Skip to main content
Log in

Targeting Interleukin-5 or Interleukin-5Rα: Safety Considerations

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Asthma is a highly prevalent chronic disease of the airways; approximately 10% of patients with asthma will experience a severe form of the disease. New understanding of the pathogenesis of asthma has enabled the development of novel drugs and provided hope for patients with asthma. Interleukin (IL)-5 and IL-5 receptor subunit α (IL-5-Rα) plays a crucial role in the development, maturation, and operation of eosinophils so were the first important therapeutic target of these new drugs. While the results of early clinical trials of these drugs were not promising, results improved once researchers discovered the drugs worked best in patients with high eosinophil levels. Patients treated with both anti-IL-5 and IL-5-Rα experienced significant decreases in exacerbations. Trials have also demonstrated promising safety profiles; adverse events have been few and frequently only observed with placebo or considered unrelated to the study drug. The positive efficacy and safety profiles of these drugs has led to trials with interesting results in other diseases that are also secondary to the action of eosinophils: Churg–Strauss syndrome, hypereosinophilic syndrome, nasal polyposis, chronic obstructive pulmonary disease, atopic dermatitis, and esophagitis. In this review, we explore the main clinical trials of anti-IL-5 and IL-5-Rα, both in asthma and in other pathologies, with particular reference to the interesting safety and efficacy results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Global Initiative for Asthma. Gina Teaching Slide Set. 2017. http://ginasthma.org/gina-teaching-slide-set/. Accessed 19 Feb 2017.

  2. De Ferrari L, Chiappori A, Bagnasco D, et al. Molecular phenotyping and biomarker development: are we on our way towards targeted therapy for severe asthma? Expert Rev Respir Med. 2016;10(1):29–38.

    Article  PubMed  Google Scholar 

  3. Bagnasco D, Ferrando M, Bernardi S, et al. The path to personalized medicine in asthma. Expert Rev Respir Med. 2016;10(9):957–65.

    Article  CAS  PubMed  Google Scholar 

  4. DeKruyff RH, Yu S, Kim HY, Umetsu DT. Innate immunity in the lung regulates the development of asthma. Immunol Rev. 2014;260(1):235–48.

    Article  CAS  PubMed  Google Scholar 

  5. Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11(1):54–61.

    Article  PubMed  Google Scholar 

  6. Ferrando M, Bagnasco D, Varricchi G, et al. Personalized medicine in allergy. Allergy Asthma Immunol Res. 2017;9(1):15–24.

    Article  PubMed  Google Scholar 

  7. Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cazzola M, Novelli G. Biomarkers in COPD. Pulm Pharmacol Ther. 2010;23:493–500.

    Article  CAS  PubMed  Google Scholar 

  9. Rossi R, De Palma A, Benazzi L, et al. Biomarker discovery in asthma and COPD by proteomic approaches. Proteomics Clin Appl. 2014;8:901–15.

    Article  CAS  PubMed  Google Scholar 

  10. 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;180:388–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Coleman JM, Naik C, Holguin F, et al. Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset. Thorax. 2012;67:1061–6.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mauri P, Riccio AM, Rossi R, et al. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol Lett. 2014;162(1 Pt A):2–10.

  13. Riccio AM, Dal Negro RW, Micheletto C, et al. Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int J Immunopathol Pharmacol. 2012;25:475–84.

    Article  CAS  PubMed  Google Scholar 

  14. Wagener AH, de Nijs SB, Lutter R, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70:115–20.

    Article  CAS  PubMed  Google Scholar 

  15. Peters MC, Mekonnen ZK, Yuan S, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133:388–94.

    Article  CAS  PubMed  Google Scholar 

  16. Oreo KM, Gibson PG, Simpson JL, et al. Sputum ADAM-8 expression in increased in severe asthma and COPD. Clin Exper Allergy. 2013;44:342–52.

    Article  Google Scholar 

  17. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of Omalizumab in allergic asthma. An analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804–11.

