Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The potential of biologics for the treatment of asthma

Key Points

  • The recent advances in the knowledge of asthma pathobiology are substantially contributing to the characterization of the various phenotypes of this complex and heterogeneous disease. Such advances can affect the development of novel anti-asthma treatments.

  • Biological therapies have the potential to be very useful for the phenotype-driven treatment of severe asthma.

  • Immunoglobulin E and pro-inflammatory cytokines are currently the main targets of biological drugs for the treatment of asthma.

  • The immunoglobulin E-targeted monoclonal antibody omalizumab is the first — and so far the only — biologic approved for the treatment of asthma. In patients with difficult-to-treat allergic asthma, omalizumab reduces disease exacerbations, emergency hostpital visits and hospitalizations.

  • Other promising biologics for the treatment of inadequately controlled asthma include monoclonal antibodies that target interleukin 5 (IL-5), such as mepolizumab, and those that target IL-13, such as lebrikizumab.

  • Antibodies that target other pro-infammatory cytokines are also in clinical development or preclinical studies.

Abstract

Recent advances in the knowledge of asthma pathobiology suggest that biological therapies that target cytokines can be potentially useful for the treatment of this complex and heterogeneous airway disease. The use of biologics in asthma has been established with the approval of the humanized monoclonal immunoglobulin E-targeted antibody omalizumab (Xolair; Genentech/Novartis) as an add-on treatment for inadequately controlled disease. Furthermore, evidence is accumulating in support of the efficacy of other biologics, such as interleukin-5 (IL-5)- and IL-13-specific drugs. Therefore, these new developments are changing the scenario of asthma therapies, especially with regard to more severe disease. The variability among patients' individual therapeutic responses highlights that it will be necessary to characterize the different asthma subtypes so that phenotype-targeted treatments based on the use of biologics can be implemented.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathobiology of asthma.
Figure 2: Mechanism of action of biological therapies for asthma.

Similar content being viewed by others

References

  1. Holgate, S. T. et al. A new look at the pathogenesis of asthma. Clin. Sci. 118, 439–450 (2010).

    CAS  Google Scholar 

  2. Anderson, G. P. Endotyping asthma: new insights into key pathogenetic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107–1119 (2008).

    PubMed  Google Scholar 

  3. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA [online], (2005).

  4. Bateman, E. D. et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL (GOAL) study. Am. J. Respir. Crit. Care Med. 170, 836–844 (2004).

    PubMed  Google Scholar 

  5. Fanta, C. H. Drug therapy: asthma. N. Engl. J. Med. 360, 1002–1014 (2009).

    CAS  PubMed  Google Scholar 

  6. Boulet, L. P. Influence of comorbid conditions on asthma. Eur. Respir. J. 33, 897–906 (2009).

    PubMed  Google Scholar 

  7. Serra-Batlles, J., Plaza, V., Morejon, E., Comella, A. & Brugues, J. Costs of asthma according to the degree of severity. Eur. Respir. J. 12, 1322–1326 (1998).

    CAS  PubMed  Google Scholar 

  8. Heaney, L. G. et al. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax 58, 561–566 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Dolan, C. M. et al. Design of baseline characteristics of the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann. Allergy Asthma Immunol. 92, 32–39 (2004).

    PubMed  Google Scholar 

  10. Haselkorn, T., Borish, L., Miller, D. P., Weiss, S. T. & Wong, D. A. High prevalence of skin test positivity in severe or difficult-to-treat asthma. J. Asthma 43, 745–752 (2006).

    CAS  PubMed  Google Scholar 

  11. Gould, H. J. & Sutton, B. J. IgE in allergy and asthma today. Nature Rev. Immunol. 8, 205–217 (2008).

    CAS  Google Scholar 

  12. Barnes, P. J. The cytokine network in asthma and chronic obstructive pulmonary disease. J. Clin. Invest. 118, 3546–3556 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Al-Ramly, W. et al. TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 123, 1185–1187 (2009).

    Google Scholar 

  14. Walsh, G. M. Novel cytokine-directed therapies for asthma. Discov. Med. 11, 283–291 (2011).

    PubMed  Google Scholar 

  15. Gruenberg, D. & Busse, W. Biologic therapies for asthma. Curr. Opin. Pulm. Med. 16, 19–24 (2010).

    PubMed  Google Scholar 

  16. Rodrigo, G. J., Neffen, H. & Castro-Rodriguez, J. A. Efficacy and safety of subcutaneous omalizumab versus placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest 139, 28–35 (2011).

