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Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930
Pharmacological Therapy of Bronchial
Asthma: The Role of Biologicals
Sebastian Heck a Juliane Nguyen c Duc-Dung Le a Robert Bals b
Quoc Thai Dinh a, b
Departments of a Experimental Pneumology and Allergology and b Internal Medicine V, Pneumology, Allergology and
Respiratory Critical Care Medicine, Saarland University Faculty of Medicine, Homburg/Saar , Germany; c Department of
Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, SUNY, Buffalo, N.Y. , USA

ment of novel biologicals that target a diverse array of phe-
notype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeu-tic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel ther-apies for severe asthma.
© 2016 S. Karger AG, Basel
Introduction
Bronchial asthma is a heterogeneous, complex, chron-
ic inflammatory and obstructive pulmonary disease char-acterized by augmented mucus secretion, airway hyper-reactivity, and, in the long term, functional and structur-al lung tissue alterations
[1] . Asthma currently affects an
estimated 235 million people worldwide. Most asthmat-ics are well controlled with asthma guideline therapies. Extrinsic (allergic) asthma is the predominant asthma subtype and usually manifests during childhood, while late-onset asthma is mostly nonallergic
[2] . However, a
small portion of asthma patients (5–10%) suffer from se-vere asthma that is refractory to high doses of inhaled steroids plus a second controller. In the uncontrolled sit-uation, long-acting β
2 agonists (LABA) and/or phospho-
diesterase inhibitors and/or long-acting anticholinergics (LAMA) are also used to treat severe asthma. Treatment Key Words
Asthma · Biologicals · Interleukins · Treatment · Tumor necrosis factor · CC chemokine receptor · Granulocyte-macrophage colony-stimulating factor · Chemoattractant receptor-homologous molecule expressed on T
H 2 cells · Macrolides
Abstract
Bronchial asthma is a heterogeneous, complex, chronic in-flammatory and obstructive pulmonary disease driven by various pathways to present with different phenotypes. A small proportion of asthmatics (5–10%) suffer from severe asthma with symptoms that cannot be controlled by guide-line therapy with high doses of inhaled steroids plus a sec-ond controller, such as long-acting β
2 agonists (LABA) or leu-
kotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new thera-peutic avenues for asthma treatment. The approval of the humanized anti-IgE antibody omalizumab for the treatment of severe allergic asthma has paved the way for other cyto-kine-targeting therapies, particularly those targeting inter-leukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithe-lium-derived cytokines IL-25, IL-33, and thymic stromal lym-phopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the develop- Received: February 9, 2015
Accepted after revision: January 5, 2016 Published online: February 20, 2016
Correspondence to: Dr. Quoc Thai Dinh
Saarland University Hospital and Saarland University Faculty of Medicine Kirrberger Strasse, Geb. 61.4 DE–66421 Homburg/Saar (Germany) E-Mail Thai.Dinh
  @   uniklinikum-saarland.de © 2016 S. Karger AG, Basel
1018–2438/16/1684–0241$39.50/0
www.karger.com/iaa
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Heck/Nguyen/Le/Bals/Dinh
Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930242with systemic steroids is also often required to control
severe asthma, which not only affects the patient’s quality of life but can also, in rare cases, cause death. Patients with severe asthma account for over 50% of the total healthcare costs associated with bronchial asthma
[3] due to fre-
quent hospital admissions, the need for emergency ser-vices, and high drug consumption. Therefore, there is an urgent need for novel, more effective strategies to treat severe asthma.
Biologicals (or biologics) are mostly genetically syn-
thesized proteins that exert therapeutic effects by activat-ing or inhibiting diverse endogenous target functions. A
number of biologicals are currently being used or tested in clinical lung research, and convincing data has been published showing a reduction in asthma exacerbations and improved lung function in asthma patients treated with biologicals. The monoclonal anti-IgE antibody omalizumab was the first biological to be approved [i.e. by the US Food and Drug Administration (FDA) in 2003 and the European Medicine Agency (EMA) in 2005] for the treatment of severe allergic asthma as an alternative to systemic steroids. Table 1. New potential drugs in the pipeline for asthma treatment and their target and developmental stage
Drug name Drug target Developmental stage Estimated time of market launch
Omalizumab IgE EMA and FDA approved Already launched
QGE-031 IgE Clinical phase III 2019MEDI-4212 IgE Clinical phase I After 2020Quilizumab IgE Clinical phase II After 2020Dupilumab IL-4Rα Clinical phase II After 2020Pitrakinra IL-4 Rα Clinical phase II NAPascolizumab IL-4 Suspended –Altrakincept IL-4 Suspended –Mepolizumab IL-5 FDA approved Already launchedReslizumab IL-5 Clinical phase II 2016Benralizumab IL-5 Rα Clinical phase II After 2020MEDI-528 IL-9 Clinical phase II NATralokinumab IL-13 Clinical phase II 2017
– 2018
Lebrikizumab IL-13 Clinical phase III 2017 – 2018
QAX-576 IL-13 Clinical phase II After 2020Anrukinzumab IL-13 Clinical phase II NAABT-308 IL-13 Clinical phase I NACNTO 5825 IL-13 Clinical phase I NAGSK679586 IL-13 Clinical phase II NABrodalumab IL-17 Clinical phase II 2019Secukinumab IL-17 Clinical phase II NAMT203 GM-CSF Clinical phase II NAGolimumab TNF-α Suspended –Infliximab TNF-α Clinical phase II NAGW766994 CCR3 Clinical phase II NAAMG 761 CCR4 Clinical phase II NAGSK2239633 CCR4 Clinical phase II NAAM211 CRTH2 Clinical phase I NAARRY-502 CRTH2 Clinical phase I NAQAV 680 CRTH2 Clinical phase II NASetipiprant CRTH2 Clinical phase II NARG7185 CRTH2 Clinical phase I NAAMG 853 CRTH2/DPR Clinical phase III NAAZD 1981 CRTH2/DPR Clinical phase II NAAMG 157 TSLP Clinical phase II NAImatinib Tyrosine kinases Clinical phase II NA
1
NA = No estimated time of market launch has been announced; – = there will be no market launch (see text).
1 Already launched/approved to treat chronic granulocyte leukemia.
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Pharmacological Therapy of Bronchial
Asthma Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930243 Given the promise of these novel agents and the di-
verse array of targets, here we review the therapeutic ap-proaches used in patients with bronchial asthma, focus-ing on biologicals as potential novel therapies for severe asthma ( table 1 ).
The Pathophysiology of Asthma
Bronchial asthma is a chronic inflammatory and ob-
structive respiratory disease characterized by mucus hy-persecretion, bronchial hyperreactivity and obstruction, and airway remodeling. These pathophysiological features contribute to a progressive loss of lung function
[4, 5] . The
major clinical symptoms of bronchial asthma are episodic cough, wheezing, chest tightness, and paroxysmal dyspnea (intermittent shortness of breath). More recently, asthma has been recognized as a heterogeneous, complex disease that presents with different phenotypes
[2, 6, 7] .
The inflammatory processes seen in asthma are initi-
ated via interplay between cytokines produced by different cells including B and T lymphocytes, basophils, eosino-phils, neutrophils, mast cells, epithelial cells, mesenchymal cells, group 2 innate lymphoid cells (ILC2)
[8] , and airway
neurons. Asthma is also known to have a hereditary etio-logical component
[9] , with its development and progres-
sion dependent on gene-environment interactions [10] .
