Series

Asthma 2
Targeting the interleukin pathway in the treatment of asthma
Kian Fan Chung

Lancet 2015; 386: 1086–96 Asthma is a common heterogeneous disease with a complex pathophysiology. Current therapies based on inhaled
See Editorial page 1014 corticosteroids and longacting β2 agonists are effective in controlling asthma in most, but not all patients, with a few
This is the second in a Series of patients falling into the severe asthma category. Severe asthma is characterised by poor asthma control, recurrent
two papers about Asthma exacerbations, and chronic airflow obstruction despite adequate and, in many cases, high-dose treatments. There is
Experimental Studies, Airway strong evidence supporting the role for interleukins derived from T-helper-2 (Th2) cells and innate lymphoid cells,
Disease Section, National Heart such as interleukins 4, 5, and 13, as underlying the eosinophilic and allergic inflammatory processes in nearly half of
and Lung Institute, Imperial
College London, London, UK
these patients. An anti-IgE antibody, omalizumab, which binds to circulating IgE, a product of B cells from the
and National Institute for actions of interleukin 4 and interleukin 13, is used as treatment for severe allergic asthma. Studies examining cytokine
Health Research (NIHR), blockers such as anti-interleukin-5, anti-interleukin-4Rα, and anti-interleukin-13 monoclonal antibodies in patients
Respiratory Biomedical with severe asthma with recurrent exacerbations and high blood eosinophil counts despite use of inhaled
Research Unit, Royal Brompton
& Harefield NHS Trust and
corticosteroids have reported improved outcomes in terms of exacerbations, asthma control, and forced expiratory
Imperial College London, volume in 1 s. The US Food and Drug Administration’s recommendation to use an anti-interleukin-5 antibody for the
London, UK treatment of severe eosinophilic asthma suggests that there will be a therapeutic place for these anti-Th2 agents.
(Prof Kian Fan Chung DSc) Biomarkers should be used to identify the right patients for such targeted approaches. More guidance will be needed
Correspondence to: as to which patients should receive each of these classes of selective antibody-based treatments. Currently, there is no
Prof Kian Fan Chung, National
Heart and Lung Institute,
treatment that targets the cytokines driving asthma associated with non-eosinophilic inflammation and low Th2
Imperial College London, expression.
Dovehouse St,
London SW3 6LY, UK Introduction slow-release theophylline, and longacting anti-
[email protected]
Asthma is the 14th most important chronic disease in the cholinergics can be added. Some patients can be offered
world in terms of the prevalence, extent, and duration of daily treatment with oral corticosteroids, whereas
disability, affecting 334 million individuals of all ages.1 treatment with the monoclonal anti-IgE antibody
Although mortality from asthma has been falling, the omalizumab may be indicated in those with an allergic
disease still accounts for 90 and 170 deaths per million in background. 5–10% of patients need such high-level
female and male individuals, respectively. The economic treatments4 and have severe asthma.5,6
costs of asthma are made up of direct costs such as To understand the processes that increase asthma
hospital care and treatment, and indirect costs such as severity, research has continued into the pathophysiology
time lost from work. In Europe, the total cost per patient of asthma, and has focused on the interleukins or
has been estimated to range from €509 for controlled cytokines and their potential role in the disease.7 (In this
asthma to €2281 for uncontrolled asthma.2 Series paper, cytokines and interleukins are terms used
Current management of asthma consists of non- interchangeably to indicate a broad and loose category of
pharmacological approaches, such as allergen avoidance, small proteins that are important in activating cell
and pharmacological approaches.3 Daily inhaled signalling in the context of the inflammatory process of
corticosteroids combined with longacting β2 agonists are asthma.) This Series paper will focus on how these
the mainstay of asthma treatment. For patients who cytokines drive the inflammatory processes and
remain uncontrolled on this combination, other pathophysiological mechanisms of asthma, and the
controller drugs such as leukotriene-receptor antagonists, results of blocking the effects of cytokines on asthma
outcome measures in patients with severe asthma,
particularly with approaches that block anticytokine
Search strategy and selection criteria
antibodies. It will also highlight the diversity of the
Data for this Series paper were identified by searches in inflammatory process in severe asthma such that it
MEDLINE and PubMed and references from relevant articles becomes important to define the phenotype that will
and reviews in English, using the search terms “asthma” or respond best to each specifically targeted treatment.
“asthma treatments” with “interleukins” and “cytokines”,
refining the search to specific interleukins or cytokines of Airway inflammation, cytokines and
interest between Jan 1, 2005 and June 30, 2015. Search was interleukins, and molecular phenotyping
also made in the abstract publications from the European Asthma is a multicellular disease. It is a chronic
Respiratory Congress held in 2014, and the American Thoracic inflammatory disease of the airways characterised by
Meeting held in May, 2014, and Sept, 2015. infiltration of eosinophils, basophils, mast cells, and
CD4 T-helper cells into the airway submucosa. This

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inflammatory process is associated with mucus allergic eosinophilic asthma. They produce
hypersecretion, airway wall remodelling, and airway interleukins 4, 5, and 13, which leads to an increase in
hyper-responsiveness, which may all contribute to IgE production and eosinophilic inflammation, whereas
chronic airway obstruction. One important initiating innate immune cytokines such as interleukins 1, 25, and
component is the airway epithelium, along with 33, and thymic stromal lymphopoietin (TSLP) released
dendritic cells and airway macrophages, responding to from airway epithelial cells can activate Th2 cells or
external environmental factors such as allergens, ILC2s, or both.9
pollutants, and infectious agents (eg, viruses). This The heterogeneity of asthma has long been recognised,
initial response leads to the transmission of signals to both in terms of clinical outcomes and response to
other cells such as T cells, B cells, and mast cells, with available treatments. Unsupervised clustering methods
activation of airway structural cells such as airway with use of clinical features and inflammatory biomarkers
smooth muscle cells, mucus goblet cells, and fibroblasts8 have identified phenotypes described by asthma control
(figure 1). Cytokines are important in the promotion of and severity, age of onset of disease, obesity, and sputum
chronic airway inflammation and remodelling9,10 by their eosinophil count.13,14 This phenotypic diversity can be
actions on inflammatory and structural cells and by accounted for by different inflammatory mechanisms
affecting and promoting cell–cell interactions.11,12 underpinned by different molecular pathways.15 Because
T-helper-2 (Th2) cells and type 2 innate lymphoid cells Th2 cells have been recognised as an important part of the
(ILC2s) are now recognised as important cells underlying mechanisms underlying asthma, a Th2-high asthma has