    CAS  PubMed  Google Scholar 

  17. Hansbro, P. M., Kaiko, G. E. & Foster, P. S. Cytokine/anti-cytokine therapy — novel treatments for asthma? Br. J. Pharmacol. 163, 81–95 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bouzigon, E. et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N. Engl. J. Med. 359, 1985–1994 (2008).

    CAS  PubMed  Google Scholar 

  19. Wenzel, S. E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nature Med. 18, 716–725 (2012).

    CAS  PubMed  Google Scholar 

  20. Moore, W. C. et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J. Allergy Clin. Immunol. 119, 405–413 (2007).

    PubMed  PubMed Central  Google Scholar 

  21. Phelan, P. D., Robertson, C. F. & Olinsky, A. The Melbourne Asthma Study: 1964–1999. J. Allergy Clin. Immunol. 109, 89–94 (2002).

    Google Scholar 

  22. Wenzel, S. Severe asthma: from characteristics to phenotypes to endotypes. Clin. Exp. Allergy 42, 650–658 (2012).

    CAS  PubMed  Google Scholar 

  23. Barrett, N. A. & Austen, K. F. Innate cells and T helper 2 cell immunity in airway inflammation. Immunity 31, 425–437 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Woodruff, P. G. et al. Th2-driven inflammation defines major sub-phenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009). This study is a cornerstone in the efforts aimed at characterizing the various asthma phenotypes and the different underlying mechanisms.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011). This important study suggests that it is possible to use the IL-13-specific monoclonal antibody lebrikizumab for the treatment of patients with specific asthma phenotypes, who are selected on the basis of the expression of appropriate biomarkers such as periostin.

    CAS  PubMed  Google Scholar 

  26. Sokol, C. L., Barton, G. M., Farr, A. G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunol. 9, 310–318 (2008).

    CAS  Google Scholar 

  27. Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).

    CAS  PubMed  Google Scholar 

  28. Nguyen, K. D., Vanichsarn, C. & Nadeau, K.C. TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy Asthma Clin. Immunol. 6, 4 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamid, Q. & Tulic, M. Immunobiology of asthma. Annu. Rev. Physiol. 71, 489–507 (2009).

    CAS  PubMed  Google Scholar 

  30. Collins, P. D., Marleau, S., Griffiths-Johnson, D. A., Jose, P. J. & Williams, T. J. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 182, 1169–1174 (1995).

    CAS  PubMed  Google Scholar 

  31. Zietkowski, Z., Tomasiak, M. M., Skiepko, R. & Bodzenta-Lukaszyk, A. RANTES in exhaled breath condensate of stable and unstable asthma patients. Respir. Med. 102, 1198–2202 (2008).

    CAS  PubMed  Google Scholar 

  32. Finkelman, F. et al. IL-4 is required to generate and sustain in vivo IgE responses. J. Immunol. 141, 2335–2341 (1988).

    CAS  PubMed  Google Scholar 

  33. Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Veldohen, M. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunol. 9, 1341–1346 (2008).

    Google Scholar 

  35. Chang, H. C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nature Immunol. 11, 527–534 (2010).

    CAS  Google Scholar 

  36. The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur. Respir. J. 22, 470–477 (2003).

  37. Zhao, Y., Yang, J., Gao, Y. D. & Guo, W. Th17 immunity in patients with allergic asthma. Int. Arch. Allergy Immunol. 151, 297–307 (2010).

    CAS  PubMed  Google Scholar 

  38. Lukacs, N. W., Strieter, R. M., Chensue, S. W., Widmer, M. & Kunkel, S. L. TNF-α mediates recruitment of neutrophils and eosinophils during airway inflammation. J. Immunol. 154, 5411–5417 (1995).

    CAS  PubMed  Google Scholar 

  39. Amrani, Y., Panettieri, R. A. Jr., Frossard, N. & Bronner, C. Activation of the TNF-α-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells. Am. J. Respir. Cell. Mol. Biol. 15, 55–63 (1996).

    CAS  PubMed  Google Scholar 

  40. ten Brinke, A. et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur. Respir. J. 26, 812–818 (2005).

    CAS  PubMed  Google Scholar 

  41. Contoli, M. & et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nature Med. 12, 1023–1026 (2006).

    CAS  PubMed  Google Scholar 

  42. Matsumoto, K. et al. Frequency of Foxp3+CD4+CD25+ T cells is associated with the phenotypes of allergic asthma. Respirology 14, 187–194 (2009).

