivation and steroid insensitivity in BEAS-2B. In addition, the local inflammation simulant model using BEAS-2B cells incubated with diluted serum from each patient confirmed omalizumab’s effects on restoration of corticosteroid sensitivity via PP2A activation; thus, omalizumab could be a promising therapeutic option for refractory eosinophilic airway inflammation with corticosteroid resistance. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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11 pages, 1171 KiB  
Article
T2-High Endotype and Response to Biological Treatments in Patients with Bronchiectasis
by Martina Oriano, Andrea Gramegna, Francesco Amati, Alice D’Adda, Michele Gaffuri, Marco Contoli, Francesco Bindo, Edoardo Simonetta, Carlotta Di Francesco, Martina Santambrogio, Giovanni Sotgiu, Francesco Blasi and Stefano Aliberti
Biomedicines 2021, 9(7), 772; https://doi.org/10.3390/biomedicines9070772 - 02 Jul 2021
Cited by 23 | Viewed by 2810
Abstract
Although bronchiectasis pathophysiology has been historically understood around the presence of airway neutrophilic inflammation, recent experiences are consistent with the identification of a type 2 inflammation (T2) high endotype in bronchiectasis. In order to evaluate prevalence and clinical characteristics of bronchiectasis patients with [...] Read more.
Although bronchiectasis pathophysiology has been historically understood around the presence of airway neutrophilic inflammation, recent experiences are consistent with the identification of a type 2 inflammation (T2) high endotype in bronchiectasis. In order to evaluate prevalence and clinical characteristics of bronchiectasis patients with a T2-high endotype and explore their response to biologicals, two studies were carried out. In a cross-sectional study, bronchiectasis adults without asthma underwent clinical, radiological, and microbiological assessment, along with blood eosinophils and oral fractional exhaled nitric oxide (FeNO) evaluation, during stable state. Prevalence and characteristics of patients with a T2- high endotype (defined by the presence of either eosinophils blood count ≥300 cells·µL−1 or oral FeNO ≥ 25 dpp) were reported. A case series of severe asthmatic patients with concomitant bronchiectasis treated with either mepolizumab or benralizumab was evaluated, and patients’ clinical data pre- and post-treatment were analyzed up to 2 years of follow up. Among bronchiectasis patients without asthma enrolled in the cross-sectional study, a T2-high endotype was present in 31% of them. These patients exhibited a more severe disease, high dyspnea severity, low respiratory function, and high impact on quality of life. Among the five patients with severe eosinophilic asthma and concomitant bronchiectasis included in the series, treatment with either mepolizumab or benralizumab significantly reduced the exacerbation rate with an effect that persists for up to 2 years of follow up. If validated across different settings, our data suggest the need to design randomized controlled trials on biological treatments targeting the T2-high endotype in bronchiectasis patients. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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11 pages, 797 KiB  
Article
Comparing Patient Characteristics, Clinical Outcomes, and Biomarkers of Severe Asthma Patients in Taiwan
by Shih-Lung Cheng, Kuo-Chin Chiu, Hsin-Kuo Ko, Diahn-Warng Perng, Hao-Chien Wang, Chong-Jen Yu, Chau-Chyun Sheu, Sheng-Hao Lin and Ching-Hsiung Lin
Biomedicines 2021, 9(7), 764; https://doi.org/10.3390/biomedicines9070764 - 01 Jul 2021
Cited by 2 | Viewed by 2088
Abstract
Purpose: To understand the association between biomarkers and exacerbations of severe asthma in adult patients in Taiwan. Materials and Methods: Demographic, clinical characteristics and biomarkers were retrospectively collected from the medical charts of severe asthma patients in six hospitals in Taiwan. Exacerbations were [...] Read more.