Allergens, viruses, particles

Pollution and oxidants

Macrophage Epithelium
Interleukin 12
TNFα B7.2 CD28
Interleukin 4Rα Interleukin 4Rα Interleukin 4Rα
Interleukin 1β
Dendritic MHCII TCR Th0
cells
nity
mu
e im mal
In nat chy
m e sen n Interleukin 6
al- rmati o
heli TGFβ
Epit transfo TSLP, interleukin 33, interleukin 25

Growth factors GM-CSF

(eg, TGFβ) CCL5, CCL11 Interleukin 4Rα
ILC2 Th2
Airway smooth muscle GATA3 GATA3
Extracellular Interleukin 4Rα Interleukin 4 Th1 Th17
matrix Interleukin 5
Interleukin 13
Interferon γ, Interleukin 17A, 17E, 17F
TNFα CXCL8
Interleukin 4Rα Interleukin 5Rα
Histamine
Cysteinyl CXCR2
leukotrienes Interleukin
IgE 4Rα
Ca2+/hypercontractile response Mast cell B cell Eosinophil Neutrophil

Airway smooth muscle cell hyper-responsiveness Eosinophilic inflammation Neutrophilic inflammation

Remodelling and repair

Severe asthma: poor asthma control, recurrent exacerbations, chronic airflow obstruction, corticosteroid insensitivity

Figure 1: Pathophysiological mechanisms underlying severe asthma and targets for anti-interleukin therapy
Interactions between environmental factors and innate and adaptive immune and inflammatory responses are initiated at the level of the airway epithelium, in
particular alveolar macrophages and dendritic cells, with the release of TSLP, interleukin 33, and interleukin 25 from the airway epithelium. Generation of Th2 cells
and ILC2s leads to the elaboration of interleukins 4, 5, and 13, which are important for the generation of an allergic eosinophilic inflammation with eosinophil
recruitment and activation, and the production of IgE. Activation of Th1 and Th17 cells can also be a feature of asthma, possibly contributing to neutrophilic
inflammation. Airway wall remodelling and repair driven by epithelial-mesenchymal transformation and the effects of interleukins on airway structural cells such as
airway smooth muscle cells and epithelial cells contribute to chronic airflow obstruction and bronchial hyper-responsiveness. Targets for interleukin intervention
against interleukins 4, 5, and 13 have included GATA3 in Th2 and ILC2 cells and antibody-directed inhibition against each individual interleukin or against relevant
receptors such as interleukin 4Rα or interleukin 5Rα. ILC2=type 2 innate lymphoid cells. TCR=T-cell receptor. Th1=T-helper-1 cell; Th2=T-helper-2 cell.
Th17=T-helper-17 cell. TFGβ=transforming growth factor β. TNFα=tumour necrosis factor α. TSLP=thymic stromal lymphopoietin.
GM-CSF=granulocyte-macrophage colony-stimulating factor.