    PubMed  Google Scholar 

  43. Provoost, S. et al. Decreased FOXP3 protein expression in patients with asthma. Allergy 64, 1539–1546 (2009).

    CAS  PubMed  Google Scholar 

  44. Abdulamir, A. S. et al. Severity of asthma: the role of CD25+, CD30+, NF-κB, and apoptotic markers. J. Investig. Allergol. Clin. Immunol. 19, 218–224 (2009).

    CAS  PubMed  Google Scholar 

  45. Turato, G. et al. Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma. Am. J. Respir. Crit. Care Med. 178, 476–482 (2008).

    PubMed  Google Scholar 

  46. Jeffery, P. K. Remodeling in asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 164, S28–S38 (2001).

    CAS  PubMed  Google Scholar 

  47. Tliba, O. & Panettieri, R. A. Jr. Noncontractile functions of airway smooth muscle in asthma. Annu. Rev. Physiol. 71, 509–535 (2009).

    CAS  PubMed  Google Scholar 

  48. Payne, D. N. et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am. J. Respir. Crit. Care Med. 167, 78–82 (2003).

    PubMed  Google Scholar 

  49. Saglani, S. et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am. J. Respir. Crit. Care Med. 176, 858–864 (2007).

    PubMed  Google Scholar 

  50. Ebina, M., Takahashi, T., Chiba, T. & Motomiya, M. Cellular hypertrophy and hyperplasia of airway smooth muscle underlying bronchial asthma. A 3D morphometric study. Am. Rev. Respir. Dis. 148, 720–726 (1993).

    CAS  PubMed  Google Scholar 

  51. Bai, T. R., Cooper, J., Koelmeyer, T., Pare, P. D. & Weir, T. D. The effect of age and duration of disease on airway structure in fatal asthma. Am. J. Respir. Crit. Care Med. 162, 663–669 (2000).

    CAS  PubMed  Google Scholar 

  52. Salvato, G. Quantitative and morphological analysis of the vascular bed in bronchial biopsy specimens from asthmatic and non-asthmatic subjects. Thorax 56, 902–906 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hoshino, M., Takahashi, M. & Aoike, N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J. Allergy Clin. Immunol. 107, 295–301 (2001).

    CAS  PubMed  Google Scholar 

  54. Hastie, A. T. et al. Asthmatic epithelial cell proliferation and stimulation of collagen production: human asthmatic epithelial cells stimulate collagen type III production by human lung fibroblasts after segmental allergen challenge. Am. J. Respir. Crit. Care Med. 165, 266–272 (2002).

    PubMed  Google Scholar 

  55. Hackett, T. L. et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-β1. Am. J. Respir. Crit. Care Med. 180, 122–133 (2009).

    CAS  PubMed  Google Scholar 

  56. Heijink, I. H., Postma, D. S., Noordhoek, J. A., Broekma, M. & Kapus, A. House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am. J. Respir. Cell. Mol. Biol. 42, 69–79 (2010).

    CAS  PubMed  Google Scholar 

  57. Vignola, A. M. et al. Transforming growth factor-β expression in mucosal biopsies in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 156, 591–599 (1997).

    CAS  PubMed  Google Scholar 

  58. Doherty, T. & Broide, D. Cytokines and growth factors in airway remodeling in asthma. Curr. Opin. Immunol. 19, 676–680 (2007).

    CAS  PubMed  Google Scholar 

  59. Pascual, R. M. & Peters, S. P. Airway remodeling contributes to the progressive loss of lung function in asthma: an overview. J. Allergy Clin. Immunol. 116, 477–486 (2005).

    PubMed  Google Scholar 

  60. Ishizaka, K. & Ishizaka, T. Identification of γE antibodies as a carrier of reaginic activity. J. Immunol. 99, 1187–1198 (1967).

    CAS  PubMed  Google Scholar 

  61. Pelaia, G., Renda, T., Romeo, P., Busceti, M. T. & Maselli, R. Omalizumab in the treatment of severe asthma: efficacy and current problems. Ther. Adv. Respir. Res. 2, 409–421 (2008).

    Google Scholar 

  62. Presta, L. G. et al. Humanization of an antibody directed against IgE. J. Immunol. 151, 2623–2632 (1993).

    CAS  PubMed  Google Scholar 

  63. Rivera, J. & Gilfillan, A. M. Molecular regulation of mast cell activation. J. Allergy Clin. Immunol. 117, 1214–1225 (2006).

    CAS  PubMed  Google Scholar 

  64. Galli, S. J. & Tsai, M. IgE and mast cells in allergic disease. Nature Med. 18, 693–704 (2012).

    CAS  PubMed  Google Scholar 

  65. Shields, R. L. et al. Inhibition of allergic reactions with antibodies to IgE. Int. Arch. Allergy Immunol. 107, 308–312 (1995).