    Article  CAS  PubMed  Google Scholar 

  18. Kazani S, Planaguma A, Ono E, et al. Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J Allergy Clin Immunol. 2013;132:547–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schwarz K, Biller H, Windt H, et al. Characterization of exhaled particles from the human lungs in airway obstruction. J Aerosol Med Pulm Drug Deliv. 2015;28:52–8.

    Article  CAS  PubMed  Google Scholar 

  20. Cai C, Yang J, Hu S, et al. Relationship between urinary cysteinyl leukotriene E4 levels and clinical response to antileukotriene treatment in patients with asthma. Lung. 2007;185:105–12.

    Article  CAS  PubMed  Google Scholar 

  21. Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130:647–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Varricchi G, Bagnasco D, Borriello F, et al. Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin Allergy Clin Immunol. 2016;16(2):186–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ray A, Oriss TB, Wenzel SE. Emerging molecular phenotypes of asthma. Am J Physiol Lung Cell Mol Physiol. 2015;308:L130–40.

    Article  CAS  PubMed  Google Scholar 

  24. Kita H. Eosinophils: multifaceted biological properties and roles in health and disease. Immunol Rev. 2011;242:161–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Furuta GT, Atkins FD, Lee NA, et al. Changing roles of eosinophils in health and disease. Ann Allergy Asthma Immunol. 2014;113:3–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Provost V, Larose MC, Langlois A, et al. CCL26/eotaxin-3 is more effective to induce the migration of eosinophils of asthmatics than CCL11/eotaxin-1 and CCL24/eotaxin-2. J Leukoc Biol. 2013;94(2):213–22.

    Article  CAS  PubMed  Google Scholar 

  27. Mukherjee M, Sehmi R, Nair P. Anti-IL5 therapy for asthma and beyond. World Allergy Organ J. 2014;7(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189–97.

    Article  PubMed  Google Scholar 

  29. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985–93.

    Article  CAS  PubMed  Google Scholar 

  31. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198–207.

    Article  PubMed  Google Scholar 

  32. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651–9.

    Article  CAS  PubMed  Google Scholar 

  33. Flood-Page PT, Menzies-Gow AN, Kay AB, et al. Eosinophil’s role remains uncertain as antiinterleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med. 2003;167:199–204.

    Article  PubMed  Google Scholar 

  34. Verzegnassi F. Hypereosinophilic syndrome and mepolizumab. N Engl J Med. 2008;358:2838–40.

    Article  CAS  PubMed  Google Scholar 

  35. Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125–32.

    Article  CAS  PubMed  Google Scholar 

  36. Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized antihuman interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med. 2003;167:1655–9.

    Article  PubMed  Google Scholar 

  37. Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133–41.

    Article  CAS  PubMed  Google Scholar 

  38. Castro M, Bacharier LB. Treatment for severe eosinophilic asthma-consistent effect of anti-interleukin-5 antibodies? Lancet. 2016;388(10056):2059–60.

    Article  PubMed  Google Scholar 

  39. Gleich GJ, Klion AD, Lee JJ, Weller PF. The consequences of not having eosinophils. Allergy. 2013;68(7):829–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kung TT, Stelts DM, Zurcher JA, et al. Involvement of IL-5 in a murine model of allergic pulmonary inflammation: prophylactic and therapeutic effect of an anti-IL-5 antibody. Am J Respir Cell Mol Biol. 1995;13:360–5.

    Article  CAS  PubMed  Google Scholar 

  41. Mauser PJ, Pitman AM, Fernandez X, et al. Effects of an antibody to interleukin-5 in a monkey model of asthma. Am J Respir Crit Care Med. 1995;152:467–72.

    Article  CAS  PubMed  Google Scholar 

  42. Geijsen N, Koenderman L, Coffer PJ. Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family. Cytokine Growth Factor Rev. 2001;12(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  43. Martinez-Moczygemba M, Huston DP. Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J. Allergy Clin Immunol. 2003;112(4):653–65 (quiz 666).