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been defined by use of genes expressed in airway epithelial of Th2 cells, synthesis of innate cytokines, such as TSLP,
brushings, consisting of a set of interleukin-13-inducible interleukin 25, and interleukin 33 from the epithelium,28
genes comprising POSTN, CLCA1, and SERPINB2.16 Only can be induced by external stimuli such as
half of a group of patients with mild-to-moderate asthma lipopolysaccharide, pollutants, and viruses.29 Additionally,
had a Th2-high asthma phenotype that was characterised these cytokines activate dendritic cells resulting in further
by a greater degree of bronchial hyper-responsiveness, differentiation and clonal expansion of Th2 cells with
higher serum IgE concentrations, and increased blood further activation of Th2 cells and tissue eosinophilia.
and airway eosinophilia.17 This finding has led to the Effector Th2 cells release interleukins 4, 5, and 13,
dichotomisation of asthma into a Th2-high and a Th2-low which are expressed in the bronchial submucosa of
endotype.18 This categorisation has implications for testing patients with asthma. An alternative source of
new compounds that target specific molecular pathways interleukin 5 and interleukin 13 is ILC2s, which express
in the clinic, particularly in identifying patients most likely no conventional lymphocyte or dendritic-cell phenotypic
to respond to these treatments.19 In the first clinical trial of markers. ILC2s require GATA3 transcription factor for
the anti-interleukin-5 antibody mepolizumab, which was their development and function; they are also stimulated
used to block the effects of the Th2-derived cytokine by TSLP and interleukins 25 and 33 to produce
interleukin 5, the drug proved ineffective in patients with interleukins 5 and 13.23 High concentrations of ILC2s
asthma recruited solely according to severity;20 however, in have been seen in eosinophilic nasal polyps, as well as in
a subsequent study in patients with severe asthma with a peripheral blood of patients with asthma.26,27
history of frequent exacerbations and eosinophilia in Although IgE is not considered an interleukin, its role
sputum or blood, mepolizumab treatment resulted in an in allergic inflammation is crucial and its production
important reduction in exacerbations compared with from B cells is a result of the effect of interleukin 4 and
placebo.21 interleukin 13 in causing a class switch in immunoglobulin
Biomarkers that are accessible in the clinic can be used synthesis towards IgE. After IgE binds to high-affinity
to stratify patients, especially for identification of those receptors on mast cells and basophils, cross-linking of
who will respond to blocking antibodies directed towards IgE receptors leads to subsequent activation of these cells
interleukins 4, 5, and 13. Eosinophil counts in blood are to release preformed mediators and cause synthesis of
positively correlated to eosinophil counts in sputum; cysteinyl leukotrienes and pro-inflammatory cytokines.
raised blood eosinophil counts of more than 220 cells per Thus, IgE-activated mast cells secrete interleukins, such
μL are present in 53% of patients with severe asthma and as interleukins 3, 4, and 5, and granulocyte-macrophage
sputum eosinophilia of more than 2% is present in 55% colony-stimulating factor, which recruit or activate
of patients with severe asthma.22 In patients with mild-to- eosinophils.
severe asthma, blood eosinophil count was also reported Omalizumab is a humanised antibody that binds to the
to have the highest accuracy in identifying sputum Cε3 domain of the free IgE heavy chain. When it binds to
eosinophilia in asthma, compared to nitric oxide free circulating IgE, there is a reduction in IgE available for
concentration in exhaled breath, or serum periostin.23 A binding to high-affinity IgE receptors (FcεR1) and also a
sputum eosinophilia of more than 2% was totally specific reduction in high-affinity FcεR1 receptors present on mast
but had a poor sensitivity for airway Th2 inflammation.24 cells and basophils.30 These events lead to an interruption
These findings suggest that blood eosinophil counts of the allergic cascade and prevention of mast-cell
alone might be useful in selecting individuals with Th2- degranulation with a reduction in eosinophilic inflam-
high asthma, and this approach has been used to indicate mation.30 Furthermore, omalizumab decreases early and
a population of patients with severe asthma who respond late asthmatic responses, sputum and tissue eosinophil
to interleukin-5 blocking agents.25 Another biomarker, counts, and submucosal cells positive for IgE and FcεR1.31–33
serum periostin, has been reported to be a better Omalizumab improved asthma-related quality-of-life
predictor of airway eosinophilic inflammation in patients measures and reduced exacerbation rates, with small
with severe asthma26 and has successfully identified improvements in FEV1 in patients with moderate-to-severe
patients with moderate-to-severe asthma who show an asthma.4,34 In severe persistent allergic asthma, omalizumab
improvement in forced expiratory volume in 1 s (FEV1) as an add-on therapy decreased clinically significant asthma
after treatment with an anti-interleukin-13 antibody.27 exacerbations by 26%, compared with placebo.35 Biomarkers
of therapeutic efficacy for omalizumab in reducing
Anti-interleukin approaches in asthma exacerbations are high concentrations of nitric oxide in
Targeting the Th2 pathway exhaled breath and high blood eosinophil counts.36 A trial
Activation of the Th2 pathway is initiated from a complex of omalizumab in both adults and children with severe
interaction between the innate and adaptive immune allergic asthma is recommended.4
responses, starting with the differentiation of Th2 cells More potent anti-IgE antibodies are in development.
from uncommitted T cells, which requires the action of QGE031 (Novartis, Basel, Switzerland) is a humanised
co-stimulatory molecules and cytokines expressed by anti-IgE antibody with a 50-fold higher affinity for IgE
dendritic cells and inflammatory cells. For the activation than omalizumab. QGE031 reduced circulating

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concentrations of IgE, FcεR1, surface IgE, and skin A

prick responses to aeroallergens to a greater extent than JAK3
Interleukin 4
omalizumab in allergic patients with well-controlled γc
asthma.37 Type I
IL4 IL4Rα
Production of IgE can be inhibited by quilizumab JAK1
(Genentech, San Francisco, CA, USA), a humanised TYK2
monoclonal antibody directed against an extracellular Interleukin 4
IL13Rα1 Interleukin-4 and
52-aminoacid segment termed M1 prime of human Type II STAT6-P interleukin-13
IL4 IL4Rα
membrane IgE through reduction of new IgE-producing response genes
JAK1
plasma cells. Quilizumab reduces total serum IgE Interleukin 13 TYK2
concentrations and allergen-specific IgE, an effect that
Type II IL13 IL13Rα1
can be longlasting. In patients with allergic asthma
undergoing allergen challenge, quilizumab blocked the IL4Rα
generation of IgE and reduced allergen-induced early JAK1