Dendritic cells (DC) recognize allergens and subse-
quently process antigen molecules ( fig. 1 ) to expose the antigens on the cell surface for presentation to naive T
H 0
cells. The resulting T H 2 activation arises from secretion
of the key interleukins (IL) IL-4, IL-5, and IL-13, probably from basophils, eosinophils, mast cells, and T cells
[11] .
T H 2 cells can release IL-5, which stimulates eosinopoiesis
and leads to the recruitment and maturation of eosino-phils, leading to severe eosinophilic bronchial asthma. Both IL-4 and IL-13 result in the production and secre-tion of IgE by inducing maturation of B lymphocytes to plasma cells
[12] . IgE is predominantly membranous, be-
ing anchored to the surface of mast cells [13] . Contact
between allergens and IgE antibodies initiates intracellu-lar signaling cascades
[14] and the secretion of histamine,
prostaglandins, cytokines, and other inflammatory me-diators
[15] . These mediators are proinflammatory and
affect a number of cell types including epithelial cells, gland cells and airway smooth muscle cells, leading to bronchoconstriction. Eosinophils, in turn, produce cyto-kines and leukotrienes, further increasing mucus secre-tion and bronchoconstriction. T
H 2 cells are also known
to release IL-4 and tumor growth factor (TGF)-β to acti-vate IL-9-producing T H 9 cells [16] . By triggering the pro-
liferation and recruitment of mast cells, IL-9 results in the release of different inflammatory cytokines. T
H 0 cells ac-
tivate T H 17 cells, a population of CD4-positive lympho-
cytes, via the release of TGF-β and IL-6 and the conse-quent production and secretion of IL-17A and IL-17F
[17–19] . IL-17A and IL-17F induce the migration and re-
cruitment of neutrophils [20] via the secretion of highly
potent chemoattractants such as CXC ligand 1 (CXCL1) and CXCL8 (IL-8). These chemoattractants are released by different airway cells such as subepithelial fibroblasts and respiratory bronchial cells
[21] .
Immune responses to viral respiratory infections are
thought to be initiated by the epithelium-derived cyto-kine thymic stromal lymphopoietin (TSLP). TSLP is a cy-tokine secreted by mast cells and bronchial epithelium. It mainly acts on DC and initiates the T
H 2-mediated asthma
response [22] . TSLP triggers the release of different cyto-
kines of the CC motif chemokine family. The CC chemo-kine receptors CC chemokine receptor type 3 (CCR3) and CCR4 are G-protein-coupled receptors that are high-ly expressed in eosinophils and basophils, T
H 1 and T H 2
cells, and airway epithelia. CCR3 and CCR4 act as recep-tors for a variety of chemokines including the eotaxins CCL5, CCL17, and CCL22, which play a role in asthma pathophysiology
[23] . There is evidence that CCR3 inhi-
bition may decrease inflammation, and CCR4 is believed to be able to recruit T
H 2 cells to inflammatory sites [24] .
CCR4 ligand binding induces the production and release of many cytokines
[25] including granulocyte-macro-
phage colony-stimulating factor (GM-CSF) [26] .
Tumor necrosis factor-α (TNF-α) is a cytokine re-
leased by macrophages, monocytes, and CD4 + T lympho-
cytes that also plays a role in neutrophilic asthma and promotes different inflammatory effects
[25, 27] .
Bronchial asthma is characterized not only by inflam-
matory processes but also by structural lung tissue altera-tions such as subepithelial fibrosis, increased airway smooth muscle cell proliferation, and extracellular matrix protein deposition. Bronchial membrane thickening de-creases lung function by limiting the airflow
[5, 25] .
Bronchial Asthma Phenotypes
The different phenotypes observed in asthma have
been explored in recent years. Although asthma was ini-tially classified into extrinsic and intrinsic types
[28] , this
classification was further characterized as T H 2 or non-
T H 2 phenotypes. The T H 2-induced phenotype includes
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Heck/Nguyen/Le/Bals/Dinh
Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930244early-onset allergic T H 2-mediated and late-onset persis-
tent eosinophilic asthma, with a range of severities [2] .
Early-onset asthma is often associated with other allergic comorbidities, and its progression can be mild to severe. Late-onset eosinophilic asthma is usually not atopic and is often severely progressive, characterized by increased numbers of sputum and blood eosinophils
[2, 29] . Asth-
ma may be triggered by environmental factors and a ge-netic predisposition
[30, 31] . The T H 2-mediated pheno-type also includes exercise-induced asthma (EIA), in
which symptoms normally occur during and/or after physical activity and increased dry and cold conditions
[2] . Asthma symptoms are often relatively mild in EIA
patients, although both high and low levels of eosinophil-ic inflammation have been reported in EIA
[32] .
Non-T H 2-mediated asthma is also divided into differ-
ent subtypes, i.e. women with late-onset asthma, obesity-related asthma, smoking-associated asthma, neutrophilic
IL-6
TGFɴ
NeutrophilTH17
Mucus Airway
musclesCXCL1
CXCL8IL-17A
IL-17F
IL-22
AnƟ-IL-17-Ab
•Broadalumab
•SecukinumabAllergensTH0
Subepithelial
FibroblastsIL-4TH2B cell
AnƟ-IL-4/IL-13-Ab
•Dupilumab
•PitrakinraAnƟ-IL-13-Ab
•Tralokinumab
•Lebrikizumab
•QAX-576
IL-13Mast cell
EosinophilTH9IgEAnƟ-IgE-Ab
•Omalizumab
•QGE-031
•MEDI-4212
•Quilizumab
AnƟ-IL-9-Ab
•MEDI-528IL-4
TGFɴIL-9
-C y t o k i n e s
– Histamines- Prostaglandins
-C y t o k i n e s
– Cysteinyl
leukotrienesIL-5
AnƟ-IL-5-Ab
•Mepolizumab
•Reslizumab
•BenralizumabAirway epithelium
DendriƟc cell
Fig. 1. Key players in the T H 2-mediated pathomechanism of asth-
ma. DC capture allergens within the cytoplasm, expose them on their surface, and present them to naive T
H 0 cells, which causes the
activation of T H 2 cells and the secretion of IL-4 and IL-13. Both of
these IL activate IgE production and secretion by inducing the mat-uration of B lymphocytes to plasma cells. The predominantly mem-branous IgE on mast cells initiates a signal cascade if activated by contact with an allergen. This leads to the secretion of histamines, prostaglandins, cytokines, and other inflammatory mediators. T
H 2
cells also release IL-5, which starts the maturation of eosinophils and finally causes increased mucus secretion in epithelial cells. The
expression of IL-4 and TGF-β activates T H 9 cells, which in turn re-
lease IL-9 and thereby cause the release of different cytokines, his-tamines, and other inflammatory mediators. The release of TGF-β and IL-6 by T
H 0 cells activates T H 17, which induces the release of
IL-17A and IL-17F. Both of these IL initiate the recruitment and expansion of neutrophils via activation of the secretion of chemoat-tractants (CXCL1 and CXCL8). CXCL1 and CXCL8 are secreted by different cellular components of lung tissue, such as subepithelial fibroblasts and respiratory bronchial cells.
Color version available online
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Pharmacological Therapy of Bronchial
Asthma Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930245asthma, and smooth muscle-mediated, paucigranulocytic
asthma [2] . Although these phenotypes represent a sub-
stantial proportion of all asthmatics, little is known about their onset
[2] . Obesity-related asthma is one of two non-
T H 2-related eosinophilic asthma phenotypes. Obesity has
a negative effect on lung function, and obese patients are more susceptible to gastroesophageal reflux, chest tight-ness, and hypoventilation; therefore, asthma may be mis-diagnosed in obese patients. Neutrophil-related asthma is another non-T
H 2-related asthma subtype that has yet to
be fully characterized [33] . There is evidence that T H 17
cells may contribute to this neutrophil-related asthma by promoting neutrophilic inflammation. T
H 17 cells release
IL-17, a major neutrophil chemoattractant, into the air-ways
[34] , and it has been shown that IL-17A and IL-17F
levels are associated with asthma severity and an increase in neutrophilic inflammation
[17] .