    CAS  PubMed  Google Scholar 

  66. Holgate, S. et al. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J. Allergy Clin. Immunol. 115, 459–465 (2005).

    CAS  PubMed  Google Scholar 

  67. Novak, N. et al. Evidence for a differential expression of the FcɛRIγ chain in dendritic cells of atopic and non atopic donors. J. Clin. Invest. 111, 1047–1056 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Campbell, A. M. et al. Expression of the high-affinity receptor for IgE on bronchial epithelial cells of asthmatics. Am. J. Respir. Cell. Mol. Biol. 19, 92–97 (1998).

    CAS  PubMed  Google Scholar 

  69. Gounni, A. S. et al. Human airway smooth muscle cells express the high affinity receptor for IgE (FcɛRI): a critical role of FcɛRI in human airway smooth muscle function. J. Immunol. 175, 2613–2621 (2005).

    CAS  PubMed  Google Scholar 

  70. Huang, Y. C., Leyko, B. & Frier, M. Effects of omalizumab and budesonide on markers of inflammation in human bronchial epithelial cells. Ann. Allergy Asthma Immunol. 95, 443–451 (2005).

    CAS  PubMed  Google Scholar 

  71. Zietkowski, Z., Skiepko, R., Tomasiak-Lozowska, M. M. & Bodzenta-Lukaszyk, A. Anti-IgE therapy with omalizumab decreases endothelin-1 in exhaled breath condensate of patients with severe persistent allergic asthma. Respiration 80, 534–542 (2010).

    CAS  PubMed  Google Scholar 

  72. Hoshino, M. & Ohtawa, J. Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. Respiration 83, 520–528 (2012).

    CAS  PubMed  Google Scholar 

  73. Riccio, A. M. et al. Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int. J. Immunopathol. Pharmacol. 25, 475–484 (2012). This very interesting study, carried out in patients with severe persistent allergic asthma, shows that the use of omalizumab as an add-on treatment for 1 year can modulate airway remodelling by reducing the thickness of the airway RBM.

    CAS  PubMed  Google Scholar 

  74. Stirling, R. G., van Rensen, E. I., Barnes, P. J. & Chung, K. F. Interleukin-5 induces CD34+ eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. Am. J. Respir. Crit. Care Med. 164, 1403–1409 (2001).

    CAS  PubMed  Google Scholar 

  75. Garlisi, C. G. et al. Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation. Am. J. Respir. Cell. Mol. Biol. 20, 248–255 (1999).

    CAS  PubMed  Google Scholar 

  76. Mauser, P. et al. Effects of an antibody to interleukin-5 in a monkey model of asthma. Am. J. Respir. Crit. Care Med. 152, 467–472 (1995).

    CAS  PubMed  Google Scholar 

  77. Molfino, N. A., Gossage, D., Kolbeck, R., Parker, J. M. & Geba, G. P. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin. Exp. Allergy 42, 712–737 (2012).

    CAS  PubMed  Google Scholar 

  78. Leckie, M. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 356, 2144–2148 (2000).

    CAS  PubMed  Google Scholar 

  79. Food-Page, P. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062–1071 (2007).

    Google Scholar 

  80. Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Nair, P. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360, 985–993 (2009). These two studies demonstrated for the first time that the IL-5-targeted monoclonal antibody mepolizumab can decrease the frequency of asthma exacerbations and corticosteroid use in small selected groups of patients with severe eosinophilic steroid-dependent asthma, who were recruited to the study on the basis of having high eosinophil levels in induced sputum.

    CAS  PubMed  Google Scholar 

  82. Pavord, I. D. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380, 651–659 (2012). This large clinical study showed that mepolizumab decreased the frequency of asthma exacerbations, even at low doses, in a large number of patients with severe asthma who had sputum and blood eosinophilia as well as elevated levels of easily measurable exhaled nitric oxide.

    CAS  PubMed  Google Scholar 

  83. Castro, M. et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184, 1125–1132 (2011).

    CAS  PubMed  Google Scholar 

  84. Busse, W. W. et al. Safety profile, pharmacokinetics and biologic activity of MEDI-563, an anti-IL-5 receptor α antibody, in a phase I study of subjects with mild asthma. J. Allergy Clin. Immunol. 125, 1237–1244 (2010).

    CAS  PubMed  Google Scholar 

  85. Ghazi, A., Trikha, A. & Calhoun, W. J. Benralizumab — a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity — a novel approach for the treatment of asthma. Expert Opin. Biol. Ther. 12, 113–118 (2012).