and late asthmatic airway responses, with a non- B

significant reduction in allergen-induced increases in JAK1 STAT5 STAT5-P
sputum eosinophil counts.38 Clinical development of Interleukin-5
Interleukin 5 βc MAPK
response genes
quilizumab for allergic asthma has been discontinued. PI3K
IL5 IL5Rα
JAK2
Anti-interleukin-4Rα antibody
Both interleukin 4 and interleukin 13 bind to the Figure 2: Signalling pathways of (A) interleukins 4 and 13, and
heterodimeric combination of the α1 chain of the (B) interleukin 5
(A) Interleukin 4 signals through type I or type II interleukin-4Rα receptors,
interleukin-13 receptor (interleukin 13Rα1) and the whereas interleukin 13 signals through type II interleukin-4Rα receptor through
α chain of the interleukin-4 receptor (interleukin 4Rα1), binding to interleukin 13Rα1. These interactions lead to the phosphorylation of
which leads to the signalling of both interleukin 4 and STAT6 with subsequent transcription of interleukin-4 and interleukin-13
interleukin 13.39 Blocking interleukin 4Rα with an response genes. (B) Interleukin-5 engagement of interleukin 5Rα leads to
recruitment of βc, resulting in the activation of the JAK/STAT pathway, MAPK
antibody targeted to this receptor chain would block the cascade, and PI3K pathway. IL=interleukin. JAK=janus kinase. MAPK=mitogen-
effects of both interleukin 4 and interleukin 13 (figure 2). activated protein kinase. PI3K=phosphoinositide-3-kinase. STAT=signal
Interleukin 4 has an important role in Th2-cell transducers and activators of transcription. TYK=tyrosine kinase.
differentiation from naive T cells. Interleukin 4, together βc=common β chain. γc=common γ chain. STAT5-P=phosphorylated STAT-5.
STAT-6P=phosphorylated STAT-6.
with interleukin 13, causes isotype class-switching of
B cells towards IgE synthesis and is involved in mast-cell
recruitment. Interleukin 4 also upregulates high-affinity There has been no further development of pitrakinra
IgE receptors on mast cells and low-affinity receptors on in asthma.
B cells and mononuclear phagocytic cells. Interleukin 4 AMG 317 (Amgen, Thousand Oaks, CA, USA) is a
and interleukin 13 upregulate vascular cell adhesion human monoclonal antibody against interleukin 4Rα
molecules on endothelial cells, thus facilitating that blocks both interleukin-4 and interleukin-13
transmigration of eosinophils, T lymphocytes, pathways. In a study of patients with moderate-to-severe
monocytes, and basophils. asthma, AMG 317 did not change Asthma Control
Interleukin 13 shares 30% homology with interleukin 4 Questionnaire (ACQ) scores from baseline and had no
and is secreted by Th2 cells, ILC2s, mast cells, basophils, effect on exacerbations compared with placebo (table).44
and eosinophils. In asthma, the effects of interleukin 13 In patients with moderate asthma with evidence of
include increases in goblet-cell differentiation, activation either sputum or blood eosinophilia, a human monoclonal
of fibroblasts, an increase in bronchial hyper- antibody that binds to interleukin 4Rα, dupilumab
responsiveness, and switching of B-cell antibody (Regeneron, Tarrytown, NY, USA), reduced asthma
production towards IgE.40 exacerbations and improved asthma control and lung
Pitrakinra, a mutated form of human interleukin 4 function compared with placebo, when longacting β2
with a high affinity for interleukin 4Rα, inhibits the agonist was discontinued and inhaled corticosteroid dose
downstream effects of both interleukin 4 and reduced and stopped.45 There was also an associated
interleukin 13 by acting as a competitive antagonist. In reduction in fractional exhaled nitric oxide with reduced
phase 2 trials, pitrakinra attenuated the late-phase serum concentrations of Th2-associated inflammatory
asthmatic response to allergen challenge in patients with markers such as CCL17 (TARC), CCL26 (eotaxin-3), and
mild atopic asthma.41 A reduction in exacerbation IgE. In a second phase 2 study of adults with uncontrolled
frequency during withdrawal of inhaled corticosteroids asthma on medium-dose to high-dose inhaled
was reported in subgroups of patients with eosinophilic corticosteroids and longacting β2 agonists, dupilumab
asthma, raised exhaled nitric oxide concentrations, and (200 mg or 300 mg every 2 weeks or every 4 weeks)
with specific interleukin-4 receptor polymorphisms.42,43 improved FEV1 at week 12 in patients with blood eosinophil

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count of 300 cells per μL or more, although not when single nebulised dose was shown to be effective in
given as a dose of 200 mg every 4 weeks.46 Dupilumab also moderate asthma and was associated with improvement in
reduced annualised severe exacerbation rates irrespective FEV1, lower use of β2 agonists, and reduced concentrations
of baseline eosinophil counts, apart from when given as a of exhaled nitric oxide compared with placebo.61 In a dosing
dose of 300 mg every 4 weeks. These findings might raise study over 12 weeks, there was significant effect in
questions about the role of blood eosinophils as a preventing reduction in FEV1 but not on exacerbation rates
predictive biomarker of response to this treatment. following reduction of maintenance doses of inhaled
corticosteroids, in moderate persistent asthma.62 However,
Anti-interleukin-4 antibody no benefits were reported in subsequent clinical trials.
Inhaled recombinant human soluble interleukin-4 There has been no further development of this soluble
receptor has been used to antagonise interleukin 4. A interleukin-4 receptor in asthma.