Purpose: To understand the association between biomarkers and exacerbations of severe asthma in adult patients in Taiwan. Materials and Methods: Demographic, clinical characteristics and biomarkers were retrospectively collected from the medical charts of severe asthma patients in six hospitals in Taiwan. Exacerbations were defined as those requiring asthma-specific emergency department visits/hospitalizations, or systemic steroids. Enrolled patients were divided into: (1) those with no exacerbations (non-exacerbators) and (2) those with one or more exacerbations (exacerbators). Receiver operating characteristic curves were used to determine the optimal cut-off value for biomarkers. Generalized linear models evaluated the association between exacerbation and biomarkers. Results: 132 patients were enrolled in the study with 80 non-exacerbators and 52 exacerbators. There was no significant difference in demographic and clinical characteristics between the two groups. Exacerbators had significantly higher eosinophils (EOS) counts (367.8 ± 357.18 vs. 210.05 ± 175.24, p = 0.0043) compared to non-exacerbators. The optimal cut-off values were 292 for EOS counts and 19 for the Fractional exhaled Nitric Oxide (FeNO) measure. Patients with an EOS count ≥ 300 (RR = 1.88; 95% CI, 1.26–2.81; p = 0.002) or FeNO measure ≥ 20 (RR = 2.10; 95% CI, 1.05–4.18; p = 0.0356) had a significantly higher risk of exacerbation. Moreover, patients with both an EOS count ≥ 300 and FeNO measure ≥ 20 had a significantly higher risk of exacerbation than those with lower EOS count or lower FeNO measure (RR = 2.16; 95% CI, 1.47–3.18; p = < 0.0001). Conclusions: Higher EOS counts and FeNO measures were associated with increased risk of exacerbation. These biomarkers may help physicians identify patients at risk of exacerbations and personalize treatment for asthma patients. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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13 pages, 5594 KiB  
Article
Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation
by Dong-Wook Kwak, Donghwan Park and Jae-Hong Kim
Biomedicines 2021, 9(5), 535; https://doi.org/10.3390/biomedicines9050535 - 11 May 2021
Cited by 6 | Viewed by 2232
Abstract
The stimulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and IL-1β synthesis are associated with chronic respiratory diseases such as neutrophil-dominant severe asthma. Leukotriene B4 (LTB4) is a principal chemoattractant molecule for neutrophil recruitment, and its [...] Read more.
The stimulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and IL-1β synthesis are associated with chronic respiratory diseases such as neutrophil-dominant severe asthma. Leukotriene B4 (LTB4) is a principal chemoattractant molecule for neutrophil recruitment, and its receptors BLT1 and BLT2 have been suggested to contribute to neutrophil-dominant asthmatic airway inflammation. However, the relationship between BLT1/2 and NLRP3 in neutrophil-dominant asthmatic airway inflammation has not been previously studied. In the present study, we investigated whether BLT1/2 play any roles in stimulating the NLRP3 inflammasome and IL-1βsynthesis. The blockade of BLT1 or BLT2 clearly suppressed the stimulation of the NLRP3 inflammasome and IL-1β synthesis in house dust mite (HDM)/lipopolysaccharide (LPS)-induced neutrophilic airway inflammation. The enzymes 5-lipoxygenase and 12-lipoxygenase, which catalyze the synthesis of BLT1/2 ligands [LTB4, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), and 12-hydroxyheptadecatreinoic acid (12-HHT)], were also critically associated with the stimulation of NLRP3 and IL-1β synthesis. Together, our results suggest that the 5-/12-LOX-BLT1/2-linked cascade are necessary for the simulation of the NLRP3 inflammasome and IL-1β synthesis, thus contributing to HDM/LPS-induced neutrophil-dominant airway inflammation. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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Review

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24 pages, 1667 KiB  
Review
Eosinophilic inflammation: An Appealing Target for Pharmacologic Treatments in Severe Asthma
by Alessandro Vatrella, Angelantonio Maglio, Corrado Pelaia, Luigi Ciampo, Giulia Pelaia and Carolina Vitale
Biomedicines 2022, 10(9), 2181; https://doi.org/10.3390/biomedicines10092181 - 03 Sep 2022
Cited by 11 | Viewed by 4336
Abstract
Severe asthma is characterized by different endotypes driven by complex pathologic mechanisms. In most patients with both allergic and non-allergic asthma, predominant eosinophilic airway inflammation is present. Given the central role of eosinophilic inflammation in the pathophysiology of most cases of severe asthma [...] Read more.
Severe asthma is characterized by different endotypes driven by complex pathologic mechanisms. In most patients with both allergic and non-allergic asthma, predominant eosinophilic airway inflammation is present. Given the central role of eosinophilic inflammation in the pathophysiology of most cases of severe asthma and considering that severe eosinophilic asthmatic patients respond partially or poorly to corticosteroids, in recent years, research has focused on the development of targeted anti-eosinophil biological therapies; this review will focus on the unique and particular biology of the eosinophil, as well as on the current knowledge about the pathobiology of eosinophilic inflammation in asthmatic airways. Finally, current and prospective anti-eosinophil therapeutic strategies will be discussed, examining the reason why eosinophilic inflammation represents an appealing target for the pharmacological treatment of patients with severe asthma. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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12 pages, 310 KiB  
Review
Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors
by Andrea Matucci, Emanuele Vivarelli, Francesca Nencini, Enrico Maggi and Alessandra Vultaggio
Biomedicines 2021, 9(10), 1497; https://doi.org/10.3390/biomedicines9101497 - 19 Oct 2021
Cited by 15 | Viewed by 3331
Abstract
Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial [...] Read more.
Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial asthma can be distinguished into type 2 (eosinophilic) or nontype 2 (noneosinophilic) endotypes. In type 2 asthma endotype, the pathogenic mechanism is sustained by an inflammatory process driven by Th2 cells, type 2 innate lymphoid cells (ILC2) and type 2 cytokines, which include interleukin (IL)-4, IL-5, IL-9 and IL-13. The definition of asthma and chronic rhinusinusitis phenotype/endotype is crucial, taking into account the availability of novel biologic agents, such as monoclonal antibodies targeting the classical type 2 cytokines. Recently, new therapeutic strategies have been proposed and analyzed in preliminary clinical trials. Among them Janus kinase (JAK) inhibitors, now largely used for the treatment of other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, is receiving great relevance. The rationale of this strategy derives from the data that JAK is a tyrosine kinase involved in the signaling of T cell receptor and of several cytokines that play a role in allergic respiratory disease, such as IL-2, IL-4 and IL-9. In this review, we discuss whether treatment with biological agents and JAK inhibitors may be equally effective in controlling type 2 inflammatory process in both asthma and CRS. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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15 pages, 642 KiB  
Review
Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological Therapies of Severe Asthma
by Corrado Pelaia, Giulia Pelaia, Federico Longhini, Claudia Crimi, Cecilia Calabrese, Luca Gallelli, Angela Sciacqua and Alessandro Vatrella
Biomedicines 2021, 9(9), 1108; https://doi.org/10.3390/biomedicines9091108 - 29 Aug 2021
Cited by 23 | Viewed by 6452
Abstract
Alarmins are innate cytokines, including thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25), which are mainly produced by airway epithelium and exert a prominent role in asthma pathobiology. In particular, several environmental factors such as allergens, cigarette smoking, airborne pollutants, and infectious [...] Read more.
Alarmins are innate cytokines, including thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25), which are mainly produced by airway epithelium and exert a prominent role in asthma pathobiology. In particular, several environmental factors such as allergens, cigarette smoking, airborne pollutants, and infectious agents trigger the release of alarmins, which in turn act as upstream activators of pro-inflammatory pathways underlying type 2 (T2-high) asthma. Indeed, alarmins directly activate group 2 innate lymphoid cells (ILC2), eosinophils, basophils, and mast cells and also stimulate dendritic cells to drive the commitment of naïve T helper (Th) cells towards the Th2 immunophenotype. Therefore, TSLP, IL-33, and IL-25 represent suitable targets for add-on therapies of severe asthma. Within this context, the fully human anti-TSLP monoclonal antibody tezepelumab has been evaluated in very promising randomized clinical trials. Tezepelumab and other anti-alarmins are thus likely to become, in the near future, valuable therapeutic options for the biological treatment of uncontrolled severe asthma. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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15 pages, 938 KiB  
Review
The Role of Dupilumab in Severe Asthma
by Fabio Luigi Massimo Ricciardolo, Francesca Bertolini and Vitina Carriero
Biomedicines 2021, 9(9), 1096; https://doi.org/10.3390/biomedicines9091096 - 27 Aug 2021
Cited by 17 | Viewed by 7292
Abstract
Dupilumab is a fully humanized monoclonal antibody, capable of inhibiting intracellular signaling of both interleukin (IL)-4 and IL-13. These are two molecules that, together with other proinflammatory cytokines such as IL-5 and eotaxins, play a pivotal role in orchestrating the airway inflammatory response [...] Read more.
Dupilumab is a fully humanized monoclonal antibody, capable of inhibiting intracellular signaling of both interleukin (IL)-4 and IL-13. These are two molecules that, together with other proinflammatory cytokines such as IL-5 and eotaxins, play a pivotal role in orchestrating the airway inflammatory response defined as Type 2 (T2) inflammation, driven by Th2 or Type 2 innate lymphoid cells, which is the major feature of the T2 high asthma phenotype. The dual inhibition of IL-4 and IL-13 activities is due to the blockade of type II IL-4 receptor through the binding of dupilumab with the subunit IL-4Rα. This results in the repression of STAT6 and in the suppression of subsequent de novo formation of several molecules involved in the T2 inflammatory signature. Several clinical trials tested the efficacy and safety of dupilumab in large populations of uncontrolled severe asthmatics, revealing significant improvements in lung function, asthma control, and exacerbation rate. Similar results were reported when dupilumab was employed in patients harboring pathogenetic processes related to T2 immune response, such as atopic dermatitis and chronic rhinosinusitis. In this review, we provide an overview of the recent research in the field of respiratory medicine about dupilumab mechanism of action and its effects. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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13 pages, 982 KiB  
Review
Biologic Therapy and Severe Asthma in Children
by Daniele Russo, Paola Di Filippo, Marina Attanasi, Mauro Lizzi, Sabrina Di Pillo and Francesco Chiarelli
Biomedicines 2021, 9(7), 760; https://doi.org/10.3390/biomedicines9070760 - 30 Jun 2021
Cited by 15 | Viewed by 3126
Abstract
Severe asthma is a heterogeneous, complex and chronic disease widespread in the pediatric population. According to the recent findings about the different endotypes of asthma in children, each one characterized by specific intracellular molecular pathways, several innovative biologic therapies have been developed. Due [...] Read more.