    CAS  PubMed  Google Scholar 

  86. Zhou, C. Y., Crocker, I. C., Koenig, G., Romero, F. A. & Townley, R. G. Anti-interleukin-4 inhibits immunoglobulin E production in a murine model of atopic asthma. J. Asthma 34, 195–201 (1997).

    CAS  PubMed  Google Scholar 

  87. Corry, D. B. et al. Interleukin-4, but not interleukin-5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183, 109–117 (1996).

    CAS  PubMed  Google Scholar 

  88. Hart, T. K. et al. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin. Exp. Immunol. 130, 93–100 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Shames, R. S. et al. The safety and pharmacokinetics of SB240683 (anti-interleukin-4 humanized monoclonal antibody) in patients with mild to moderate asthma. J. Allergy Clin. Immunol. 163, A523 (2001).

    Google Scholar 

  90. Henderson, W. R. Jr., Chi, E. Y. & Maliszewski, W. J. Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J. Immunol. 164, 1086–1095 (2000).

    CAS  PubMed  Google Scholar 

  91. Borish, L. C. et al. IL-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160, 1816–1823 (1999).

    CAS  PubMed  Google Scholar 

  92. Borish, L. C. et al. IL-4R Asthma Study Group. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J. Allergy Clin. Immunol. 107, 963–970 (2001).

    CAS  PubMed  Google Scholar 

  93. Steinke, J. W. Anti-interleukin-4 therapy. Immunol. Allergy Clin. North Am. 24, 599–614 (2004).

    PubMed  Google Scholar 

  94. Blanchet, M. R., Gold, M. J. & McNagny, K. M. Mouse models to evaluate the function of genes associated with allergic airway disease. Curr. Opin. Allergy Clin. Immunol. 12, 467–474 (2012).

    CAS  PubMed  Google Scholar 

  95. Reddy, A. T., Lakshmi, S. P. & Reddy, R. C. Murine model of allergen induced asthma. J. Vis. Exp. 63, e3771 (2012).

    Google Scholar 

  96. Tomkinson, A. et al. A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J. Immunol. 166, 5792–5800 (2001).

    CAS  PubMed  Google Scholar 

  97. Tomkinson, A. et al. Inhaled versus subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma. Allergy 65, 69–77 (2010).

    CAS  PubMed  Google Scholar 

  98. Burmeister Getz, E., Fisher, D. M. & Fuller, R. Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma. J. Clin. Pharmacol. 49, 1025–1036 (2009).

    PubMed  Google Scholar 

  99. Wenzel, S. et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370, 1422–1431 (2007).

    CAS  PubMed  Google Scholar 

  100. Wenzel, S. E. et al. Inhaled pitrakinra, an IL-4/IL-13 antagonist, reduced exacerbations in patients with eosinophilic asthma. Eur. Respir. J. 36, P3980 (2010).

    Google Scholar 

  101. Slager, R. E. et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist. J. Allergy Clin. Immunol. 130, 516–522 (2012). This is the first large pharmacogenetic analysis showing that a therapeutic asthma strategy based on IL-4 and IL-13 antagonism can be effective in lowering the frequency of asthma exacerbations in selected patients who have specific polymorphisms in the gene encoding the α-chain of the IL-4 receptor.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Perkins, C., Wills-Karp, M. & Finkelman, F. D. IL-4 induces IL-13-independent allergic airway inflammation. J. Allergy Clin. Immunol. 118, 410–419 (2006).

    CAS  PubMed  Google Scholar 

  103. Maes, T., Joos, G. F. & Brusselle, G. G. Targeting interleukin-4 in asthma: lost in translation? Am. J. Respir. Cell. Mol. Biol. 47, 261–270 (2012).

    CAS  PubMed  Google Scholar 

  104. Kakkar, T. et al. Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL-4 receptor. Pharm. Res. 28, 2530–2542 (2011).

    CAS  PubMed  Google Scholar 

  105. Corren, J. et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Rα antagonist. Am. J. Respir. Crit. Care Med. 181, 788–796 (2010).

    CAS  PubMed  Google Scholar 

  106. McCusker, C. T. et al. Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT6 peptide. J. Immunol. 179, 2556–2564 (2007).

    CAS  PubMed  Google Scholar 

  107. Chiba, Y., Todoroki, M., Nishida, Y., Tanabe, M. & Misawa, M. A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am. J. Respir. Cell. Mol. Biol. 41, 516–524 (2009).