Antibody Patient characteristics and biomarkers Effects of antibody treatment

Interleukin 4Rα 44
AMG 317 Patients with moderate-to-severe asthma No effect on ACQ scores or exacerbations
Interleukin 4Rα45 Dupilumab Patients with moderate-to-severe asthma with sputum Reduction in exacerbations of 89% (6% of patients had exacerbations in dupilumab group
eosinophilia (≥3%) or blood eosinophilia (≥300 cells per μL). vs 44% in placebo group). Significant improvement in FEV1 (0·27 L compared with placebo)
LABA was discontinued and ICS dose tapered and stopped and in ACQ-5 score (−0·73 points compared with placebo)
Interleukin 4Rα46 Dupilumab Patients with uncontrolled asthma on medium-dose to Improved FEV1 in patients with blood eosinophil count of ≥300 cells per μL (apart from
high-dose ICS plus LABA. Stratified according to blood dose of 200 mg every 4 weeks). Reduced annualised severe exacerbations rates irrespective
eosinophil count <300 or ≥300 cells per μL. Dupliumab given of baseline eosinophil count (apart from dose of 300 mg every 4 weeks)
as 200 mg or 300 mg every 2 weeks or every 4 weeks
Interleukin 1347 Lebrikizumab Patients with mild asthma undergoing allergen challenge Non-significant reduction in late-phase response; those with increased blood eosinophil
counts, serum IgE, or periostin had a greater reduction. Decrease in serum IgE and
chemokine ligands 13 and 17
Interleukin 1327 Lebrikizumab Patients with moderate-to-severe asthma not well controlled Mean FEV1 improved by 5·5% in patients treated with lebrikizumab, with patients with
on ICS with or without LABA with mean FEV1 of 65% of high serum periostin concentration showing 8·2% improvement vs 1·6% in those with low
predicted. 80% were on LABA. Stratification according to periostin. No effect on ACQ-5 or exacerbations
serum periostin concentration
Interleukin 1348 Lebrikizumab Patients with uncontrolled asthma despite daily use of high- Lower exacerbation rates reported in lebrikizumab group than in placebo group, with 60%
dose ICS and a second asthma controller. Two studies testing reduction in patients with high periostin concentration vs 5% in those with low periostin.
37·5 mg, 125 mg, 250 mg, or placebo given subcutaneously No dose response evident. Treatment with lebrikizumab improved FEV1 by 9·1% in
every 4 weeks patients with high periostin vs 2·6% in patients with low periostin. (Study discontinued in
middle of study period with no definitive statistics)
Interleukin 1349 Tralokinumab Patients with moderate-to-severe uncontrolled asthma No change in ACQ-6 at 13 weeks. Increase in FEV1 of 0·21 L with tralokinumab vs 0·06 L
despite controller therapies with ACQ-6 >1·5 and one or more with placebo (p=0·072). β2 agonist use decrease of −0·68 puffs per day with tralokinumab
exacerbations in past year vs −0·10 puffs per day with placebo (p=0·020). Better response in those with higher
interleukin-13 concentrations in sputum
Interleukin 1350 Tralokinumab Patients with severe uncontrolled asthma on ICS plus LABA No effect on primary endpoint of annualised exacerbations. Significant increase in FEV1 in
plus other controllers including oral corticosteroids those receiving treatments every 2 weeks, with greater improvements in those with high
serum concentrations of periostin or DPP-4
Interleukin 1351 GSK679586 Patients with severe asthma No improvements in asthma control, pulmonary function, or exacerbations
Interleukin 552 Mepolizumab Patients with mild asthma undergoing allergen challenge No effect on late-phase response or bronchial hyper-responsiveness despite reduction in
blood and sputum eosinophil counts
Interleukin 520 Mepolizumab Patients with asthma with persistent symptoms despite ICS Reduced blood and sputum eosinophil counts. No statistically significant effect on clinical
(400–1000 μg per day of beclometasone or equivalent) endpoints. A trend towards reduced exacerbation rates
Interleukin 553 Mepolizumab Patients with refractory eosinophilic asthma with recurrent Reduction in exacerbation rate (exacerbations per patient, 2·0 in mepolizumab group vs
severe exacerbations 3·4 in placebo group, relative risk ratio 0·57) and improvement in AQLQ (0·55 in
mepolizumab group vs 0·19 in placebo group). No effect on FEV1 or bronchial
hyper-responsiveness
Interleukin 554 Mepolizumab Patients with severe asthma on OCS with persistent sputum Reduction in exacerbations and in prednisolone dose with improved asthma control
eosinophilia and FEV1
Interleukin 521 Mepolizumab Patients with asthma with recurrent severe asthma All doses of mepolizumab reduced exacerbations: reduction from 2·40 per patient to
exacerbations and evidence of eosinophilic inflammation 1·24 per patient (48% reduction) with 75 mg; reduction to 1·46 per patient per year
(raised blood or sputum eosinophil counts or raised FENO) (39% reduction) with 250 mg; and reduction to 1·15 per patient per year (52% reduction)
despite 880 μg fluticasone or equivalent per day. with 750 mg. No effect on ACQ, AQLQ, or FEV1
Mepolizumab given intravenously at doses of 75 mg, 250 mg,
or 750 mg
Interleukin 555 Mepolizumab Patients with severe asthma with recurrent exacerbations on Rate of exacerbation reduced by 47% with intravenous mepolizumab and by 53% with
high-dose ICS and evidence of eosinophil count ≥150 cells per subcutaneous mepolizumab. Baseline FEV1 increased by a mean of 100 mL with
μL at screening or ≥300 cells per μL in past year. Mepolizumab intravenous mepolizumab, and 98 mL with subcutaneous mepolizumab. ACQ-5 improved
given either 75 mg intravenously or 100 mg subcutaneously by 0·42 and 0·44 points, respectively
(Table continues on next page)

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Antibody Patient characteristics and biomarkers Effects of antibody treatment

(Continued from previous page)
Interleukin 556 Mepolizumab Patients with severe asthma on ICS and LABA and OCS; blood Primary endpoint is decrease in dose of OCS. Likelihood of decrease in corticosteroid dose
eosinophil count ≥150 cells per μL at screening or ≥300 cells was 2·39 times greater with mepolizumab than with placebo, (median percentage
per μL in past year. Mepolizumab dose 100 mg reduction in the mepolizumab-treated group of 50%). Reduced exacerbation rates by 32%
subcutaneously (1·44 in mepolizumab group vs 2·12 in placebo group). ACQ-5 improved by 0·52 points.
Trend towards greater changes from baseline of FEV1 in mepolizumab group
Interleukin 557 Reslizumab Patients with severe asthma on ICS plus LABA with sputum Improved ACQ score by −0·7 in reslizumab group compared with −0·3 in placebo group
eosinophilia of >3% (p=0·054). FEV1 improved with a change of 0·18 L after reslizumab compared with −0·08 L
after placebo (p=0·002). Reduction in sputum eosinophil count. Trend towards reduced
exacerbations in reslizumab group
Interleukin 558 Reslizumab Patients inadequately controlled on ICS with a blood eosinophil Significantly reduced exacerbations with a rate ratio of 0·50 and 0·41 in these two studies.
count of >400 cells per μL with one or more exacerbations in Improvement in FEV1, AQLQ scores, and ACQ-7 scores. Improvement in FEV1 increased with
the previous year. Two duplicate studies reported disease severity: mean increase of 0·113 L for those on ICS plus LABA only. Proportion of
patients with minimally important differences of ≥0·5-point improvement from baseline
to endpoint in AQLQ was 74% in reslizumab group vs 65% in placebo group (p=0·03)
Interleukin 5Rα59 Benralizumab Patients on high-dose ICS, with 2–6 exacerbations per year, Decrease in asthma exacerbations in patients with baseline blood eosinophil count
raised blood eosinophil count, blood eosinophil index and >300 cells per μL at 20 mg and 100 mg doses of benralizumab (0·30 vs 0·68 compared
FENO >50 ppb. Three doses of benralizumab tested: 2 mg, with placebo with 57% reduction; 0·38 vs 0·68 with 43% protection, respectively). In
20 mg, and 100 mg doses in patients with eosinophilic eosinophilic asthma, mean FEV1 and ACQ-6 improved compared with baseline with 0·10 L
asthma, and only 100 mg dose in patients with non- for FEV1 and −0·26 units for ACQ-6
eosinophilic asthma
Interleukin 5Rα60 Benralizumab Patients presenting with acute exacerbation of asthma in Reduced subsequent exacerbation rate by 49%, including those needing hospital
emergency room. Single infusion of benralizumab admission by 60%

