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Tezepelumab: a Potential New Biological Therapy for Severe Refractory Asthma

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Tezepelumab: a Potential New Biological Therapy for Severe Refractory Asthma International Journal of Molecular Sciences Review Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma Corrado Pelaia 1,* , Giulia Pelaia 2, Claudia Crimi 3, Angelantonio Maglio 4 , Luca Gallelli 1 , Rosa Terracciano 5 and Alessandro Vatrella 4 1 Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; [email protected] 2 Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; [email protected] 3 Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy; [email protected] 4 Department of Medicine, Surgery, and Dentistry, University of Salerno, 84084 Salerno, Italy; [email protected] (A.M.); [email protected] (A.V.) 5 Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0961-3647007; Fax: +39-0961-3647193 Abstract: Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells Citation: Pelaia, C.; Pelaia, G.; Crimi, involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody C.; Maglio, A.; Gallelli, L.; that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary Terracciano, R.; Vatrella, A. results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and Tezepelumab: A Potential New efficacy profile in patients with severe, uncontrolled asthma. Biological Therapy for Severe Refractory Asthma. Int. J. Mol. Sci. Keywords: asthma; alarmins; TSLP; tezepelumab 2021, 22, 4369. https://doi.org/ 10.3390/ijms22094369 Academic Editor: Nicola Scichilone 1. Introduction Received: 28 March 2021 Asthma is a chronic obstructive respiratory disease, mainly characterized by airflow Accepted: 18 April 2021 limitation due to bronchial inflammation and airway remodeling [1,2]. A hallmark of Published: 22 April 2021 asthma is the heterogeneity of airway inflammation, expressed by several phenotypes sustained by underlying different endotypes, which consist of complex cellular and molec- Publisher’s Note: MDPI stays neutral ular pathogenic mechanisms (Figure1)[ 3–5]. The most frequent endotypes are grouped with regard to jurisdictional claims in under the umbrella term “type 2” (T2) asthma, which includes allergic and non-allergic published maps and institutional affil- traits, mostly outlined by eosinophilic inflammation [6,7]. Differently from type 2 airway iations. inflammation, T2-low asthma can be featured by either neutrophilic or paucigranulocytic patterns [8–10]. In addition to chronic inflammation, all asthma endotypes are often characterized by airway structural changes, which span throughout the various layers of the bronchial Copyright: © 2021 by the authors. wall [11]. These remodeling features include goblet cell metaplasia/hyperplasia, subep- Licensee MDPI, Basel, Switzerland. ithelial fibrosis sustained by activation of fibroblasts and myofibroblasts, smooth muscle This article is an open access article thickening, and neo-angiogenesis [11]. distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 4369. https://doi.org/10.3390/ijms22094369 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4369 2 of 13 Figure 1. Putative role of TSLP in several asthma pathways. In allergic asthma, via activation of dendritic cells, TSLP promotes the differentiation of Th2 lymphocytes secreting IL-4, IL-5, IL-9, and IL-13, which target B cells, eosinophils, mast cells, and airway smooth muscle cells, respectively. IL-4 and IL-13 are also produced by basophils. In non-allergic eosinophilic asthma, TSLP stimulates ILC2 to release IL-5 and IL-13. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of neutrophil-activating Th17 lymphocytes. In paucigranulocytic asthma, TSLP mediates the complex crosstalks involving inflammatory cellular elements, such as mast cells, and airway structural cells including epithelial cells, fibroblasts, and smooth muscle cells. TSLP: thymic stromal lymphopoetin; Th: T helper; ILC2: group 2 innate lymphoid cells; IL: interleukin; TGF-β: transforming growth factor-β. This original figure was created by the authors using BioRender.com. In T2-high asthma, the development, persistence, and amplification of eosinophilic inflammation are driven and orchestrated by multiple cellular elements including den- dritic cells, T helper 2 (Th2) lymphocytes, group 2 innate lymphoid cells (ILC2), mast cells, basophils, and airway epithelial