    CAS  PubMed  Google Scholar 

  108. Wills-Karp, M. Interleukin-13 in asthma pathogenesis. Immunol. Rev. 202, 175–190 (2004).

    CAS  PubMed  Google Scholar 

  109. Yang, G. et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine 28, 224–232 (2004).

    CAS  PubMed  Google Scholar 

  110. Blanchard, C. et al. Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human interleukin-13 antibody (CAT-354). Clin. Exp. Allergy 35, 1096–1103 (2005).

    CAS  PubMed  Google Scholar 

  111. Singh, D. et al. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma. BMC Pulm. Med. 10, 3 (2010).

    PubMed  PubMed Central  Google Scholar 

  112. Gauvreau, G. M. et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am. J. Respir. Crit. Care Med. 183, 1007–1014 (2011).

    CAS  PubMed  Google Scholar 

  113. Cheng, G. et al. Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am. J. Respir. Crit. Care Med. 166, 409–416 (2002).

    PubMed  Google Scholar 

  114. White, B., Leon, F., White, W. & Robbie, G. Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy volunteers. Clin. Ther. 31, 728–740 (2009).

    CAS  PubMed  Google Scholar 

  115. Parker, J. M. 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. 11, 14 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Yamashita, N. et al. Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte-macrophage colony stimulating factor (GM-CSF). Cell. Immunol. 219, 92–97 (2002).

    CAS  PubMed  Google Scholar 

  117. Krinner, E. M. et al. A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF. Mol. Immunol. 44, 916–925 (2007).

    CAS  PubMed  Google Scholar 

  118. Lukacs, N. W. et al. TNF-α mediates recruitment of neutrophils and eosinophils during airway inflammation. J. Immunol. 154, S411–S417 (1995).

    Google Scholar 

  119. Howarth, P. H. et al. Tumour necrosis factor-α (TNF-α) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60, 1012–1018 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Berry, M. A. et al. Evidence of a role of tumor necrosis factor-α in refractory asthma. N. Engl. J. Med. 354, 697–708 (2006).

    CAS  PubMed  Google Scholar 

  121. Holgate, S. T. et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur. Respir. J. 37, 1352–1359 (2011).

    CAS  PubMed  Google Scholar 

  122. Erin, E. M. et al. The effects of a monoclonal antibody directed against tumor necrosis factor-α in asthma. Am. J. Respir. Crit. Care Med. 174, 753–762 (2006).

    CAS  PubMed  Google Scholar 

  123. Wenzel, S. E. et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 (2009). This paper reports the results of a large clinical trial in patients with severe persistent asthma, which showed that the TNFα-targeted monoclonal antibody golimumab has an unfavourable risk-benefit profile, suggesting that such a therapeutic strategy may not be suitable for all patients with severe asthma.

    CAS  PubMed  Google Scholar 

  124. Hellings, P. W. et al. Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. Am. J. Respir. Cell. Mol. Biol. 28, 42–50 (2003).

    CAS  PubMed  Google Scholar 

  125. Wakashing, H. et al. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am. J. Respir. Crit. Care Med. 178, 1023–1032 (2008).

    Google Scholar 

  126. Li, Y. et al. Silencing IL-23 expression by a small hairpin RNA protects against asthma in mice. Exp. Mol. Med. 43, 197–204 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. Park, S. J. & Lee, Y. C. Interleukin-17 regulation: an attractive therapeutic approach for asthma. Respir. Res. 11, 78 (2010).

    PubMed  PubMed Central  Google Scholar 

  128. Tamachi, T. et al. IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice. J. Allergy Clin. Immunol. 118, 606–614 (2006).

    CAS  PubMed  Google Scholar 

  129. Kearley, J., Buckland, K. F., Mathie, S. A. & Lloyd, C. M. Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am. J. Respir. Crit. Care Med. 179, 772–781 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Fujita, J. et al. Interleukin-33 induces interleukin-17F in bronchial epithelial cells. Allergy 67, 744–750 (2012). This very interesting study, in human bronchial epithelial cells, showed that mouse antibodies directed against the ST2 receptor of the innate cytokine IL-33 are able to inhibit IL-33-induced expression of IL-17F. Therefore, these findings suggest that the IL-33–IL-17F axis is involved in allergic airway inflammation and can be considered as a novel therapeutic target.

    CAS  PubMed  Google Scholar 

  131. Shi, L. et al. Local blockade of TSLP receptor alleviated allergic disease by regulating airway dendritic cells. Clin. Immunol. 129, 202–210 (2008).

    CAS  PubMed  Google Scholar 

  132. Li, J. J. et al. IL-27/IFN-γ induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J. Immunol. 185, 4401–4409 (2010).