ACQ=Asthma Control Questionnaire. AQLQ=Asthma Quality of Life Questionnaire. DPP-4=dipeptidyl peptidase 4. FENO=exhaled nitric oxide concentration. FEV1=forced expiratory volume in 1 s. ICS=inhaled
corticosteroid; LABA=long acting β2 agonist. OCS=oral corticosteroid. ppb=parts per billion.

Table: T-helper-2 (Th2)-directed monoclonal antibodies in severe asthma

Anti-interleukin-13 antibody expression who were treated with lebrikizumab.

Lebrikizumab (Genentech, San Francisco, CA, USA) is However, because a host-cell impurity in the study drug
an IgG4 humanised monoclonal antibody that blocks was discovered during the study, treatment was
binding of interleukin 13 to interleukin 4Rα to prevent discontinued such that only a mean duration of treatment
signalling through the interleukin-4Rα and interleukin- of 24 weeks was available for analysis.48
13Rα1 heterodimer (figure 2). In patients with mild Tralokinumab (MedImmune, Cambridge, UK) is an
asthma who underwent bronchial allergen challenge, interleukin-13-neutralising IgG4 monoclonal antibody
lebrikizumab reduced the late asthmatic response that blocks the binding of interleukin 13 to
compared with placebo, although not significantly, but interleukin 13Rα1 and interleukin 13Rα2. In patients with
did not affect the early-phase response.47 In patients with moderate-to-severe uncontrolled asthma, tralokinumab
uncontrolled asthma despite use of inhaled did not improve symptoms but resulted in a non-
corticosteroids and longacting β2 agonists, treatment significant increase in FEV1 compared with placebo, with
with lebrikizumab improved FEV1 by 8·2% above the greater effects in patients with detectable sputum
baseline value in patients with a high concentration of interleukin-13 concentrations.49 In patients with
serum periostin, whereas patients with a low uncontrolled asthma on high-dose inhaled corticosteroids
concentration of serum periostin showed no FEV1 and longacting β2 agonists with or without other controller
response.27 By contrast, Noonan and colleagues63 enrolled drugs, tralokinumab had no effect on exacerbation rates,
patients with asthma who had never received treatment and subgroup analysis showed a trend towards a reduction
with inhaled corticosteroids and reported no improve- in exacerbations in those with high serum concentrations
ment in FEV1 with lebrikizumab in individuals with a of periostin and dipeptidyl peptidase 4.50 There was a
high concentration of serum periostin and a minor significant increase in FEV1 from baseline in patients
increase in those with low periostin concentration. treated every 2 weeks, but not in those treated every
In two studies that examined the effect on exacerbations 4 weeks, after an initial 2-weekly treatment period, but no
as a primary endpoint, lebrikizumab reduced the rate of change in ACQ-6 or Asthma Quality of Life Questionnaire
asthma exacerbations in patients with uncontrolled (AQLQ) scores for both treatment categories.
asthma despite daily use of high-dose inhaled GSK679586 (GlaxoSmithKline, Greater London, UK)
corticosteroid and a second asthma controller, with the blocks the binding of interleukin 13 to interleukin 13Rα1.
reduction in exacerbation rate being more pronounced Treatment with GSK679586 during a 3-month period did
in patients with high periostin expression than in those not result in clinically meaningful improvements in
with low periostin expression.48 There was also an asthma control, pulmonary function, or exacerbations in
improvement in FEV1 in patients with high periostin patients with severe asthma compared with placebo.51

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Anti-interleukin-5 antibody and anti-interleukin-5 exacerbations and in asthma symptoms as measured on