Current Pharmacotherapy
According to the Global Initiative for Asthma (GINA),
asthmatics should receive low- to high-dose inhaled ste-roids alone or in combination with other controllers such as LABA and/or leukotriene receptor antagonists (mon-telukast) and/or theophylline. Additionally, the long-act-ing muscarinic receptor antagonist tiotropium is recom-
mended for the treatment of severe asthma. Systemic ste-roids are also often needed in patients with severe asthma. The first biological licensed for asthma is an anti-IgE agent (omalizumab), which is recommended as the pre-ferred controller for patients with severe perennial aller-gic asthma and may be a suitable alternative treatment to systemic steroids ( table 2 ).
Anti-IgE Therapy
IgE levels are often increased in allergic asthmatics and
they are sometimes associated with allergic symptoms
[35] . To significantly reduce IgE-induced symptoms,
monoclonal anti-IgE antibodies have been recommended for the treatment of severe allergic asthma. Anti-IgE an-tibodies can bind free serous IgE and membranous IgE at the surface of mast cells and B lymphocytes
[36] .
Omalizumab binds free IgE with a high affinity by in-
teracting with its Cε3 domain [37] , thereby reducing asth-
ma exacerbations [38] . Moreover, omalizumab reduces
the expression of FcεRI on basophils and DC [39] . IgE
binding and the reduction in expressed FcεRI leads to in-hibition of further interactions with ligands and deactiva-tion of signaling cascades. The reduced interaction be- Table 2. Asthma classification and therapy: level of severity, associated symptoms, and suggested pharmacotherapy (GINA modified)
Level of asthma severity Symptoms Suggested therapy
1 (intermittent) <1 daytime and 2 nighttime symptoms/week
FEV 1 and PEF ≥80%
Diurnal variability of PEF <20%RABA if needed
2 (low-grade, persistent) Same but stronger symptoms than in level 1
More restrictions in physical activity and sleepDiurnal variability of PEF between 20 and 30%Low-dose ICS; alternatively,
LTRA (montelukast)
3 (moderate, persistent) Daily occurring symptoms
>1 nighttime symptomFEV and PEF of 60
– 80%
Diurnal variability of PEF >30%Middle-dose ICS or low-dose ICS
plus LABA
4 (high-grade, persistent) Persistent day-to-day symptoms;
Many exacerbations at day- and nighttime;High negative impact on physical activitiesFEV and PEF ≤60%Diurnal variability of PEF >30%Middle-to-high-dose ICS plus LABA
5 (uncontrolled, high-grade,
persistent)Same but stronger symptoms than in level of
severity 4Oral corticosteroids; monoclonal
antibodies in IgE-mediated asthma
RABA = Rapid-acting β
2 agonists; LTRA = leukotriene receptor antagonist.
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DOI: 10.1159/000443930246tween IgE and FcεRI avoids allergen-induced degranula-
tion. As well as reducing circulating IgE levels, new IgE production can be limited or prevented
[40] . Further-
more, inhibition of IgE-FcεRI binding on DC reduces an-tigen presentation to T lymphocytes.
However, omalizumab use is bound by specific clinical
criteria. Apart from being approved only for patients with severe asthma (level 5), patients need to: (a) have a forced expiratory volume in 1 s (FEV
1 ) under 80%, (b) be prick
test or radioallergosorbent test positive for a perennial inhalation allergen (e.g. mold or house dust), (c) have a serous IgE level between 30 and 1,500 IE/ml, and (d) not weigh over 150 kg. Omalizumab side effects include pru-ritus, headache, syncope, paresthesia, and anaphylaxis, which could ultimately be lethal due to anaphylactic shock, but, in general, the drug is well tolerated
[41] .
Based on a study to evaluate its postlaunch safety [42] , a
higher risk of suffering from thrombotic events caused by the therapy with omalizumab was reported.
Ligelizumab (QGE-031; Novartis) is a humanized
monoclonal anti-IgE antibody currently in phase III clin-ical trials. It binds with a higher affinity to IgE than oma-lizumab, and analyses have shown an almost 50-fold in-creased binding affinity to human IgE compared to omal-izumab
[43] . Ligelizumab suppresses free IgE more
rapidly and to a greater extent and also significantly re-duces the wheal diameter in skin prick tests compared to placebo and omalizumab
[44] . Ligelizumab is suggested
for the treatment of IgE-induced diseases like severe al-lergic asthma and atopic dermatitis.
MEDI-4212 (AstraZeneca) is also an antibody direct-
ed against human IgE that inhibits IgE-FcεRI binding and IgE-CD23 binding. Due to its strong inhibitory effect on IgE-FcεRI binding, MEDI-4212 is specific for the treat-ment of asthma patients with high circulating IgE.
Quilizumab (anti-M1 prime mAb; Roche) is a human-
ized monoclonal antibody currently in phase II clinical trials. Quilizumab binds the M1 prime domain of mem-branous IgE, thus preventing the differentiation of B lym-phocytes into IgE-producing plasma cells. Based on phase II clinical trial data, quilizumab may be suitable for the treatment of moderate to severe asthma. The drug has been retracted due to a lack of effect.
Anti-IL-5 Therapy
IL-5, which is secreted mainly by T H 2 cells but also in
smaller amounts by eosinophils and mast cells, plays a key role in the immune reaction by activating eosino-phils. The IL-5 receptor is the single interaction partner
of IL-5, but it also works in synergy with other signaling molecules such as chemokines, eotaxins, and IL-4 and IL-13 to drive the eosinophilic immune response
[45] .
The IL-5 receptor (IL-5R) is composed of α and β sub-units
[45, 46] . The α subunit binds peptides and the β
subunit is the signal transduction domain. The IL-5 re-ceptor is expressed on the surface of eosinophils, Eos progenitors (CD34+; eosinophil progenitor cells), mast cells, and basophils
[45, 46] . The intracellular signal is
mainly transduced via the Janus kinase-activated 2 (JAK2)/signal transducer and activator of transcription 3 (STAT-3) pathway
[46] .
Mepolizumab, a humanized monoclonal anti-IL-5 an-
tibody, reduced eosinophils in patients suffering from eo-sinophilic asthma, significantly lowering the number of eosinophils in circulation and in the lung and bone mar-row
[47] . Asthma exacerbations were distinctly decreased
[48, 49] , and side effects have not been observed to the
date of reporting [50] . Mepolizumab has just been ap-
proved for asthma therapy by the FDA (11/2015) and the approval from the EMA is launched.
Another humanized monoclonal anti-IL-5 antibody,
reslizumab, has been evaluated for the treatment of severe eosinophilic asthma
[51] . Animal studies revealed a 75%
decrease in eosinophil accumulation, and current clinical trials have shown a nonsignificant decrease in the asthma exacerbation rate
[52] .
Benralizumab also belongs to the group of monoclonal
anti-IL-5 antibodies, and it binds IL-5Rα with a high af-finity even in the presence of slight conformational changes of the epitope. This leads to interruption of IL-5R-mediated signal transduction and inhibition of IL-5R-dependent cell proliferation
[53] . There is evi-
dence to suggest that benralizumab may be effective in both serum and tissue
[54] , perhaps increasing the ulti-
mate clinical significance of this drug. Benralizumab is afucosylated, which improves the antibody dependent cell-mediated cytotoxicity
[55] .