    CAS  PubMed  Google Scholar 

  133. Masuda, E. S. & Schmitz, J. Syk inhibitors as treatment for allergic rhinitis. Pulm. Pharmacol. Ther. 21, 461–467 (2008).

    CAS  PubMed  Google Scholar 

  134. Stenton, G. R. et al. Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase. J. Immunol. 169, 1028–1036 (2002).

    CAS  PubMed  Google Scholar 

  135. Meltzer, E. O., Berkowitz, R. B. & Grossbard, E. B. An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J. Allergy Clin. Immunol. 115, 791–796 (2005).

    CAS  PubMed  Google Scholar 

  136. Szefler, S. J. et al. Asthma outcomes: biomarkers. J. Allergy Clin. Immunol. 129, S9–S23 (2012).

    PubMed  PubMed Central  Google Scholar 

  137. Massanari, M. et al. Effect of omalizumab on peripheral blood eosinophilia in allergic asthma. Respir. Med. 104, 188–196 (2010).

    CAS  PubMed  Google Scholar 

  138. Terracciano, R. et al. Peptidome profiling of induced sputum by mesoporous silica beads and MALDI-TOF MS for non-invasive biomarker discovery of chronic inflammatory lung diseases. Proteomics 11, 3402–3414 (2011).

    CAS  PubMed  Google Scholar 

  139. von Mutius, E. & Drazen, J. M. Choosing asthma step-up care. N. Engl. J. Med. 362, 1042–1043 (2010).

    CAS  PubMed  Google Scholar 

  140. Busse, W. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 108, 184–190 (2001).

    CAS  PubMed  Google Scholar 

  141. Solér, M. et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur. Respir. J. 18, 254–261 (2001).

    PubMed  Google Scholar 

  142. Holgate, S. T. et al. Efficacy and tolerability of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin. Exp. Allergy 34, 632–638 (2004).

    CAS  PubMed  Google Scholar 

  143. Vignola, A. M. et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 59, 709–717 (2004).

    CAS  PubMed  Google Scholar 

  144. Ayres, J. G. et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma. Allergy 59, 701–708 (2004).

    CAS  PubMed  Google Scholar 

  145. Humbert, M. et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 60, 309–316 (2005). This is one of the most important pre-marketing trials showing that an add-on treatment with omalizumab improves the control of inadequately controlled allergic asthma, thus reducing the occurrence of disease exacerbations, emergency hospital visits and hospitalizations.

    CAS  PubMed  Google Scholar 

  146. Pelaia, G. et al. Omalizumab decreases exacerbation frequency, oral intake of corticosteroids and peripheral blood eosinophils in atopic patients with uncontrolled asthma. Int. J. Clin. Pharmacol. Ther. 49, 713–721 (2011).

    CAS  PubMed  Google Scholar 

  147. Molimard, M. de Blay, F., Didier, A. & Le Gros, V. Effectiveness of omalizumab (Xolair) in the first patients treated in real-life practice in France. Respir. Med. 102, 71–76 (2008).

    PubMed  Google Scholar 

  148. Cazzola, M. et al. Italian real-life experience of omalizumab. Respir. Med. 104, 1410–1416 (2010). This is a post-marketing study that, in addition to corroborating the findings of pre-marketing clinical trials, highlights the ability of omalizumab to reduce the use of other asthma drugs such as corticosteroids, leukotriene inhibitors and theophylline.

    CAS  PubMed  Google Scholar 

  149. Miller, C. W. T., Krishnaswamy, N., Johnston, C. & Krishnaswamy, G. Severe asthma and the omalizumab option. Clin. Mol. Allergy 6, 4 (2008).

    PubMed  PubMed Central  Google Scholar 

  150. Busse, W. et al. Omalizumab and the risk of malignancy: results from a pooled analysis. J. Allergy Clin. Immunol. 129, 983–989 (2012).

    CAS  PubMed  Google Scholar 

  151. Cox, L. et al. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force report on omalizumab-associated anaphylaxis. J. Allergy Clin. Immunol. 120, 1373–1377 (2007).

    CAS  PubMed  Google Scholar 

  152. US Food and Drug Adminisration (FDA). Early communication about an ongoing safety review of omalizumab (marketed as Xolair). FDA website [online], (2009).

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Girolamo Pelaia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

ClinicalTrials.gov website

Rigel website (R343 — Asthma)

University of Southampton website — “Positive results in Southampton-led patient trial for new asthma treatment” (19 April 2012 press release)

Glossary

Corticosteroids

A class of steroid hormones that generally inhibit inflammation and immunity.

Eosinophilia

The accumulation of eosinophils (white blood cells that produce cytokines, cationic proteins and reactive oxygen species) in tissue or blood.