receptor antibody ACQ-5.56 Not all patients in this study responded to
Interleukin 5, produced by Th2 cells and ILC2s, is a mepolizumab: 36% of patients treated with mepolizumab
cytokine specifically targeted at eosinophils; it is important reported no reduction in oral corticosteroid dose, or a lack
for their terminal differentiation and maturation. Together of asthma control, or withdrew from the study, compared
with CCL11 (eotaxin), interleukin 5 mobilises eosinophils with 56% in the placebo group.
and eosinophil precursors into the circulation. Interleukin 5 Reslizumab (Teva, Philadelphia, PA, USA) is an IgG4κ
primes eosinophils for increased survival and increased humanised monoclonal antibody against interleukin 5.
cytotoxicity. Eosinophil infiltration and degranulation lead In patients with severe asthma on inhaled corticosteroids
to the release of cytotoxic products including major basic and longacting β2 agonists with sputum eosinophilia of
protein, eosinophil cationic protein, eosinophil-derived more than 3%, reslizumab improved asthma control and
neurotoxin, and eosinophil peroxidase, which contribute to FEV1 with a trend towards fewer exacerbations than in
airway epithelial damage, mucus hypersecretion from those receiving placebo.57 In two phase 3 studies in
goblet cells, bronchial hyper-responsiveness, and impaired patients inadequately controlled on inhaled corticosteroids
ciliary beating. Eosinophils also secrete cysteinyl with a blood eosinophil count of more than 400 cells per
leukotrienes (LTC4, LTD4, and LTE4). μL and one or more exacerbations in the previous year,
Mepolizumab (GlaxoSmithKline, Greater London, UK) reslizumab significantly reduced the frequency of
is a humanised monoclonal IgG1 antibody to interleukin 5. exacerbations compared with placebo, with rate ratios of
In two early studies, mepolizumab reduced sputum and 0·50 and 0·41 in the two studies respectively.58 There was
blood eosinophil counts compared with placebo,20,52 but also an improvement in FEV1, AQLQ score, and
had no effect on response after allergen challenge. ACQ-7 score.
Additionally, in a cohort of adults with moderately severe Benralizumab (MedImmune, Gaithersburg, MD, UK) is
asthma recruited on the basis of asthma severity, a recombinant IgG1 antibody directed against the α chain
mepolizumab had no beneficial effects on symptom of the interleukin-5 receptor. The removal of a fucose sugar
control or exacerbations.20 In later studies in a specific residue in the CH2 region of human IgG1 has allowed for
cohort of patients with severe asthma on a combination an increased affinity for the activating Fcγ receptor on cells
of inhaled corticosteroids and longacting β2 agonists with such as eosinophils; there is evidence that this alteration
a history of exacerbations and persistent sputum or blood results in amplification of eosinophil apoptosis.65 In
eosinophilia, mepolizumab decreased exacerbations, patients with uncontrolled asthma using medium-dose to
reduced use of oral corticosteroids, and improved high-dose inhaled corticosteroids, with between two and
symptoms and lung function compared with placebo.53,64 six exacerbations per year and with eosinophilic
Subsequently, in a phase 2 study in patients with recurrent inflammation defined by an algorithm to predict raised
severe asthma exacerbations and eosinophilic sputum eosinophil counts, subcutaneous injection of
inflammation, mepolizumab was effective in reducing benralizumab at 20 mg or 100 mg doses reduced asthma
exacerbation rates, but did not improve FEV1 or quality of exacerbations by 36% and 41%, respectively, compared
life.21 In this study, a blood eosinophil count of 150 cells with placebo.59 Patients receiving benralizumab also had
per μL or more was associated with a reduction in improvements in mean FEV1 compared with baseline
exacerbation rate of 72% compared with a reduction of at 1 year (mean difference in change from
30% in those with a blood eosinophil count of less than baseline for 100 mg dose vs placebo 0·10 L for FEV1 and
150 cells per μL. Patients with a sputum eosinophil count −0·26 for ACQ-6 score). This finding was supported by
of 3% or more showed similar reductions to those with a results from another study in which patients who were
count of less than 3%. However, the reduction in recruited after being treated for an exacerbation of asthma
exacerbation rate in either group was more than 66%.25 received a single infusion of benralizumab. Compared
In subsequent studies in patients with recurrent with placebo, benralizumab reduced asthma exacerbation
exacerbations of asthma (more than two exacerbations per rates by 49% and exacerbations needing hospital admission
year) despite high-dose inhaled corticosteroids and by 60%.60
eosinophilic inflammation (>300 cells per μL blood in the
past year), use of mepolizumab led to a substantial Anti-TSLP antibody
reduction in exacerbations and improved asthma TSLP is an interleukin-7-related cytokine secreted by
control.55,56 There was also an improvement in FEV1 at airway epithelial cells on allergen and environmental
32 weeks with mepolizumab compared with placebo.55 exposure;66,67 it activates dendritic cells to release
Furthermore, in patients with severe eosinophilic asthma chemokines that recruit and activate Th2 cells.68
on oral corticosteroid therapy, there was a median Expression of interleukin 33 and TSLP is increased in
reduction in corticosteroid dose of 50% from baseline in the airway epithelium of patients with asthma,
the mepolizumab group compared with no reduction in particularly in those with severe asthma.69,70 TSLP may
the placebo group. This reduction in corticosteroid dose also be involved in airway wall remodelling by acting on
was accompanied by a reduction in the rate of lung fibroblasts.71

