The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: a review

Figures & data

Figure 1 Eosinophil (eos) trafficking and maturation in asthma.

Notes: Stimulation at the epithelial cell surface leads to the generation of cytokines and chemokines that increase production of IL-5. Generation of IL-5 by Th2 cells, ILC2, and mast cells is essential in eosinophil survival and activation in peripheral tissue. This figure also shows the mechanisms of action for mepolizumab, reslizumab, and benralizumab, as well as the secretory products of eosinophils. Red arrows represent inhibitory pathways, while blue arrows are activating pathways.
Abbreviations: EDN, eosinophil-derived neurotoxin; ECP, eosinophil cationic protein; EPO, eosinophil peroxidase; IL, Interleukin; TGF-α/β, transforming growth factor-α/β; INF-γ, interferon gamma; RANTES, regulated upon activation, normal T cell expressed and secreted; MIP1α, macrophage inflammatory proteins-1α; PAF, platelet-activating factor; VIP, vasoactive intestinal peptide; NGF, nerve growth factor; TSLP, thymic stromal lymphopoietin; ILC2, innate lymphoid cells (type 2).

Table 1 Pivotal studies in anti-IL-5 therapies

Drug	Study	Population	Study design	Dosing	Measured end points	Findings in treatment groups
Mepolizumab	Leckie et al, 2000^Citation30	Male subjects with mild allergic asthma and FEV1 of at least 70%	n=24 mc, db, pc	Single IV dose of 2.5 or 10 mg/kg	Responses to inhaled allergen challenge, sputum eosinophils, airway hyperresponsiveness to histamine, blood eosinophils	• Decreased blood eosinophils for up to 16 weeks and sputum eosinophils at 4 weeks • No significant effect on late asthmatic response to allergen challenge or airway hyperresponsiveness
	Flood-Page et al, 2007^Citation31	Asthmatic subjects with continued symptoms on inhaled corticosteroid therapy with and FEV1 between 50% and 80%	n=362 mc, db, pc	Three IV doses of 250 or 750 mg per month	Morning peak expiratory flow, FEV1, daily β2-agonist use, symptom scores, exacerbation rates, quality of life measures, blood eosinophils, sputum eosinophils (subgroup of 37)	• Decreased blood and sputum eosinophils • No statistically significant changes in any of clinical end points measured
	Nair et al, 2009^Citation32	Asthmatic subjects with sputum eosinophilia ≥3% and persistent airway symptoms despite treatment with dose inhaled corticosteroid and prednisone	n=20 sc, db, pc	Five IV doses of 750 mg per month	Prednisone dose, sputum and blood eosinophils, symptoms, airflow limitation	• Patients were able to reduce their prednisone dose significantly • Significantly fewer asthma exacerbations • Decreased sputum and blood eosinophils • Improvements in asthma control and FEV1
	Haldar et al, 2009^Citation34	Asthmatic subjects with history of severe persistent exacerbations with sputum eosinophilia ≥3%	n=61 sc, db, pc	Twelve IV doses of 750 mg per month	Severe exacerbations, asthma symptoms, Asthma Quality of Life Questionnaire (AQLQ), FEV1 after bronchodilator use, airway hyperresponsiveness, blood and putum eosinophils	• Significantly fewer asthma exacerbations • Significant improvement in scores on AQLQ • Decreased sputum and blood eosinophils • No significant difference in symptoms, FEV1 after bronchodilator use, or airway hyperresponsiveness
	Pavord et al, 2012^Citation37	Asthmatic subjects with either a sputum eosinophil count ≥3%, an exhaled nitric oxide (FeNO) concentration of ≥50 ppb, asthma-related peripheral blood eosinophil count of ≥300 cells/µL, or prompt deterioration of asthma control after a 25% or less reduction in regular maintenance inhaled or oral steroids	n=621 mc, db, pc	Three SubQ doses of 75, 250, or 750 mg every 4 weeks	Exacerbations, FeNO, lung function, symptom scores, sputum, and blood eosinophils	• Significant reductions in exacerbations • No changes in FeNO, lung function, or symptom scores • Dose response for reduction in sputum eosinophils and to a lesser extent, blood eosinophils
	Ortega et al, 2014^Citation38	Subjects with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled corticosteroids	n=576 mc, db, pc	Nine doses of 75 mg IV or 100 mg SC every 4 weeks	Exacerbations, lung function, ACQ5 symptom score, blood eosinophil count, SGRQ, quality of life tool	• Reduced exacerbation rates • Significant improvements in lung function (FEV1), ACQ5, and SGRQ • Decreased blood eosinophils
	Bel et al, 2014^Citation39	Subjects on systemic glucocorticoids and evidence of eosinophilic nflammation (blood eosinophil level of either ≥300 cells/mL before screening or ≥150 cells/mL during optimization phase)	n=135 mc, db, pc	Six SubQ doses of 100 mg every 4 weeks	% reduction in daily oral steroid dose, exacerbations, ACQ5 symptom scores, SGRQ quality of life score, FEV1	• 50% reduction in daily oral steroid dose • Significant reductions in rate of exacerbations • I mprovement in ACQ5 scores and SGRQ scores • Trend for improvement in FEV1
Reslizumab	Kips et al, 2003^Citation41	Subjects with severe persistent asthma, defined as those being symptomatic despite being treated with high doses of inhaled and/or oral corticosteroids	n=28 mc, db, pc	Single IV dose of 0.03, 0.1, 0.3, or 1 mg/kg	Sputum and blood eosinophil counts, symptom severity, lung function parameters, and physician-evaluated overall condition	• Dose dependently reduced circulating eosinophil counts • No significant changes in other clinical measurements of disease activity
	Castro et al, 2011^Citation40	Subjects with asthma treated with high dose inhaled corticosteroids with at least one other agent that was poorly controlled and ≥3% sputum eosinophils	n=106 mc, db, pc	Four SubQ doses of 3 mg/kg every 4 weeks	Change in ACQ score, FEV1 eosinophils, asthma exacerbation – measured in all patients versus those with nasal polyps	• Significant reduction in ACQ score in patients with nasal polyps (versus trend in entire treatment group) • Decreased sputum eosinophils • Improvements in airway function (significant reduction in FEV1) • Trend toward reduced exacerbations
	Bjermer et al, 2014^Citation44	Subjects with uncontrolled asthma on at least medium ICS and blood eosinophil level of ≥400/µL	n=311 mc, db, pc	Four IV doses of 0.3–3 mg/kg every 4 weeks	Pre-dose and pre-bronchodilator pulmonary function (primarily FEV1) and ACQ scores	• Significant improvement in FEV1 • Significant reduction in ACQ scores • Higher dose showed earlier FEV1 increase
Benralizumab	Castro et al, 2014^Citation46	Asthmatic subjects on maximal conventional therapies with peripheral blood eosinophil counts ≥300 cell/µL	n=609 mc, db, pc	Seven SubQ doses of 2, 20, or 100 mg for eosinophilic patients and 100 mg for non-eosinophilic	Annual exacerbation rate, FEV1, ACQ, blood eosinophils	• Trend toward decreased exacerbation rate in 100 mg group • Significant improvement in FEV1 and ACQ in eosinophilic patients • Decreased blood eosinophils • High incidence of adverse reactions in treatment group