Dyspnoea

Shortness of breath that causes discomfort.

Airway hyperresponsiveness

An exaggerated contractile response of airway smooth muscle that has been exposed to potentially bronchoconstrictive stimuli.

Antigen presentation

An immunological event that is mediated by antigen-presenting cells. These cells internalize and process antigens, then display antigenic peptidic fragments on their surface, together with co-stimulatory molecules that are required for the activation of the cognate lymphocytes.

TH1 polarization

Interleukin 12 (IL-12)-driven expansion of T helper 1 (TH1) cells, which produce large amounts of TH1 cytokines (such as interferon-γ and IL-2), activate macrophages and are essential for the defence against intracellular pathogens.

TH2-adaptive responses

A type of adaptive immunity mediated by T helper 2 (TH2) cells; a TH cell subset that produces TH2 cytokines (for example, interleukin 4 (IL-4), IL-5 and IL-13), which are involved in atopic immune responses.

Immunoglobulin class switching

Interleukin-4 (IL-4)- and IL-13-mediated induction of B cells to perform immunoglobulin class recombination, resulting in prevalent production of immunoglobulin E.

CD4+ T cell

A subset of helper T lymphocytes expressing the cell surface glycoprotein called CD4.

Neutrophilic inflammation

A type of inflammation that is mediated by the recruitment and activation of neutrophils (white blood cells that produce pro-inflammatory cytokines, proteases and reactive oxygen species).

IL-17

Interleukin-17; a T helper 17 (TH17) cell-derived cytokine that induces neutrophil recruitment.

Adaptive immunity

The ability of the immune system to recognize and remember a specific pathogen, causing the host to induce a strong immune response every time that pathogen is encountered.

Epithelial shedding

Epithelial detachment from the basement membrane, which results in the loss of ciliated cells from the layer of epithelial cells in the airway.

Goblet cell

A modified columnar epithelial cell that produces and secretes mucus.

Epithelial reticular basement membrane

(RBM). A histological structure that is underneath epithelial cells in the airway.

Mesenchyme

Embryological tissue from which all types of connective tissue are derived.

Long-acting β2-adrenergic receptor agonists

A class of inhaled drugs that act by providing a prolonged bronchodilation, which is mediated by the stimulation of β2-adrenergic receptors expressed by airway smooth muscle cells.

Complementarity-determining region

A specific region of an antibody that consists of a highly variable amino acid sequence and confers antigen-binding specificity.

Fcɛ receptor I

A high-affinity receptor for immunoglobulin E that is expressed by mast cells, basophils and a variety of other cell types, and is essential for several biological functions of immunoglobulin E.

Early-phase asthmatic responses

Bronchoconstrictive reactions that occur within minutes of the airway being exposed to allergens.

Late-phase asthmatic responses

Bronchoconstrictive reactions that occur several hours after allergens have been inhaled.

Cɛ3 domain

The third domain of the constant region of immunoglobulin E that contains the Fcɛ receptor I (FcɛRI)-binding function.

Peak expiratory flow

(PEF). An individual's maximum speed of expiration that acts as an indicator of changes in the functioning of the airway.

Asthma Control Questionnaire

(ACQ). A list of questions that are used to assess how well a patient's asthma is controlled; includes questions about symptoms during the day and at night, limitations in daily activity, airway functioning and the use of rescue bronchodilators.

Atopic status

The propensity to generate allergic responses to antigens, mediated by an exaggerated production of immunoglobulin E.

Rescue bronchodilators

Rapidly acting inhaled drugs, which provide immediate relief of bronchoconstriction.

Forced vital capacity

(FVC). A spirometric indicator of lung function.

FEV1/FVC ratio

A ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). A decrease in this ratio from normal values indicates that a patient has limitations in airflow through the bronchi.

IgG4κ

A subclass of immunoglobulin G4 that has a structure characterized by the presence of κ light chains.

Nasal polyposis

Mucosal protrusions that contain oedema fluid and variable levels of eosinophils.

Area under the curve

A pharmacokinetic parameter that estimates drug bioavailability. It is extrapolated from the area under the graph of drug plasma concentration plotted against time after administration.

Volume of distribution

The amount of drug in the body divided by the concentration of the drug in blood or plasma; the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce its desired blood concentration.

Innate immune responses

Rapid and non-specific cellular responses to pathogens and/or tissue injury, which stimulate and influence the relatively slow development of specific adaptive immune responses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pelaia, G., Vatrella, A. & Maselli, R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov 11, 958–972 (2012). https://doi.org/10.1038/nrd3792

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3792

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research