Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs

Abstract

Purpose of review: Human eosinophils were first identified and named by Paul Ehrlich in 1879 on the basis of the cell's granular uptake of eosin. Although eosinophils represent approximately 1% of peripheral blood leukocytes, they have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophils and their mediators are critical effectors to asthma and eosinophilic granulomatosis with polyangiitis (EGPA). Eosinophils are equipped with a large number of cell-surface receptors and produce specific cytokines and chemokines.

Recent findings: Eosinophils are the major source of interleukin-5 and highly express the interleukin-5Rα on their surface. Clinical trials evaluating monoclonal antibodies to interleukin-5 (mepolizumab and reslizumab) and its receptor interleukin-5Rα (benralizumab) have been or are underway in patients with eosinophilic asthma, EGPA and chronic obstructive pulmonary disease (COPD). Overall, targeting interleukin-5/interleukin-5Rα is associated with a marked decrease in blood and sputum eosinophilia, the number of exacerbations and improvement of some clinical parameters in adult patients with severe eosinophilic asthma. Pilot studies suggest that mepolizumab might be a glucocorticoid-sparing treatment in patients with EGPA. A preliminary study found that benralizumab did not reduce the exacerbations and did modify lung function in patients with eosinophilic COPD.

Summary: The review examines recent advances in the biology of eosinophils and how targeting the interleukin-5 pathway might offer benefit to some patients with severe asthma, EGPA, and COPD. Interleukin-5/interleukin-5Rα-targeted treatments offer promises to patients with eosinophilic respiratory disorders.

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FIGURE 1

Human eosinophils display a wide spectrum of surface receptors that are important for their pleiotropic functions. Eosinophils express cell-surface receptors for cytokines and growth factors, chemokines, adhesion molecules, lipid mediators, chemoattractants, complement, immunoglobulins, Siglecs, histamine, PIRs, PARs, PPRs, CD40, CD80/CD86, and MHC class II. The epidermal growth factor-like module containing mucin-like hormone receptor 1 (EMR1) appears truly eosinophil specific [17]. Eosinophils contain the glucocorticoid receptor in high copy number [19]. The α variant of the glucocorticoid receptor is five-fold higher in eosinophils than in neutrophils making these cells highly susceptible to the therapeutic effects of glucocorticoids. Eosinophils contain specific granules containing several cationic proteins, primary granules, lipid bodies, and sombrero vesicles. CC, chemokine ligand; CCR, CC-chemokine receptor; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor; PIRs, paired immunoglobulin-like receptors; PARs, proteinase-activated receptors; PPRs, pattern-recognition receptors.

FIGURE 2

Eosinophils contain and/or release a wide array of preformed and de novo synthesized mediators important for their effector functions. Specific granules contain several cationic proteins, including MBP, ECP, EDN, and EPX. Eosinophils can degranulate by exocytosis or by piecemeal degranulation whereby individual granule contents are differentially secreted by activated eosinophils without disruption of the cell membrane. Sombrero vesicles are morphologically distinct vesicles that carry granules to the plasma membrane. Lipid bodies are structurally distinct sites within eosinophils that are responsible for synthesis of eicosanoid mediators of inflammation [26]. Eosinophils produce numerous chemokines, cytokines, growth and angiogenic factors that mediate allergic inflammation, fibrosis, and thrombosis. Eosinophils generate extracellular DNA traps [24] and secrete exosomes [27]. A nonexhaustive list of these products is shown in boxes. ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPX, eosinophil peroxidase; MBP, major basic protein; PAF, platelet activating factor; PDGF, platelet-derived growth factor; SCF, stem cell factor; TF, tissue factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

FIGURE 3

Eosinophils modulate the functions of a multitude of cells of the innate and adaptive immune system. Although not professional antigen-presenting cells (APC), eosinophils can express MHC class II and costimulatory molecules (CD80 or CD86), process antigens and stimulate T cells to proliferate and produce cytokines in an antigen-specific manner. Acting with dendritic cells (DCs), eosinophils regulate the recruitment of T helper 2 (T_h2) cells in response to allergen sensitization by producing CCL17 and CCL22. Eosinophil can also favor T follicular helper (T_fh) cell differentiation through the production of interleukin-6 [35]. Eosinophils also prime B cells and sustain long-lived plasma cells in bone marrow via the production of APRIL and interleukin-6. Eosinophils stimulated by CpG DNA and by EDN promotes the maturation and activation of DCs. MBP activates neutrophils causing the release of superoxide and interleukin-8 and increases their expression of the cell-surface integrin complement receptor 3 (CR3). Eosinophils also maintain alternatively activated macrophages (M2 macrophages) by producing interleukin-4 and interleukin-13. MBP, ECP, and EPX activate basophils and mast cells, resulting in the release of histamine. Eosinophil granule proteins also activate platelets. Eosinophil-derived NGF primes human basophils and modulates several functions of mast cells.

FIGURE 4

Interleukin-5 plays a fundamental role in the proliferation, maturation in the bone marrow, recruitment and activation at sites of allergic inflammation of eosinophils. The engagement of interleukin-5R through the interaction of interleukin-5 with interleukin-5αR and the βc subunit results in differentiation and maturation of eosinophils in the bone marrow, enhanced cell migration, release of granule proteins, and respiratory burst of eosinophils. Interleukin-3 and GM-CSF interact only with the βc subunit of interleukin-5R and enhance the functional response to stimuli of eosinophils (left side). Anti-interleukin-5 monoclonal antibodies (mepolizumab and reslizumab) bind to different epitopes of interleukin-5 blocking its ligation to interleukin-5Rα highly expressed on the human eosinophil membrane. Benralizumab is a humanized monoclonal antibody that binds to human interleukin-5Rα, resulting in inhibition of interleukin-5 activation. The latter approach also leads to antibody-dependent cellular cytotoxicity (ADDC) caused by Fc receptor binding on natural killer cells to the anti-interleukin-5Rα antibody on eosinophil (right side).