Anti-IL5 therapy for asthma and beyond

Abstract

Airway inflammation is considered to be the primary component contributing to the heterogeneity and severity of airway disorders. Therapeutic efficacies of diverse novel biologics targeting the inflammatory pathways are under investigation. One such target is IL-5, a type-1 cytokine that is central to the initiation and sustenance of eosinophilic airway inflammation. Over the past decade, anti-IL5 molecules have been documented to have mixed therapeutic benefits in asthmatics. Post hoc analyses of the trials reiterate the importance of identifying the IL-5-responsive patient endotypes. In fact, the currently available anti-IL5 treatments are being considered beyond asthma management; especially in clinical complications with an underlying eosinophilic pathobiology such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis and polyangitis (EGPA). In addition, closer analyses of the available data indicate alternative mechanisms of tissue eosinophilia that remain uncurbed with the current dosage and delivery platform of the anti-IL5 molecules.

Keywords: Benralizumab; Chronic bronchitis; Chronic obstructive pulmonary disorder (COPD); Churg-strauss syndrome; Eosinophil; Eosinophilic asthma; Eosinophilic granulamatosis and polyangitis (EGPA); Hypereosinophilic syndrome (HES); IL-5; Mepolizumab; Reslizumab.

Figure 1

A schematic representation of eosinophilia in the airways. The figure portrays (A) the complex eosinophil biology: Maturation: CD34⁺ myeloid progenitor cells (bone-marrow) differentiate into the IL5α⁺ CCR3⁺ eosinophil-committed progenitor cells under the influence of the different transcription factors like GATA2 and C/EBPα. IL-5, IL-3 and GM-CSF stimulate their further maturation into eosinophils. Migration: release into the circulation is coordinated synergistically by IL-5 and eotaxin. Transmigration: under the influence of IL-5 and eotaxin, the eosinophils ‘seep’ out through the endothelium. Recruitment: Eosinophil trafficking into the site of inflammation is selectively regulated by IL-5, eotaxin and CCL5, in addition to a multitude of cytokines. Activation: IL-5 binds to IL-5Rα and activates eosinophils to release a multitude of cytokines, eosinophilic granular proteins, cysteinyl leukotrienes, that lead to tissue damage and further aggravates the inflammatory process. Survival and stabilisation: IL-5 released from different sources and products from mast cell (MC) degranulation suppresses apoptosis and allows survival of eosinophils in the submucosa. (B) Different sources of IL-5 (in red) and sustenance of eosinophilia: (i) the canonical T_H2 pathway initiated by dendritic cell (DC) activation releases IL-5. (ii) MC activation is another source of IL-5 that can be triggered by IgE binding to the FCϵRI receptor or by epithelial-derived Type 2 alarmins like TSLP and IL33; or via T_H9 pathway (iii) Type-2 alarmins (IL-33, IL-25, TSLP) can activate the lineage negative ID2⁺ lymphoid cells resident in the tissue to differentiate into lineage negative ILC₂s that can release IL-5 and IL-13, and drive eosinophilic inflammation (iv) IL-13 and IL-4 can recruit CD34⁺ progenitors cells from bone marrow into the lung tissue where it can differentiate into eosinophils in presence of IL-5. N.B. Diagram is not up to scale. Mechanisms relevant to only eosinophilic inflammation has been included.