Drugs Targeting IL-9
IL-9, derived from T H 2 and T H 9 cells, and the IL-9 re-
ceptor (IL-9R) are overexpressed in the airways of asth-matics
[56] . This leads to eosinophilic inflammation as-
sociated with airway hyperresponsiveness (AHR), mucus hyperplasia, mast cell proliferation
[57] , and augmented
expression of IgE and other T H 2-related cytokines [21] .
Additionally, IL-9 triggers IL-13 secretion.
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Pharmacological Therapy of Bronchial
Asthma Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930247 MEDI-528 is a humanized monoclonal anti-IL-9 anti-
body currently in phase II trials. Clinical trial results have differed; when MEDI-528 was used in addition to stan-dard asthma medication, there were no significant effects on asthma exacerbation rates, asthma control question-naire-6 (ACQ-6) scores, or FEV
1 compared to placebo
controls [58] . In patients with mild to moderate asthma,
there are some data to suggest that MEDI-528 might have clinical relevance. The two studies performed to the date of reporting indicate an improved quality of life with the use of this agent with respect to asthma symptoms and exacerbations
[59] .
Drugs Targeting IL-13
IL-13 plays a key role in the initiation and mainte-
nance of inflammation in bronchial asthma, where it ex-erts the following functions: (i) initiation of the IgM-to-IgE isotype switch in B lymphocytes
[60, 61] , (ii) media-
tion of the activation and proliferation of mast cells [62]
and smooth muscle cells [63] , and (iii) triggering of the
adhesion of eosinophils to vascular endothelial cells [64] .
In contrast to IL-4, which is able to mediate its effects via the type I IL-4R (IL-4α and IL-4) or the type II IL-4R, evidence suggests that IL-13 binds solely to the type II IL-4R, which consists of 2 subunits, i.e. the IL-13R-α1 and IL-4R-α chains. Therefore, it is thought that an IL-4-in-dependent IL-13 signaling pathway exists
[65] .
Tralokinumab is a humanized anti-IL-13 monoclonal
antibody currently in phase II trials. Furthermore, exper-iments in tralokinumab-treated mice showed that AHR and eosinophilic influx are reduced in an allergic airway inflammation model
[66] .
In a randomized multicenter study, lebrikizumab,
which blocks IL-13, significantly improved lung function in asthmatic patients. The drug seemed to have a marked differential impact depending on the asthma phenotype, being particularly effective in T
H 2 phenotypes with high
serous periostin levels.
Other anti-IL-13 agents include: QAX-576, an IL-13
antibody, which is being tested in an early-stage study of patients with moderate to severe asthma; anrukinzumab, a humanized monoclonal anti-IL-13 antibody currently in phase II clinical trials and showing significant im-provements in patients with mild atopic asthma
[25] ;
ABT-308, a high-affinity anti-human IL-13 antibody that prevents IL-13 binding to the IL-13Rα1 and IL-13Rα2 subunits, currently in phase I trials after showing signifi-cant effects in mice; CNTO 5825, a human monoclonal anti-IL-13 antibody that has exhibited good safety and
tolerability profiles in phase I clinical trials
[67] , and GSK
679586, a humanized anti-IL-13 IgG1 monoclonal anti-body that has currently completed phase II testing. GSK 679586 showed dose-dependent pharmacological activity in a randomized, placebo-controlled phase I dose escala-tion study
[68] .
Drugs Targeting IL-4
IL-4 and IL-13 share one receptor, i.e. the IL-4
α-subunit. The mechanism via which IL-13 is activated by IL-4R is not fully understood
[69] . It is known, however,
that IL-4 contributes to the pathomechanism of asthma by initiating T
H 2 differentiation, isotype switching of B lym-
phocytes during IgE synthesis, mast cell development, eo-sinophil recruitment, and mucus metaplasia
[21] . More-
over, IL-4 is a key player in fibronectin and collagen syn-thesis
[70] , which ultimately leads to airway remodeling.
Dupilumab, a human monoclonal antibody, is direct-
ed against IL-4Rα. IL-4 and IL-13 blockade directly af-fects IL-4R and indirectly affects downstream IL-13R pathways since IL-13 also binds to IL-4Rα. A clinical trial in moderate to severe asthmatics revealed a reduced risk of exacerbations and a significant improvement in most lung function tests
[71] .
Pitrakinra is a recombinant human protein that acts as
an IL-4 and IL-13 antagonist by competitively blocking IL-4Rα, thereby affecting both pathways simultaneously. By inhibiting IL-4 and IL-13, pitrakinra inhibits T
H 2-me-
diated immune responses [51] . Clinical and preclinical
animal studies have shown that pitrakinra is significantly more effective on AHR when inhaled rather than subcu-taneously injected
[72] .
Pascolizumab is a humanized anti-IL-4 antibody that
inhibits both upstream and downstream T H 2 pathway
events [73] . Pascolizumab was very well tolerated in a
phase I trial in adult patients with mild to moderate asth-ma, but it lacked clinical efficacy in a large-scale multi-dose phase II trial in steroid-naive patients with symp-tomatic asthma
[25] .
Altrakincept, a soluble recombinant human IL-4 re-
ceptor, contains the IL-4Rα chain but lacks the other do-mains. Thus, it cannot activate downstream cascades. IL-4 binds to the IL-4Rα domain of altrakincept and is therefore removed from the circulation. However, phase II clinical trials revealed no significant improvement in lung function and asthma symptoms
[74] with altrakin-
cept and no new studies are currently planned.
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Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930248 Drugs Targeting IL-17
IL-17 is secreted by T H 17 cells and plays an important
role in airway remodeling and neutrophilic inflamma-tion. IL-17 molecules comprise several subtypes, i.e. IL-17A, IL-17B, IL-17C, IL-17E (IL-25), and IL-17F
[17] .
IL-17 appears to be a promising drug target in asthma, with 2 antibodies in particular, i.e. broadalumab and secukinumab, showing promise. However, their thera-peutic effect, tolerability, and safety need to be confirmed in further clinical evaluations.
Brodalumab is a human IL-17-specific monoclonal
antibody in phase II clinical trials of patients with severe asthma not adequately controlled by inhaled corticoste-roids and LABA. Secukinumab targets IL-17A and is in phase II trials. It is suggested for use in patients with se-vere asthma that cannot be controlled with inhaled corti-costeroids and LABA.
Drugs Targeting GM-CSF
GM-CSF is a glycoprotein that plays a role in the trans-
duction of inflammatory reactions. GM-CSF is generated with other proinflammatory mediators, mainly by epi-thelial cells but also by fibroblasts, macrophages, mast cells, and natural killer cells; it is then released into the circulation
[75] . This leads to activation and differentia-
tion of various cell types that induce airway inflammation with resulting damage to the airway epithelium
[76] . Be-
cause of the role of GM-CSF during inflammatory events, it may represent a potential future drug target for the treatment of asthma
[77] .
Drugs Targeting TNF-α
TNF-α, a proinflammatory innate cytokine secreted by
macrophages, mast cells, T H 1 lymphocytes, and many oth-
er cell types, is overexpressed in the lung tissue of asthmat-ics and stimulates respiratory smooth muscle
[25] . During
airway inflammation, TNF-α recruits eosinophils and neu-trophils
[27] . Despite several controversies (regarding the
assertion that blocking TNF-α may lead to a higher risk of infection and cancer), clinical studies with infliximab, etanercept, and golimumab have been undertaken.
