biomedicines Review Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological Therapies of Severe Asthma Corrado Pelaia 1,* , Giulia Pelaia 2, Federico Longhini 2 , Claudia Crimi 3 , Cecilia Calabrese 4, Luca Gallelli 1 , Angela Sciacqua 2 and Alessandro Vatrella 5 1 Department of Health Sciences, University “Magna Graecia” of Catanzaro, Viale Europa-Località Germaneto, 88100 Catanzaro, Italy; [email protected] 2 Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; [email protected] (G.P.); [email protected] (F.L.); [email protected] (A.S.) 3 Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy; [email protected] 4 Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; [email protected] 5 Department of Medicine, Surgery, and Dentistry, University of Salerno, 84084 Salerno, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0961-3647007; Fax: +39-0961-3647193 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 agents trigger the release of alarmins, which in turn act as upstream activators of pro-inflammatory pathways underlying type 2 (T2-high) asthma. Citation: Pelaia, C.; Pelaia, G.; Indeed, alarmins directly activate group 2 innate lymphoid cells (ILC2), eosinophils, basophils, and Longhini, F.; Crimi, C.; Calabrese, C.; mast cells and also stimulate dendritic cells to drive the commitment of naïve T helper (Th) cells Gallelli, L.; Sciacqua, A.; Vatrella, A. Monoclonal Antibodies Targeting towards the Th2 immunophenotype. Therefore, TSLP, IL-33, and IL-25 represent suitable targets Alarmins: A New Perspective for for add-on therapies of severe asthma. Within this context, the fully human anti-TSLP monoclonal Biological Therapies of Severe antibody tezepelumab has been evaluated in very promising randomized clinical trials. Tezepelumab Asthma. Biomedicines 2021, 9, 1108. and other anti-alarmins are thus likely to become, in the near future, valuable therapeutic options for https://doi.org/10.3390/ the biological treatment of uncontrolled severe asthma. biomedicines9091108 Keywords: asthma; TSLP; IL-33; IL-25; tezepelumab; anti-alarmins Academic Editors: Hiroshi Wakao and Berislav Bošnjak Received: 18 July 2021 1. Introduction Accepted: 26 August 2021 Published: 29 August 2021 Asthma is a chronic inflammatory disease of the respiratory tract, usually characterized by variable airflow limitation and affecting more than 300 million people worldwide [1,2]. Publisher’s Note: MDPI stays neutral Asthma phenotypes are heterogeneous and include eosinophilic patterns, underpinned by either with regard to jurisdictional claims in allergic or non-allergic mechanisms, as well as neutrophilic and paucigranulocytic traits [3–5]. published maps and institutional affil- Eosinophilic asthma is driven by complex cellular and molecular pathways which shape the iations. so-called type 2 (T2-high) airway inflammation, a term based on the key pathogenic roles played by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2), releasing the interleukins 4 (IL-4), 5 (IL-5), 9 (IL-9), and 13 (IL-13) [6–8]. Within this pathobiological context, the bronchial epithelium exerts pivotal functions by producing three innate cytokines named alarmins, which include thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. interleukin-25 (IL-25) [9–11]. The secretion of these cytokines occurs when airway epithelial cells This article is an open access article undergo injuries caused by several environmental triggers such as allergens, respiratory viruses, distributed under the terms and bacteria, cigarette smoking, and airborne pollutants (Figure1) [ 12]. Therefore, TSLP,IL-33, and conditions of the Creative Commons IL-25 provide alarm signals which solicit the immune system to react to bronchial epithelial Attribution (CC BY) license (https:// damage [9]. As a consequence, these alarmins behave as upstream activators of both innate and creativecommons.org/licenses/by/ adaptive immune responses involved in type 2 asthma (Figure1). Indeed, alarmins are able to 4.0/). induce conventional dendritic cells to drive the differentiation and expansion of Th2 cells, as Biomedicines 2021, 9, 1108. https://doi.org/10.3390/biomedicines9091108 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 15 1) [12]. Therefore, TSLP, IL-33, and IL-25 provide alarm signals which solicit the immune Biomedicines 2021, 9system, 1108 to react to bronchial epithelial damage [9]. As a consequence, these alarmins 2 of 15 behave as upstream