    Article  CAS  PubMed  Google Scholar 

  44. Ghazi A, Trikha A, Calhoun WJ. 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. 2012;12(1):113–8.

    Article  CAS  PubMed  Google Scholar 

  45. Leckie MJ. Anti-interleukin-5 monoclonal antibodies: preclinical and clinical evidence in asthma models. Am J Respir Med. 2003;2(3):245–59.

    Article  CAS  PubMed  Google Scholar 

  46. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062–71.

    Article  CAS  PubMed  Google Scholar 

  47. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66.

    Article  CAS  PubMed  Google Scholar 

  48. Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799–810.

    Article  PubMed  Google Scholar 

  49. Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150(4):789–98.

    Article  PubMed  Google Scholar 

  50. 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(6):1237–44.

    Article  CAS  PubMed  Google Scholar 

  51. Gossage D, Geba G, Gillen A, et al. A multiple ascending subcutaneous dose study of MEDI-563, A humanized anti-IL-5RA monoclonal antibody, in adult asthmatics (clinicaltrails.gov Identifier: NCT00783289). Annual Congress of the European Respiratory Society (ERS); 2010.

  52. 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(5):1086–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2(11):879–90.

    Article  CAS  PubMed  Google Scholar 

  54. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128–41.

    Article  CAS  PubMed  Google Scholar 

  55. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–27.

    Article  CAS  PubMed  Google Scholar 

  56. Nowak RM, Parker JM, Silverman RA, et al. A randomized trial of benralizumab, an antiinterleukin 5 receptor α monoclonal antibody, after acute asthma. Am J Emerg Med. 2015;33(1):14–20.

    Article  PubMed  Google Scholar 

  57. Zeneca A. A safety extension study with benralizumab for asthmatic adults on inhaled corticosteroid plus long-acting β2 agonist (MELTEMI). 2017. https://clinicaltrials.gov/ct2/show/NCT02808819. Accessed 14 Mar 2017.

  58. Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol. 2004;113(1):115–9.

    Article  CAS  PubMed  Google Scholar 

  59. Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358(12):1215–28.

    Article  CAS  PubMed  Google Scholar 

  60. 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(2):461–7 (e1–5).

    Article  CAS  PubMed  Google Scholar 

  61. Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. Allergy Clin Immunol. 2006;118(6):1312–9.

    Article  CAS  Google Scholar 

  62. Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut. 2010;59(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  63. Assa’ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology. 2011;141(5):1593–604.

    Article  PubMed  Google Scholar 

  64. Moosig F, Gross WL, Herrmann K, et al. Targeting interleukin-5 in refractory and relapsing Churg-Strauss syndrome. Ann Intern Med. 2011;155(5):341–3.

    Article  PubMed  Google Scholar 

  65. Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60(5):693–6.

    Article  CAS  PubMed  Google Scholar 

  66. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128(5):989–95 (e1–8).

    Article  CAS  PubMed  Google Scholar 

  67. Hulse KE, Stevens WW, Tan BK, Schleimer RP. Pathogenesis of nasal polyposis. Clin Exp Allergy. 2015;45(2):328–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133–41.

    Article  CAS  PubMed  Google Scholar 

  69. Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: Results of a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2012;129(2):456–63.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the Associazione Ricerca Malattie Immunologiche e Allergiche (ARMIA), Genoa.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giorgio Walter Canonica.

Ethics declarations

Conflicts of interest

Giorgio Walter Canonica has participated in scientific boards organized by Astra Zeneca and Teva; Bagnasco Diego, Matteo Ferrando, Marco Caminati, Alice Bragantini, Gilda Varricchi, Francesca Puggioni, and Giovanni Passalacqua have no conflicts of interest that are relevant to the content of this article.

Funding

No sources of funding were used to conduct this study or prepare of this manuscript.

Additional information

Diego Bagnasco and Matteo Ferrando authors contributed equally to the writing of the paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bagnasco, D., Ferrando, M., Caminati, M. et al. Targeting Interleukin-5 or Interleukin-5Rα: Safety Considerations. Drug Saf 40, 559–570 (2017). https://doi.org/10.1007/s40264-017-0522-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-017-0522-5

Keywords

Navigation