The human-murine chimeric monoclonal anti-TNF-α
antibody infliximab significantly improved lung function parameters (e.g. peak expiratory flow) and exacerbations in patients with moderate asthma
[78] . Etanercept is a recom-binant protein that binds both TNF-α and lymphotoxin
(TNF-β) with a high affinity; however, it showed no sig-nificant positive effects in a randomized, double-blind, pla-cebo-controlled phase II trial
[79] . Golimumab is an anti-
TNF-α antibody that should have been a candidate bio-logical for severe asthma. However, a large multicenter study revealed side effects including infection, pneumonia, tuberculosis, and malignancy (breast cancer and B-cell lymphoma)
[80] . Understandably, the research communi-
ty subsequently withdrew from further anti-TNF-α trials.
Drugs Targeting CCR3 and CCR4
Chemokines play a pivotal role in respiratory inflam-
mation [81] . The CC chemokine receptors CC chemo-
kine receptor type 3 (CCR3) and CCR4 are G-protein-coupled proteins that are highly expressed in eosinophils, basophils, T
H 1 and T H 2 cells, and airway epithelia. CCR3
and CCR4 act as receptors for a variety of chemokines such as eotaxins and CCL5, which play a role in the patho-genesis of bronchial asthma
[23] . There is evidence to
suggest that CCR3 inhibition may decrease airway in-flammation. CCR4 is believed to be able to recruit T
H 2
cells to the site of inflammation [24] .
GW 766994 is a selective, competitively binding CCR3
antagonist that has already completed phase I trials in pa-tients with mild to moderate asthma and high sputum eosinophilia
[23] . Mogamulizumab (AMG 761) is a hu-
manized monoclonal afucosylated anti-CCR4 IgG1 anti-body
[82] . It is currently in phase I trials, and no safety
and efficiency data has yet been published.
GSK2239633 [N-(3-[(3-[5-chlorothiophene-2-sulf o-
namido]-4-methoxy-1H-indazol-1-yl)methyl]benzyl)-2-hydroxy-2-methylpropanamide] is a potent CCR4 an-tagonist that acts by inhibiting CCR4-TARC (thymus and activation-regulated chemokine) binding and interrupting downstream signaling cascades
[24] . The drug is currently
in phase I trials. In an open-label study and a randomized clinical trial, GSK 2239633 significantly inhibited TARC from activating the CCR4 receptor
[24] .
Drugs Targeting CRTH2 and CRTH2/DPR
Chemoattractant receptor-homologous molecule ex-
pressed on T H 2 cells (CRTH2) and D-type prostanoid
receptor (DPR) are G-protein-coupled prostaglandin (PGD
2 ) receptors. PGD 2 is secreted by mast cells during
inflammation, including in asthma [83] . Binding of PGD 2
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Asthma Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930249to CRTH2 and DPR, respectively, mediates basophil, eo-
sinophil, and T H 2 cell chemotaxis, prolongs their survival
[84] , and stimulates the secretion of different cytokines
[85] . Hence, potent CRTH2 and/or DPR antagonists might
be a promising strategy in asthma treatment. Several en-couraging antagonists are in different stages of develop-ment.
The two CRTH2 antagonists in phase I clinical trials
are AM211 [(2 ′-[3-benzyl-1-ethyl-ureidomethyl]-6-
methoxy-4 ′-trifluoromethyl-biphenyl-3-yl)-acetic acid
sodium salt] [86] and RG7185. To the date of reporting,
three CRTH2 antagonists have been tested in phase II tri-als, i.e. NAV-QAV680, which showed good bioavailabil-ity in rats and rodents
[87] , setipiprant [2-(2-[1-naph tho-
yl]-8-fluoro-3,4-dihydro-1H-pyrido(4, 3-b)indol-5[2H]-yl)acetic acid]
[88] , and ARRY-502.
Two CRTH2/DRP antagonists are also currently un-
der clinical investigation. AMG853 showed no clinicalefficacy in a phase II trial
[89] , while AZD1981 [4-
(acetylamino)-3-([4-chlorophenyl] thio)-2-methyl-1H-indole-1-acetic acid] is a new CRTH2/DPR antagonist in phase II clinical trials. To date, no data on its clinical and pharmaceutical properties have been published
[90] . The
major symptoms of aspirin-exacerbated respiratory dis-ease (also termed Samter’s triad) are nasal polyps, chron-ic hypertrophic eosinophilic sinusitis, and asthma. Aspi-rin and other nonsteroidal anti-inflammatory drugs are known to inhibit the cyclooxygenase-1 (COX-1) enzyme. Inhibition of the COX pathway may cause rhinitis, con-junctivitis, laryngospasm, and bronchospasm. This leads to a shift to increased leukotriene production, resulting in airway inflammation and bronchoconstriction. Under physiological conditions, PGD
2 suppresses the release of
histamines and prostaglandins from mast cells. In the presence of aspirin and other nonsteroidal anti-inflam-matory drugs, the COX-1/PGD
2 -induced inhibition of
mast cell activation is diminished, which leads to the ac-tivation of mast cells, including the release of histamines and PGD
2 [91] . As CRTH2/DRP antagonists, AMG853
and AZD1981 may be useful in the therapy of aspirin-induced respiratory diseases.
Drugs Targeting Epithelium-Derived Cytokines
The epithelial cells that line mucosal surfaces not only
act as a physical barrier but also participate in immune reactions. Small-airway epithelial cells produce different cytokines and thus affect T
H 2-mediated immune re-
sponses. TSLP, IL-25, and IL-33 represent a group of so-called epithelial cell-derived cytokines. Treatment of pa-
tients with mild atopic asthma with the human anti-TSLP monoclonal immunoglobulin AMG 157 in a double-blind, placebo-controlled study showed a decrease in al-lergen-induced bronchoconstriction
[92] . In mice, anti-
IL-33 reduced airway inflammation and decreased airway remodeling
[93] . IL-25 (also IL-17E) and its receptor
were recently shown to be expressed on eosinophils from patients with allergic asthma
[94] . Application of a mono-
clonal anti-IL-25 antibody in mice prevented AHR [95] ,
and IL-25 may represent another promising drug target.
Drugs Inhibiting Tyrosine Kinases
Tyrosine kinases play a pivotal role in the course of
asthma, especially in remodeling processes in lung tissue
[96] . The activation of tyrosine kinases initiates a broad
spectrum of downstream effector molecules and repre-sents a promising target for drug treatment of asthma. A study in an animal model of asthma in guinea pigs showed encouraging results concerning the reduction of inflam-matory effects of the broad-range protein tyrosine-kinase inhibitor genistein
[97] . The use of imatinib, a tyrosine
kinase inhibitor in a phase II trial, which is already ap-proved for the treatment of chronic granulocytic leuke-mia, showed promising results in a mouse model for al-lergic airway inflammation concerning the prevention of inflammatory and remodeling events in lung tissue
[98] .
Another drug against chronic granulocyte leukemia that has already shown promising and even more positive ef-fects than imatinib is nilotinib
[99] . Clinical trials con-
cerning safety and efficacy in asthma are yet to come.
Drug Use for an Unapproved Indication
In addition to guideline-driven treatment, some drugs
have also been used to treat bronchial asthma as an unap-proved indication.
Asthma patients are often also treated with macrolides
(azithromycin, roxithromycin, and clarithromycin). Macrolides are often used as antibiotics to treat acute bac-terial respiratory infections. There is growing evidence that macrolides not only exert an antibacterial effect but also modulate the immune system to improve inflamma-tory responses
[100] . The long-term use of macrolides
may improve several lung function parameters such as the FEV
1 and the peak expiratory flow and decrease
symptoms like AHR [101] .
