Reslizumab and Eosinophilic Asthma: One Step Closer to Precision Medicine?

Abstract

Human eosinophils represent approximately 1% of peripheral blood leukocytes. However, these cells have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophilic inflammation is present in a significant proportion of patients with severe asthma. Asthma is a chronic inflammatory disorder that affects more than 315 million people worldwide, with 10% having severe uncontrolled disease. Although the majority of patients can be efficiently treated, severe asthmatics continue to be uncontrolled and are at risk of exacerbations and even death. Interleukin-5 (IL-5) plays a fundamental role in eosinophil differentiation, maturation, activation and inhibition of apoptosis. Therefore, targeting IL-5 is an appealing approach to the treatment of patients with severe eosinophilic asthma. Reslizumab, a humanized anti-IL-5 monoclonal antibody, binds with high affinity to amino acids 89-92 of IL-5 that are critical for binding to IL-5 receptor α. Two phase III studies have demonstrated that reslizumab administration in adult patients with severe asthma and eosinophilia (≥400 cells/μL) improved lung function, asthma control, and symptoms. Thus, the use of blood eosinophils as a baseline biomarker could help to select patients with severe uncontrolled asthma who are likely to achieve benefits in asthma control with reslizumab. In conclusion, targeted therapy with reslizumab represents one step closer to precision medicine in patients with severe eosinophilic asthma.

Keywords: IL-5 receptor; anti-IL-5; asthma; eosinophils; interleukin-5; reslizumab.

Figure 1

Eosinophils and their mediators activate or modulate a plethora of cells of the innate and adaptive immune system. Major basic protein (MBP) activates human neutrophils. Eosinophils prime/activate human basophils and mast cells through the release of cytokines [interleukin-5 (IL-5), interleukin-5 (IL-3), granulocyte-macrophage colony-stimulating (GM-CSF), NGF, and PGD₂] or cationic proteins [eosinophil cationic protein (ECP), MBP, and eosinophil peroxidase (EPX)]. IL-4 and IL-13 favor M2 polarization of macrophages. EDN promotes the migration, maturation, and activation of dendritic cells (DCs). Eosinophils can act as antigen-presenting cells to initiate T cell responses and contribute to the recruitment of Th2 cells by producing the chemokines CCL17 and CCL22. These cells also favor T follicular helper (Tfh) cell maturation via the production of IL-6. Eosinophils promote B cell proliferation through an unknown mechanism. Eosinophils prime B cells and sustain plasma cells through the production of APRIL and IL-6. MBP and EPX induce platelet aggregation.

Figure 2

Interleukin-5 (IL-5) plays a fundamental role in the growth, maturation, and activation of human eosinophils. Group 2 innate lymphoid cell (ILC2), Th2 cells, mast cells, natural killer cells (NK T cells), and eosinophils themselves produce IL-5. This cytokine specifically binds to IL-5 receptor α (IL-5Rα) and recruits the βc subunit on the membrane of eosinophils. The βc subunit is the signal-transducing molecule shared with IL-3 and granulocyte-macrophage colony-stimulating (GM-CSF). This IL-5Rα/βc interaction leads to a series of biochemical events that control eosinophil differentiation and maturation in the bone marrow, cell migration to the site of allergic inflammation, the release of pro-inflammatory mediators, and inhibition of apoptosis. IL-3 and presumably GM-CSF, through binding to the βc of IL-5 receptor, can also function as eosinophil survival factors. Reslizumab binds with high affinity (K_d of approximately 50 pM) to amino acids 89–92 of human IL-5 that are critical for binding to IL-5Rα, resulting in inhibition of eosinophil maturation and activation.