cells [12–14]. Within this endotypic context, a key pathophysiologic role is played by thymic stromal lymphopoietin (TSLP), an innate cy- tokine especially involved in type 2 eosinophilic inflammation, but also implicated in neutrophilic and paucigranulocytic asthma [15–17]. Indeed, TSLP stimulates dendritic cells to guide the differentiation of naïve Th cells towards the Th2 lineage, but can also promote Th17 commitment [15]. Moreover, TSLP activates ILC2, mast cells, and basophils, induces eosinophil survival and transmigration, and also affects the functions of airway structural cells such as fibroblasts and airway smooth muscle cells [15]. Most patients with mild or moderate asthma are well controlled by inhaled corticos- teroids (ICS), eventually integrated by the addition of long-acting β2-adrenergic agonists (LABA) within ICS/LABA fixed combinations [18]. Furthermore, asthmatics with more severe disease may need additional medications such as leukotriene modifiers, tiotropium, and even oral corticosteroids (OCS) [19,20]. Despite all these treatments, severe asthma can remain uncontrolled, thus requiring adjunctive biological therapies based on the use Int. J. Mol. Sci. 2021, 22, 4369 3 of 13 of monoclonal antibodies directed against immunoglobulins E (IgE), interleukin 5 (IL-5), IL-5 receptor, or interleukin-4 (IL-4) receptor [21–26]. These are excellent add-on treat- ments, but they could not be effective for all patients with severe T2-high asthma, and they do not provide any benefit for T2-low asthmatic patients. In particular, the most relevant goals of biological therapies for severe asthma include the decreases in both ex- acerbation rate and OCS intake, as recently highlighted by the PONENTE trial (Study NCT03557307, https://clinicaltrials.gov/ website. Poster presentation at the American Academy of Allergy Asthma & Immunology, 26 February–1 March 2021). In addition to the already approved, above-mentioned anti-asthma biologics, other monoclonal antibodies are currently undergoing clinical investigation, which might poten- tially guarantee a wider coverage of therapeutic advantages [27]. Among the latter, one of the most promising biologic drugs for asthma treatment is tezepelumab, a fully human monoclonal antibody that specifically interacts with TSLP, thus preventing its binding to the TSLP receptor complex [28]. Given the relevant importance of TSLP as a master player of asthma pathobiology, this alarmin, acting as an upstream inducer of strategic proinflammatory and remodeling pathways, appears to be a potential suitable target for perspective biological therapies of severe asthma. Therefore, tezepelumab deserves close attention as a possible future anti-asthma biologic. In light of the above considerations, this article aims to review the role of TSLP in asthma pathophysiology, as well as to discuss the therapeutic properties of tezepelumab as an eventual add-on treatment option for severe asthma. 2. Pathogenic Role of TSLP in Asthma Originally identified in thymic stromal cells, TSLP is an innate pleiotropic cytokine belonging to the four-helix-bundle cytokine family and is distantly related to interleukin-7 (IL-7) [29]. Two TSLP variants exist, including a long isoform (159 amino acids) and a short one (60 amino acids), whose expressions are respectively regulated by different gene promoters, which are responsive to distinct patterns of environmental agents [30,31]. Short TSLP is constitutively present in many tissues where it plays a homeostatic role, whilst the production of the long isoform can be induced by proinflammatory stimuli and is increased in asthmatic patients [31]. The long variant of TSLP exerts its biological functions by selectively binding to its cognate receptor (TSLPR), and this interaction is promoted by the electrostatic attraction occurring between the positive charges of TSLP surface and the negative charges of TSLPR [32,33]. The resulting TSLP/TSLPR binary molecular aggregate in turn recruits the α subunit of the IL-7 receptor (IL-7Rα). As a consequence, the assembly of the extracellular ternary complex TSLP/TSLPR/IL-7Rα leads to activation of an intracellular signaling network including Janus kinases 1 and 2 (JAK1/2), signal transducers and activators of transcription 3 and 5 (STAT3/5), as well as nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPK), and phosphoinositide 3 kinase
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