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DOI: 10.1159/000443930250 References
1 Dougherty RH, Fahy JV: Acute exacerbations
of asthma: epidemiology, biology and the ex-acerbation-prone phenotype. Clin Exp Aller-gy 2009;
39: 193–202.
2 Wenzel SE: Asthma phenotypes: the evolu-
tion from clinical to molecular approaches. Nat Med 2012;
18: 716–725.
3 Custovic A, Johnston SL, Pavord I, et al:
EAACI position statement on asthma exacer-bations and severe asthma. Allergy 2013;
68:
1520–1531.
4 D’Agostino B, Advenier C, De PR, et al: The
involvement of sensory neuropeptides in air-way hyper-responsiveness in rabbits sensi-tized and challenged to Parietaria judaica.
Clin Exp Allergy 2002;
32: 472–479.
5 Pascual RM, Peters SP: Airway remodeling
contributes to the progressive loss of lung function in asthma: an overview. J Allergy Clin Immunol 2005;
116: 477–486.
6 Loxham M, Davies DE, Blume C: Epithelial
function and dysfunction in asthma. Clin Exp Allergy 2014;
44: 1299–1313.
7 Woodruff PG, Modrek B, Choy DF, et al: T-
helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;
180: 388–395.
8 Duerr CU, McCarthy CD, Mindt BC, et al:
Type I interferon restricts type 2 immunopa-thology through the regulation of group 2 in-nate lymphoid cells. Nat Immunol 2015;
17:
65–75.
9 Lluis A, Ballenberger N, Illi S, et al: Regulation
of T17 markers early in life through maternal farm exposure. J Allergy Clin Immunol 2014;

133: 864–871.
10 Bouzigon E, Corda E, Aschard H, et al: Effect
of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 2008;
359:
1985–1994.
11 Sokol CL, Barton GM, Farr AG, Medzhitov R:
A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Im-munol 2008;
9: 310–318.
12 Beier KC, Kallinich T, Hamelmann E: Master
switches of T-cell activation and differentia-tion. Eur Respir J 2007;
29: 804–812.
13 Galli SJ, Tsai M: IgE and mast cells in allergic
disease. Nat Med 2012; 18: 693–704.
14 Gould HJ, Sutton BJ: IgE in allergy and asth-
ma today. Nat Rev Immunol 2008; 8: 205–217.
15 Rivera J, Gilfillan AM: Molecular regulation
of mast cell activation. J Allergy Clin Immu-nol 2006;
117: 1214–1225.
16 Veldhoen M, Uyttenhove C, Van SJ, et al:
Transforming growth factor-beta ‘repro-grams’ the differentiation of T helper 2cells and promotes an interleukin 9-pro-ducing subset. Nat Immunol 2008;
9: 1341–
1346. 17 Al-Ramli W, Prefontaine D, Chouiali F, et al:
T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immu-nol 2009;
123: 1185–1187.
18 Naji N, Smith SG, Gauvreau GM, O’Byrne
PM: T helper 17 cells and related cytokines after allergen inhalation challenge in allergic asthmatics. Int Arch Allergy Immunol 2014;

165: 27–34.
19 Herbert C, Shadie AM, Kumar RK: Interleu-
kin-17 signalling in a murine model of mild chronic asthma. Int Arch Allergy Immunol 2013;
162: 253–262.
20 Wang A, Wang Z, Cao Y, et al: CCL2/CCR2-
dependent recruitment of Th17 cells but not Tc17 cells to the lung in a murine asthma mod-el. Int Arch Allergy Immunol 2015;
166: 52–62.
21 Barnes PJ: The cytokine network in asthma
and chronic obstructive pulmonary disease. J Clin Invest 2008;
118: 3546–3556.
22 Zhou B, Comeau MR, De ST, et al: Thymic
stromal lymphopoietin as a key initiator of al-lergic airway inflammation in mice. Nat Im-munol 2005;
6: 1047–1053.
23 Neighbour H, Boulet LP, Lemiere C, et al:
Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 2014;
44: 508–
516. Cyclosporine is another off-label drug used to treat
asthma. Cyclosporine is immunosuppressive by inhibit-ing T lymphocyte function
[102] and avoiding the release
of proinflammatory mediators by basophils and mast cells
[103] . Specifically, it inhibits GM-CSF, IL-5, eotaxin,
and bronchial eosinophilia [104] . Cyclosporine has been
shown to improve several lung function parameters [105] ,
but adverse side effects such as infection, hypertrichosis, tremor, and paraesthesia limit its use
[102] .
Methotrexate is an immunotherapy that inhibits the
enzyme dihydrofolate reductase [103] , IL-1, and baso-
philic histamine release [106] . Since no large-scale studies
have been conducted to test its safety and efficacy, meth-otrexate use for the treatment of severe asthma remains controversial due to potentially severe side effects includ-ing a deranged liver function, disordered hematopoiesis, and infections that can ultimately lead to sepsis
[107] .
Azathioprine is another immunosuppressive agent
that is used as an oral corticosteroid-sparing agent [108] .
Azathioprine inhibits purine synthesis and thus inhibits lymphocyte proliferation
[109] . However, there is only
limited efficacy and safety data on azathioprine in the context of asthma, and more studies will need to be per-formed to evaluate its use in asthma. Likewise, interferon may also be a potent asthma treatment, particularly
interferon-λ, which has been found to modulate the re-lease of T
H 1 cytokines and activate T H 1 pathway drift
[110] .
In general, these off-label drugs can disrupt hemato-
poiesis, derange liver enzymes, and lead to infections. The outcome of an off-labeled drug therapy is dependent on the individual and therapy is not always successful.
Conclusion
Bronchial asthma is a heterogeneous, complex, chron-
ic inflammatory and obstructive disease with many dif-ferent phenotypes. The recognition, identification, and characterization of T
H 2 and non-T H 2 phenotypes have
driven the development of molecular targeted therapies that are likely to become available in the near future. Many promising drugs are currently undergoing clinical trials that not only target the main IL but also receptors (such as chemokine receptors) and other signaling pro-teins. These are showing promise in meeting the ultimate goal of controlling severe, treatment-refractory asthma.

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Pharmacological Therapy of Bronchial
Asthma Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930251 24 Cahn A, Hodgson S, Wilson R, et al: Safety,
tolerability, pharmacokinetics and pharma-codynamics of GSK2239633, a CC-chemo-kine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol 2013;
14: 14.
25 Pelaia G, Vatrella A, Maselli R: The potential
of biologics for the treatment of asthma. Nat Rev Drug Discov 2012;
11: 958–972.
26 Hamid Q, Tulic M: Immunobiology of asth-
ma. Annu Rev Physiol 2009; 71: 489–507.
27 Lukacs NW, Strieter RM, Chensue SW, Wid-
mer M, Kunkel SL: TNF-alpha mediates re-cruitment of neutrophils and eosinophils during airway inflammation. J Immunol 1995;
154: 5411–5417.
28 Barnes PJ: Intrinsic asthma: not so different
from allergic asthma but driven by superanti-gens? Clin Exp Allergy 2009;
39: 1145–1151.
29 Fitzpatrick AM, Teague WG, Meyers DA, et
al: Heterogeneity of severe asthma in child-hood: confirmation by cluster analysis of chil-dren in the National Institutes of Health/Na-tional Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Im-munol 2011;
127: 382–389.
30 Moore WC, Meyers DA, Wenzel SE, et al:
Identification of asthma phenotypes using cluster analysis in the Severe Asthma Re-search Program. Am J Respir Crit Care Med 2010;
181: 315–323.