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AMG 157 (Amgen, Thousand Oaks, CA, USA), a Brodalumab (Amgen, Thousand Oaks, CA, USA), a
human anti-TSLP monoclonal antibody, attenuated human anti-interleukin-17RA monoclonal antibody, had
allergen-induced early and late asthmatic responses in no effect on asthma control scores, symptom-free days,
mild allergic asthma. It also reduced blood and sputum and FEV1 in patients with inadequately controlled
eosinophil counts before and after allergen challenge, moderate-to-severe asthma who were receiving inhaled
and fractional exhaled nitric oxide concentrations.72 corticosteroid therapy. Furthermore, analysis of nine
prespecified patient subgroups showed a high-
Antagonists of CRTh2 reversibility subgroup with a post-bronchodilator FEV1
Prostaglandin D2, released during allergen-induced improvement of 20% or more who showed a significant
reactions in the airways, activates a G-protein-coupled improvement in ACQ score at the 210 mg but not at the
receptor, chemoattractant receptor-homologous molecule 280 mg dose.82 A follow-up phase 2b study focusing on
expressed on Th2 cells (CRTh2, also known as DP2 this phenotype was stopped because of a lack of reported
receptor), present on Th2 cells, ILC2s, and eosinophils, efficacy in an interim analysis. There has been no further
and induces the chemotaxis of these cells.73 Production of development of this antibody in asthma.
Th2-type cytokines by ILC2s is also stimulated by CXCL8 is a chemokine (chemoattractant cytokine)
prostaglandin D2 via activation of its CRTh2 receptor,24 involved in the chemoattraction and activation of
and also by leukotriene D4 (LTD4).25 neutrophils through the CXCR2 receptor.
In patients with moderate persistent asthma who were SCH527123 (Merck, Whitehouse Station, NJ, USA), a
not taking inhaled corticosteroids, the CRTh2 antagonist CXCR2 antagonist, inhibited ozone-induced sputum
OC000459 (Oxagen, Abingdon, UK) improved FEV1, neutrophilia in patients without asthma.83 It also reduced
asthma-related quality of life scores, and night-time sputum neutrophilia in adults with severe asthma, with a
symptoms, without affecting sputum eosinophil counts, modest reduction in mild exacerbations, but did not
compared with placebo.74 The CRTh2 antagonist AMG improve asthma control.84
853 (Amgen, Thousand Oaks, CA, USA), used as an add- Tumour necrosis factor α (TNFα) is a pro-inflammatory
on to inhaled corticosteroid therapy, did not improve Th1 cytokine that induces airway inflammation and hyper-
asthma symptoms or lung function in patients with responsiveness, mucus hypersecretion, and activation of
uncontrolled moderate-to-severe disease.75 Another macrophages. In two small, placebo-controlled, double-
CRTh2 antagonist, BI671800 (Boehringer Ingelheim, blind, crossover studies of patients with corticosteroid-
Ingelheim am Rhein, Germany), caused a small refractory asthma, treatment with etanercept (Pfizer,
improvement in FEV1 in symptomatic patients who had Collegeville, PA, USA) (a soluble recombinant dimer
not previously used controller treatment and in patients protein consisting of two human TNFα receptors fused
on inhaled corticosteroids.76 In a phase 2a study in patients with the Fc domain of human IgG1) resulted in clinical
with mild-to-severe asthma with sputum eosinophil improvements in PC20 (the concentration of metha-
counts of more than 2%, treatment with another CRTh2 choline required to provoke a 20% decrease in FEV1),
antagonist, QAW039 (Novartis, Basel, Switzerland), quality of life scores, and lung function in one study,85 and
resulted in a 3·5-fold reduction in sputum eosinophil improvements in ACQ scores with reductions in the use of
count compared with placebo, accompanied by a 2·3-fold nebulised β2 agonists in the other.86 However, in a
reduction in eosinophil count in bronchial biopsies.77 subsequent larger study in adults with uncontrolled severe
QAW039 improved AQLQ score, but not ACQ-7 score, persistent asthma, the anti-TNFα antibody golimumab
compared with placebo. (Centocor, Malvern, PA, USA) had no overall beneficial
effects. A post-hoc analysis suggested that patients
Targeting non-Th2 targets with substantial bronchodilator reversibility had fewer
Th17 cells are CD4 T cells that express interleukins 17A, exacerbations while on golimumab.87 Serious side-effects
17E, 17F, and 22, and are able to mediate neutrophil with golimumab included an increased frequency of
activation via the production of CXCL8 (interleukin 8).78,79 infections and malignancies compared with placebo,
Allergens and environmental stimuli such as cigarette which probably represents the importance of TNFα in the
smoke and diesel exhaust particles can trigger innate immune response to infections and cancer.
Th17-mediated airway inflammation in asthma.80
Overexpression of interleukin 17A and interleukin 17F Summary and conclusions
has been shown in lung tissue from patients with Blockade of the effects of interleukin 5 with a monoclonal
asthma, with expression levels correlating with asthma antibody directed towards interleukin 5 or its receptor,
severity, especially in patients with neutrophilic interleukin 5Rα, in patients with severe asthma with
corticosteroid-resistant disease.81 Interleukin 17A or eosinophilia in blood or sputum led to a reduction in
interleukin 17F, or both, stimulate airway structural cells, asthma exacerbation rates and an improvement in asthma
including bronchial epithelial cells and subepithelial control and FEV1 (table). Blocking the effects of
fibroblasts, to secrete neutrophil chemoattractants such interleukin 13 with anti-interleukin-13 antibody has led to
as CXCL8 and CXCL1. an improvement in FEV1, particularly in patients with a

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high serum concentration of periostin, with a reduction in bacterial or viral infections, and linked to corticosteroid
exacerbations with lebrikizumab, but not with insensitivity, and also to airway wall remodelling.
tralokinumab. Blocking interleukin 4Rα with dupilumab, Additionally, there might be interactions between Th2
which neutralises the effects of interleukin 4 and and non-Th2 mechanisms.
interleukin 13, reduced exacerbations irrespective of Targeting the interleukin pathway has led to the
baseline eosinophil count, improved FEV1 in those with formulation of antibody therapies against interleukins 4,
high blood eosinophil count, and reduced serum IgE 5, and 13, which are important cytokines underlying the
concentrations. Interleukin 5, therefore, has a most eosinophilic inflammation in asthma. These treatments
important pathogenic role in exacerbations through its will hopefully become available for patients with severe
role in activating eosinophils, and the modest improvement asthma in the coming decade and will represent an
in airflow obstruction after antibody treatment perhaps important milestone in the management of severe
results from disruption of the interaction between asthma.
eosinophils and airway smooth muscle cells. Alternatively, Contributors
the improvement in FEV1 with anti-interleukin-13 antibody I am sole author and contributor.
might result from direct inhibition of airway smooth Declaration of interests
muscle contractility and bronchial hyper-responsiveness. I have received honoraria for participating in advisory board meetings
The reduction in exacerbations noted with anti-interleukin- regarding treatments for asthma and chronic obstructive pulmonary
disease for GlaxoSmithKline, AstraZeneca, Novartis, and Johnson &
4Rα antibody might result from inhibition of both Johnson, and have received research grant funding through my
interleukin 4 and interleukin 13, which could implicate the institution from Pfizer, GSK, and Merck. I have also been remunerated
biomarkers that were inhibited—namely, IgE and the for speaking engagements by AstraZeneca, Merck, and Novartis.
chemokines CCL17 and CCL26. Acknowledgments
With the recent recommendation by the US Food and Work carried out in my laboratory is funded by the UK Medical Research
Drug Administration for use of mepolizumab as an add-on Council, National Environmental Research Council UK, the US National
Institute of Environmental Health Sciences, and the NIHR Respiratory
maintenance treatment in patients aged 18 years or older Biomedical Research Unit, Royal Brompton & Harefield NHS Trust and
with severe eosinophilic asthma, other antibody-based Imperial College London, UK.
therapies will also be approved for severe asthma. References
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