Abbreviations: sc, single center; mc, multicenter; db, double-blind; pc, placebo controlled; SubQ, subcutaneous; IV, intravenous; AQLQ, Asthma Quality of Life Questionnaire; ACQ, Asthma Control Questionnaire; SGRQ, St George’s Respiratory Questionnaire; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroids.

LeckieMJten BrinkeAKhanJEffects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic responseLancet200035692482144214811191542

 PubMed Web of Science ®Google Scholar

Flood-PagePSwensonCFaifermanIA study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthmaAm J Respir Crit Care Med2007176111062107117872493

 PubMed Web of Science ®Google Scholar

NairPPizzichiniMMKjarsgaardMMepolizumab for prednisone-dependent asthma with sputum eosinophiliaN Engl J Med20093601098599319264687

 PubMed Web of Science ®Google Scholar

HaldarPBrightlingCEHargadonBMepolizumab and exacerbations of refractory eosinophilic asthmaN Engl J Med20093601097398419264686

 PubMed Web of Science ®Google Scholar

PavordIDKornSHowarthPMepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trialLancet2012380984265165922901886

 PubMed Web of Science ®Google Scholar

OrtegaHGLiuMCPavordIDMepolizumab treatment in patients with severe eosinophilic asthmaN Engl J Med2014371131198120725199059

 PubMed Web of Science ®Google Scholar

BelEHWenzelSEThompsonPJOral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthmaN Engl J Med2014371131189119725199060

 PubMed Web of Science ®Google Scholar

KipsJCO’ConnorBJLangleySJEffect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot studyAm J Respir Crit Care Med2003167121655165912649124

 PubMed Web of Science ®Google Scholar

CastroMMathurSHargreaveFReslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled studyAm J Respir Crit Care Med2011184101125113221852542

 PubMed Web of Science ®Google Scholar

BjermerCLMasperoJorgeCiesielskaMonikaO’BrienChristopherZangrilliJamesA randomized phase 3 study of the efficacy and safety of reslizumab in subjects with asthma with elevated eosinophilsEuropean Respiratory Journal2014445829925082909

 PubMed Web of Science ®Google Scholar

CastroMWenzelSEBleeckerERBenralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging studyLancet Respir Med201421187989025306557

 PubMed Web of Science ®Google Scholar