31 Molfino NA, Gossage D, Kolbeck R, Parker
JM, Geba GP: Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy 2012;
42: 712–
737.
32 Karjalainen EM, Laitinen A, Sue-Chu M, Al-
traja A, Bjermer L, Laitinen LA: Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperre-sponsiveness to methacholine. Am J Respir Crit Care Med 2000;
161: 2086–2091.
33 Jatakanon A, Uasuf C, Maziak W, Lim S,
Chung KF, Barnes PJ: Neutrophilic inflam-mation in severe persistent asthma. Am J Respir Crit Care Med 1999;
160: 1532–1539.
34 Laan M, Cui ZH, Hoshino H, et al: Neutrophil
recruitment by human IL-17 via C-X-C che-mokine release in the airways. J Immunol 1999;
162: 2347–2352.
35 Platts-Mills TA: The role of immunoglobulin
E in allergy and asthma. Am J Respir Crit Care Med 2001;
164:S1–S5.
36 Chang TW: The pharmacological basis of anti-
IgE therapy. Nat Biotechnol 2000; 18: 157–162.
37 Takaku Y, Soma T, Nishihara F, et al: Omali-
zumab attenuates airway inflammation and interleukin-5 production by mononuclear cells in patients with severe allergic asthma. Int Arch Allergy Immunol 2013;
161(suppl
2):107–117.
38 Hanania NA, Alpan O, Hamilos DL, et al:
Omalizumab in severe allergic asthma inade-quately controlled with standard therapy: a randomized trial. Ann Intern Med 2011;
154:
573–582. 39 Chanez P, Contin-Bordes C, Garcia G, et al:
Omalizumab-induced decrease of FcεRI ex-pression in patients with severe allergic asth-ma. Respir Med 2010;
104: 1608–1617.
40 Holgate S, Casale T, Wenzel S, Bousquet J,
Deniz Y, Reisner C: The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol 2005;
115: 459–465.
41 Vignola AM, Humbert M, Bousquet J, et al:
Efficacy and tolerability of anti-immunoglob-ulin E therapy with omalizumab in patients with concomitant allergic asthma and persis-tent allergic rhinitis: SOLAR. Allergy 2004;
59:
709–717.
42 Ali AK, Hartzema AG: Assessing the associa-
tion between omalizumab and arteriothrom-botic events through spontaneous adverse event reporting. J Asthma Allergy 2012;
5: 1–9.
43 Menzella F, Lusuardi M, Galeone C, Zucchi L:
Tailored therapy for severe asthma. Multidis-cip Respir Med 2015;
10: 1.
44 Arm JP, Bottoli I, Skerjanec A, et al: Pharma-
cokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy 2014;
44: 1371–1385.
45 Rosenberg HF, Phipps S, Foster PS: Eosino-
phil trafficking in allergy and asthma. J Al-lergy Clin Immunol 2007;
119: 1303–1310.
46 Ogata N, Kouro T, Yamada A, et al: JAK2 and
JAK1 constitutively associate with an inter-leukin-5 (IL-5) receptor alpha and betac sub-unit, respectively, and are activated upon IL-5 stimulation. Blood 1998;
91: 2264–2271.
47 Busse WW, Ring J, Huss-Marp J, Kahn JE: A
review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syn-dromes and asthma. J Allergy Clin Immunol 2010;
125: 803–813.
48 Haldar P, Brightling CE, Hargadon B, et al:
Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;
360:
973–984.
49 Nair P, Pizzichini MM, Kjarsgaard M, et al:
Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;
360: 985–993.
50 Roufosse FE, Kahn JE, Gleich GJ, et al: Long-
term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol 2013;
131: 461–467.
51 Hambly N, Nair P: Monoclonal antibodies for
the treatment of refractory asthma. Curr Opin Pulm Med 2014;
20: 87–94.
52 Walsh GM: Profile of reslizumab in eosino-
philic disease and its potential in the treat-ment of poorly controlled eosinophilic asth-ma. Biologics 2013;
7: 7–11.
53 Busse WW, Katial R, Gossage D, et al: Safety
profile, pharmacokinetics, and biologic activ-ity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol 2010;

125: 1237–1244. 54 Laviolette M, Gossage DL, Gauvreau G, et al:
Effects of benralizumab on airway eosino-phils in asthmatic patients with sputum eo-sinophilia. J Allergy Clin Immunol 2013;
132:
1086–1096.
55 Kolbeck R, Kozhich A, Koike M, et al: MEDI-
563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol 2010;
125: 1344–1353.
56 Zhou Y, McLane M, Levitt RC: Th2 cytokines
and asthma: interleukin-9 as a therapeutic target for asthma. Respir Res 2001;
2: 80–84.
57 Louahed J, Zhou Y, Maloy WL, et al: Interleu-
kin 9 promotes influx and local maturation of eosinophils. Blood 2001;
97: 1035–1042.
58 Oh CK, Leigh R, McLaurin KK, Kim K,
Hultquist M, Molfino NA: A randomized, controlled trial to evaluate the effect of an an-ti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res 2013;
14: 93.
59 Parker JM, Oh CK, LaForce C, et al: Safety
profile and clinical activity of multiple subcu-taneous doses of MEDI-528, a humanized an-ti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm Med 2011;
11: 14.
60 Punnonen J, de Vries JE: IL-13 induces prolif-
eration, Ig isotype switching, and Ig synthesis by immature human fetal B cells. J Immunol 1994;
152: 1094–1102.
61 Punnonen J, Aversa G, Cocks BG, et al: Inter-
leukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 1993;
90: 3730–3734.
62 Kaur D, Hollins F, Woodman L, et al: Mast
cells express IL-13R alpha 1: IL-13 promotes human lung mast cell proliferation and Fc ep-silon RI expression. Allergy 2006;
61: 1047–
1053.
63 Risse PA, Jo T, Suarez F, et al: Interleukin-13
inhibits proliferation and enhances contrac-tility of human airway smooth muscle cells without change in contractile phenotype. Am J Physiol Lung Cell Mol Physiol 2011;

300:L958–L966.
64 Horie S, Okubo Y, Hossain M, et al: Interleu-
kin-13 but not interleukin-4 prolongs eosino-phil survival and induces eosinophil chemo-taxis. Intern Med 1997;
36: 179–185.
65 Munitz A, Brandt EB, Mingler M, Finkelman
FD, Rothenberg ME: Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci USA 2008;
105: 7240–7245.
66 Walsh GM: Tralokinumab, an anti-IL-13
mAb for the potential treatment of asthma and COPD. Curr Opin Investig Drugs 2010;

11: 1305–1312.
67 van HB, Nnane IP, Bouman-Thio E, et al:
Safety, tolerability and pharmacokinetics of a human anti-interleukin-13 monoclonal anti-body (CNTO 5825) in an ascending single-dose first-in-human study. Br J Clin Pharma-col 2013;
75: 1289–1298.
Downloaded by:
87.248.178.222 – 1/26/2017 7:25:03 PM

Heck/Nguyen/Le/Bals/Dinh
Int Arch Allergy Immunol 2015;168:241–252
DOI: 10.1159/000443930252 68 Hodsman P, Ashman C, Cahn A, et al: A
phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 mono-clonal antibody in healthy subjects and mild asthmatics. Br J Clin Pharmacol 2013;
75: 118–
128.
69 Long AA: Monoclonal antibodies and other
biologic agents in the treatment of asthma. MAbs 2009;
1: 237–246.
70 Sempowski GD, Beckmann MP, Derdak S,
Phipps RP: Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors: role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immu-nol 1994;
152: 3606–3614.