activators of both innate and adaptive immune responses involved in type 2 asthma (Figure 1). Indeed, alarmins are able to induce conventional dendritic cells to drive the differentiation and expansion of Th2 cells, as well as to directly promote ILC2 activationwell and as proliferation to directly promote [13]. Moreover, ILC2 activation by stimulating and proliferation the commitment [13]. Moreover, of naïve by stimulating the Th lymphocytescommitment towards the of Th17 naïve cellular Th lymphocytes immunophenotype, towards the Th17 TSLP cellular can also immunophenotype, contribute TSLP can to the pathogenesisalso contribute of T2-low to neutrophilic the pathogenesis asthma of T2-low[14]. neutrophilic asthma [14]. Figure 1. PathogenicFigure 1. Pathogenic actions of alarmins actions of in alarmins type 2 asthma. in type As 2 aasthma. result ofAs injuries a result caused of injuries by several caused noxious by several agents, airway epithelial cellsnoxious release agents, alarmins airway (TSLP, epithelial IL-33, andcells IL-25).release Thesealarmins cytokines (TSLP, induce IL-33, theand activationIL-25). These of the cytokines adaptive immune induce the activation of the adaptive immune system, thus driving dendritic cell-mediated system, thus driving dendritic cell-mediated differentiation of Th2 lymphocytes, leading to B cell-dependent production of differentiation of Th2 lymphocytes, leading to B cell-dependent production of immunoglobulins E immunoglobulins E (IgE). Alarmins also elicit innate immune responses by directly stimulating group 2 innate lymphoid (IgE). Alarmins also elicit innate immune responses by directly stimulating group 2 innate lymphoid cells (ILC2),cells eosinophils, (ILC2), eosinophils, basophils, andbasophils, mast cells. and Uponmast cells activation. Upon induced activation by induce alarmins,d by Th2 alarmins, and ILC2 Th2 cells and release high amounts ofILC2 IL-4, cells IL-5, release and IL-13. high This amounts original of figureIL-4, IL-5, was createdand IL-13. by theThis authors original using figure “BioRender.com” was created by (accessedthe on 8 August 2021).authors using “BioRender.com”(accessed on 8 August 2021). Because of theirBecause relevant of pathogenic their relevant functi pathogenicons, alarmins functions, represent alarmins suitable represent molecular suitable molecular targets for emergingtargets biological for emerging therapies biological of asthma therapies [15–20]. of asthma In particular, [15–20]. In neutralization particular, neutralization of of alarmins viaalarmins specific viaantibodies specific potentiall antibodiesy potentiallyprovides an provides effective an therapeutic effective therapeutic strategy strategy capa- capable of interferingble of interfering at a very at upstream a very upstream level with level the with complex the complex immunopathologic immunopathologic cascades cascades leadingleading to type to type2 asthma. 2 asthma. In fact, In fact, this this approach approach can can impact impact more more broadly broadly on on asthma patho- asthma pathobiologybiology withwith respect respect to currentto current downstream downstream therapies therapies targeting circumscribedtargeting pathways circumscribed mediatedpathways bymediated single cytokinesby single cytokines (IL-4, IL-5, (IL-4, and IL-5, IL-13) and or receptorsIL-13) or receptors (IL-4 receptor and IL-5 (IL-4 receptor andreceptor) IL-5 receptor) [21]. Among [21]. anti-alarmins, Among anti-alarmins, the most studiedthe most anti-TSLP studied anti-TSLP monoclonal antibody in monoclonal antibodyclinical trialsin clinical is tezepelumab trials is [20 ,tezepelumab22,23]; some anti-IL-33[20,22,23]; antibodies some anti-IL-33 are under investigation, whereas no anti-IL-25 drug has entered clinical evaluation so far [18]. In this regard, it antibodies are under investigation, whereas no anti-IL-25 drug has entered clinical is noteworthy that anti-alarmins could induce effective therapeutic benefits for patients evaluation so far [18]. In this regard, it is noteworthy that anti-alarmins could induce with uncontrolled T2-high asthma by lowering disease exacerbations, as well as by im- effective therapeutic benefits for patients with uncontrolled T2-high asthma by lowering proving symptom control, lung function, quality of life, and oral corticosteroid (OCS) disease exacerbations, as well as by improving symptom control, lung function, quality of dependence [18,20].