Bronchial asthma is a heterogeneous, complex, chronic inflammatory 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 guideline therapy with high doses of inhaled steroids plus a second controller, such as long-acting β2 agonists (LABA) or leukotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new therapeutic 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 cytokine-targeting therapies, particularly those targeting interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithelium-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the development of novel biologicals that target a diverse array of phenotype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeutic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel therapies for severe asthma.

1.
Dougherty RH, Fahy JV: Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy 2009;39:193-202.
2.
Wenzel SE: Asthma phenotypes: the evolution 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 exacerbations and severe asthma. Allergy 2013;68:1520-1531.
4.
D'Agostino B, Advenier C, De PR, et al: The involvement of sensory neuropeptides in airway hyper-responsiveness in rabbits sensitized 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 immunopathology through the regulation of group 2 innate 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 Immunol 2008;9:310-318.
12.
Beier KC, Kallinich T, Hamelmann E: Master switches of T-cell activation and differentiation. 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 asthma today. Nat Rev Immunol 2008;8:205-217.
15.
Rivera J, Gilfillan AM: Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006;117:1214-1225.
16.
Veldhoen M, Uyttenhove C, Van SJ, et al: Transforming growth factor-beta ‘reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing 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 Immunol 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: Interleukin-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 model. 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 allergic airway inflammation in mice. Nat Immunol 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.
24.
Cahn A, Hodgson S, Wilson R, et al: Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine 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 asthma. Annu Rev Physiol 2009;71:489-507.
27.
Lukacs NW, Strieter RM, Chensue SW, Widmer M, Kunkel SL: TNF-alpha mediates recruitment 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 superantigens? Clin Exp Allergy 2009;39:1145-1151.
29.
Fitzpatrick AM, Teague WG, Meyers DA, et al: Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol 2011;127:382-389.
30.
Moore WC, Meyers DA, Wenzel SE, et al: Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research 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, Altraja A, Bjermer L, Laitinen LA: Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness 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 inflammation 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 chemokine 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: Omalizumab 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 inadequately 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 expression in patients with severe allergic asthma. 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-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004;59:709-717.
42.
Ali AK, Hartzema AG: Assessing the association between omalizumab and arteriothrombotic 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. Multidiscip Respir Med 2015;10:1.
44.
Arm JP, Bottoli I, Skerjanec A, et al: Pharmacokinetics, 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: Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol 2007;119:1303-1310.
46.
Ogata N, Kouro T, Yamada A, et al: JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, 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 syndromes 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 eosinophilic disease and its potential in the treatment of poorly controlled eosinophilic asthma. Biologics 2013;7:7-11.
53.
Busse WW, Katial R, Gossage D, et al: Safety profile, pharmacokinetics, and biologic activity 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 eosinophils in asthmatic patients with sputum eosinophilia. 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: Interleukin 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 anti-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 subcutaneous doses of MEDI-528, a humanized anti-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 proliferation, 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: Interleukin 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 epsilon RI expression. Allergy 2006;61:1047-1053.
63.
Risse PA, Jo T, Suarez F, et al: Interleukin-13 inhibits proliferation and enhances contractility 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: Interleukin-13 but not interleukin-4 prolongs eosinophil survival and induces eosinophil chemotaxis. 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 antibody (CNTO 5825) in an ascending single-dose first-in-human study. Br J Clin Pharmacol 2013;75:1289-1298.
68.
Hodsman P, Ashman C, Cahn A, et al: A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal 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 Immunol 1994;152:3606-3614.
71.
Wenzel S, Ford L, Pearlman D, et al: Dupilumab in persistent asthma with elevated eosinophil 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 antagonist in asthma. J Clin Pharmacol 2009;49:1025-1036.
73.
Hart TK, Blackburn MN, Brigham-Burke M, et al: Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol 2002;130:93-100.
74.
Steinke JW: Anti-interleukin-4 therapy. Immunol 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 expression. 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 epithelium 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 asthma. Am J Respir Crit Care Med 2006;174:753-762.
79.
Holgate ST, Noonan M, Chanez P, et al: Efficacy 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-controlled 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 approval. 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 antagonists as novel therapeutic agents for inflammatory 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: Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2. J Clin Pharmacol 2012;52:1482-1493.
87.
Sandham DA, Arnold N, Aschauer H, et al: Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases. Bioorg Med Chem 2013;21:6582-6591.
88.
Fretz H, Valdenaire A, Pothier J, et al: Identification 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 potent, selective, and orally bioavailable chemoattractant 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 receptor antagonist AMG 853 in asthmatic patients. J Allergy Clin Immunol 2013;131:339-345.
90.
Schmidt JA, Bell FM, Akam E, et al: Biochemical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asthma. 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-sensitive 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: Interleukin-33 and alveolar macrophages contribute to the mechanisms underlying the exacerbation 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 hyperresponsiveness 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 effects of genistein, a tyrosine kinase inhibitor, 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 thickening 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 effects of macrolides. Am J Med 2004;117(suppl 9A):5S-11S.
101.
Tong X, Guo T, Liu S, et al: Macrolide antibiotics 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: Therapeutic 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 associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor, and eotaxin. 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: Methotrexate in bronchial asthma. J Allergy Clin Immunol 1991;88:274-276.
107.
Attar SM: Adverse effects of low dose methotrexate 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 corticosteroid sparing agent for asthma. Cochrane 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-lambda in allergic asthma. J Innate Immun 2015;7:224-230.
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