71 Wenzel S, Ford L, Pearlman D, et al: Dupi-
lumab in persistent asthma with elevated eo-sinophil levels. N Engl J Med 2013;
368: 2455–
2466.
72 Burmeister GE, Fisher DM, Fuller R: Human
pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antago-nist in asthma. J Clin Pharmacol 2009;
49:
1025–1036.
73 Hart TK, Blackburn MN, Brigham-Burke M,
et al: Preclinical efficacy and safety of pascoli-zumab (SB 240683): a humanized anti-inter-leukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol 2002;
130: 93–
100.
74 Steinke JW: Anti-interleukin-4 therapy. Im-
munol Allergy Clin North Am 2004; 24: 599–
614, vi.
75 Mir-Kasimov M, Sturrock A, McManus M,
Paine R 3rd: Effect of alveolar epithelial cell plasticity on the regulation of GM-CSF ex-pression. Am J Physiol Lung Cell Mol Physiol 2012;
302:L504–L511.
76 Holgate ST, Roberts G, Arshad HS, Howarth
PH, Davies DE: The role of the airway epithe-lium and its interaction with environmental factors in asthma pathogenesis. Proc Am Thorac Soc 2009;
6: 655–659.
77 Krinner EM, Raum T, Petsch S, et al: A human
monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF. Mol Immunol 2007;
44: 916–925.
78 Erin EM, Leaker BR, Nicholson GC, et al: The
effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asth-ma. Am J Respir Crit Care Med 2006;
174:
753–762.
79 Holgate ST, Noonan M, Chanez P, et al: Effi-
cacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J 2011;
37: 1352–1359.
80 Wenzel SE, Barnes PJ, Bleecker ER, et al: A
randomized, double-blind, placebo-con-trolled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009;
179: 549–558.
81 Alkhouri H, Moir LM, Armour CL, Hughes
JM: CXCL1 is a negative regulator of mast cell chemotaxis to airway smooth muscle cell products in vitro. Clin Exp Allergy 2014;
44:
381–392. 82 Subramaniam JM, Whiteside G, McKeage K,
Croxtall JC: Mogamulizumab: first global ap-proval. Drugs 2012;
72: 1293–1298.
83 Arima M, Fukuda T: Prostaglandin D(2) and
T(H)2 inflammation in the pathogenesis of bronchial asthma. Korean J Intern Med 2011;

26: 8–18.
84 Schuligoi R, Sturm E, Luschnig P, et al:
CRTH2 and D-type prostanoid receptor an-tagonists as novel therapeutic agents for in-flammatory diseases. Pharmacology 2010;
85:
372–382.
85 Kostenis E, Ulven T: Emerging roles of DP
and CRTH2 in allergic inflammation. Trends Mol Med 2006;
12: 148–158.
86 Bain G, King CD, Brittain J, et al: Pharmaco-
dynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2. J Clin Phar-macol 2012;
52: 1482–1493.
87 Sandham DA, Arnold N, Aschauer H, et al:
Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 re-ceptor antagonist suitable for clinical testing in allergic diseases. Bioorg Med Chem 2013;

21: 6582–6591.
88 Fretz H, Valdenaire A, Pothier J, et al: Identi-
fication of 2-[2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido(4, 3-b)indol-5(2H)-yl]acetic acid (setipiprant/ACT-129968), a po-tent, selective, and orally bioavailable che-moattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist. J Med Chem 2013;
56: 4899–4911.
89 Busse WW, Wenzel SE, Meltzer EO, et al:
Safety and efficacy of the prostaglandin D2 re-ceptor antagonist AMG 853 in asthmatic pa-tients. J Allergy Clin Immunol 2013;
131: 339–
345.
90 Schmidt JA, Bell FM, Akam E, et al: Biochem-
ical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asth-ma. Br J Pharmacol 2013;
168: 1626–1638.
91 Fischer AR, Rosenberg MA, Lilly CM, et al:
Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensi-tive asthma. J Allergy Clin Immunol 1994;
94:
1046–1056.
92 Gauvreau GM, O’Byrne PM, Boulet LP, et al:
Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 2014;
370: 2102–2110.
93 Mizutani N, Nabe T, Yoshino S: Interleu-
kin-33 and alveolar macrophages contribute to the mechanisms underlying the exacerba-tion of IgE-mediated airway inflammation and remodelling in mice. Immunology 2013;

139: 205–218.
94 Tang W, Smith SG, Beaudin S, et al: IL-25 and
IL-25 receptor expression on eosinophils from subjects with allergic asthma. Int Arch Allergy Immunol 2014;
163: 5–10. 95 Ballantyne SJ, Barlow JL, Jolin HE, et al:
Blocking IL-25 prevents airway hyperre-sponsiveness in allergic asthma. J Allergy Clin Immunol 2007;
120: 1324–1331.
96 Wong WS: Inhibitors of the tyrosine kinase
signaling cascade for asthma. Curr Opin Pharmacol 2005;
5: 264–271.
97 Duan W, Kuo IC, Selvarajan S, Chua KY,
Bay BH, Wong WS: Antiinflammatory ef-fects of genistein, a tyrosine kinase inhibi-tor, on a guinea pig model of asthma. Am J Respir Crit Care Med 2003;
167: 185–192.
98 Rhee CK, Kim JW, Park CK, et al: Effect of
imatinib on airway smooth muscle thicken-ing in a murine model of chronic asthma. Int Arch Allergy Immunol 2011;
155: 243–
251.
99 Rhee CK, Kang JY, Park CK, et al: Effect of
nilotinib on airway remodeling in a murine model of chronic asthma. Exp Lung Res 2014;
40: 199–210.
100 Tamaoki J, Kadota J, Takizawa H: Clinical
implications of the immunomodulatory ef-fects of macrolides. Am J Med 2004;

117(suppl 9A):5S–11S.
101 Tong X, Guo T, Liu S, et al: Macrolide anti-
biotics for treatment of asthma in adults: a meta-analysis of 18 randomized controlled clinical studies. Pulm Pharmacol Ther 2014;

31: 99–108.
102 Alexander AG, Barnes NC, Kay AB: Trial of
cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet 1992;
339:
324–328.
103 Mathew J, Aronow WS, Chandy D: Thera-
peutic options for severe asthma. Arch Med Sci 2012;
8: 589–597.
104 Khan LN, Kon OM, MacFarlane AJ, et al:
Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is as-sociated with inhibition of bronchial eosin-ophils, interleukin-5, granulocyte macro-phage colony-stimulating factor, and eotax-in. Am J Respir Crit Care Med 2000;
162:
1377–1382.
105 Coren ME, Rosenthal M, Bush A: The use of
cyclosporin in corticosteroid dependent asthma. Arch Dis Child 1997;
77: 522–523.
106 Calderon E, Coffey RG, Lockey RF: Metho-
trexate in bronchial asthma. J Allergy Clin Immunol 1991;
88: 274–276.
107 Attar SM: Adverse effects of low dose meth-
otrexate in rheumatoid arthritis patients: a hospital-based study. Saudi Med J 2010;
31:
909–915.
108 Dean T, Dewey A, Bara A, Lasserson TJ,
Walters EH: Azathioprine as an oral corti-costeroid sparing agent for asthma. Co-chrane Database Syst Rev 2004;CD003270.
109 Sahasranaman S, Howard D, Roy S: Clinical
pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008;
64:
753–767.
110 Koch S, Finotto S: Role of interferon-lamb-
da in allergic asthma. J Innate Immun 2015;
7: 224–230.

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