Severe asthma is a heterogeneous, complex and chronic disease widespread in the pediatric population. According to the recent findings about the different endotypes of asthma in children, each one characterized by specific intracellular molecular pathways, several innovative biologic therapies have been developed. Due to their precise ability to target specific inflammatory type 2 mediators, biologics have revolutionized the care of chronic allergic diseases in the pediatric and adult population. In this review, we aim to provide the latest evidence about the use, indications, efficacy and safety of biologic therapies to treat severe asthma in children and adolescents. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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11 pages, 1276 KiB  
Review
Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab
by Francesco Menzella, Giulia Ghidoni, Carla Galeone, Silvia Capobelli, Chiara Scelfo and Nicola Cosimo Facciolongo
Biomedicines 2021, 9(4), 348; https://doi.org/10.3390/biomedicines9040348 - 30 Mar 2021
Cited by 10 | Viewed by 3097
Abstract
Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In [...] Read more.
Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although extremely limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which can stabilize the effector cells, and is becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allow a great improvement in the management of asthma. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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15 pages, 514 KiB  
Systematic Review
Effects of Therapeutic Antibodies on Gene and Protein Signatures in Asthma Patients: A Comparative Systematic Review
by Maria J. Martin, Miguel Estravís, Asunción García-Sánchez, Jacqueline Pérez-Pazos, María Isidoro-García, Ignacio Dávila and Catalina Sanz
Biomedicines 2022, 10(2), 293; https://doi.org/10.3390/biomedicines10020293 - 27 Jan 2022
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Abstract
Several biologic therapies that target inflammatory modulators are now used for treating patients with uncontrolled, severe asthma. Knowledge about how this type of treatment modifies the molecular milieu is rapidly increasing. Thus, this systematic review aimed to compile the reported effects of therapeutic [...] Read more.
Several biologic therapies that target inflammatory modulators are now used for treating patients with uncontrolled, severe asthma. Knowledge about how this type of treatment modifies the molecular milieu is rapidly increasing. Thus, this systematic review aimed to compile the reported effects of therapeutic antibodies on the transcriptome or proteome of asthma patients. Studies of asthmatic patients under biological treatment describing transcriptomic or proteomic changes upon treatment were included. Preclinical or single gene/protein studies were not considered. PubMed and Scopus search was performed in August and September 2021. Following PRISMA guidelines and GRADE recommendations, we selected 12 studies on gene or protein expression changes in patients treated with the antibodies currently approved by EMA and the FDA. All studies were at low risk of bias as per the RoB2 tool. Different gene clusters have been identified to change upon omalizumab treatment, found a reduction in eosinophil-associated gene signatures after benralizumab treatment, and protein profiles were different in patients treated with mepolizumab and in those treated with benralizumab. The main potential biomarkers proposed by the selected studies are shown. These results may contribute to discovering biomarkers of response and selecting the best therapy for each patient. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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18 pages, 1076 KiB  
Systematic Review
The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review
by Luigino Calzetta, Marina Aiello, Annalisa Frizzelli, Giuseppina Bertorelli, Beatrice Ludovica Ritondo, Paola Rogliani and Alfredo Chetta
Biomedicines 2021, 9(9), 1281; https://doi.org/10.3390/biomedicines9091281 - 21 Sep 2021
Cited by 15 | Viewed by 3482
Abstract
Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma [...] Read more.
Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma pathogenesis, the overexpression of several type 2 inflammatory mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with ASM hyperreactivity, all of which can be targeted by humanized monoclonal antibodies (mAbs). Therefore, the aim of this review was to systematically assess evidence across the literature on mAbs for the treatment of asthma with respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab were found to be effective in modulating the contractility of the ASM and preventing the AHR, but no available studies concerning the impact of reslizumab on the ASM were identified from the literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate the ASM in asthma, by specifically blocking the interaction between IgE, IL-4, and TSLP, and their receptors are located on the surface of ASM cells. Conversely, mepolizumab and benralizumab have prevalently indirect impacts against AHR by targeting eosinophils and other immunomodulatory effector cells promoting inflammatory processes. AHR has been suggested as the main treatable trait towards precision medicine in patients suffering from eosinophilic asthma, therefore, well-designed head-to-head trials are needed to compare the efficacy of those mAbs that directly target ASM contractility specifically against the AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab. Full article
(This article belongs to the Special Issue Molecular Targets for Biological Therapies of Severe Asthma)
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