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Published in:

01-06-2011

Monoclonal Antibodies for the Treatment of Severe Asthma

Authors: Salvatore Clienti, Jaymin B. Morjaria, Elisa Basile, Riccardo Polosa

Published in: Current Allergy and Asthma Reports | Issue 3/2011

Abstract

Patients with severe asthma have a significant unmet need with persistent symptoms and/or frequent exacerbations despite treatment with high-dose steroid and other currently available therapies. These patients are also at risk of developing steroid-related side effects, and their severe, unrelenting symptoms have a huge impact on health care resources due to frequent hospital admissions and requirement for intensive medication use. Consequently, a compelling need exists for more effective and safer pharmacotherapies to help them achieve adequate disease control. Recent novel therapies for severe asthma are now emerging, some of the most promising of which are monoclonal antibodies. Monoclonal antibodies represent a form of immunotherapy used in a wide variety of therapeutic roles. The spectrum of disease states in which monoclonal antibodies have been approved for therapeutic use now includes respiratory and allergic diseases. At present, only one drug is licensed for allergic asthmatics with severe disease, omalizumab. We review some of the currently available biologics that are approved or under investigation for use in severe asthma. Some have shown to be useful in specifically targeted subpopulations of patients with severe asthma, whereas other have proven to be unsafe and/or unsuccessful. Despite these developments, more effort should be devoted to identifying new molecular targets, testing innovative approaches, and establishing the best use of what is available. Regarding this latter point, identifying individual characteristics that predict successful responses to these treatments is highly desirable.

Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–7.PubMedCrossRef

Milstein C. With the benefit of hindsight. Immunol Today. 2000;21(8):359–64.PubMedCrossRef

Hudson PJ, Souriau C. Engineered antibodies. Nat Med. 2003;9(1):129–34.PubMedCrossRef

Smith SL. Ten years of Orthoclone OKT3 (Muromonab-CD3): a review. J Transpl Coord. 1996;6(3):109–19.PubMed

Scott SD. Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin’s lymphoma. Cancer Pract. 1998;6(3):195–7.PubMedCrossRef

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080591.htm.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicaticons/TherapeuticBiologicApplications/ucm093373.htm.

Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006;368(9537):780–93.PubMedCrossRef

BTS/SIGN (British Thoracic Society/Scottish Intercollegiate Network). British guideline on the management of asthma: a national clinical guideline. Thorax. 2008;63(Suppl IV):iv1–iv121.CrossRef

10.

Polosa R. An overview of chronic severe asthma. Intern Med J. 2008;38(3):190–8.PubMedCrossRef

11.

Smith DH, Malone DC, Lawson KA, Okamoto LJ, Battista C, Saunders WB. A national estimate of the economic costs of asthma. Am J Respir Crit Care Med. 1997;156(3 Pt 1):787–93.PubMed

12.

Antoncelli L, Bucca C, Neri M, De Benedetto F, Saabbatani PBF. Asthma severityand medical resource utilzation. Eur Respir J. 2004;23:723–9.CrossRef

13.

Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J. 2002;19(1):61–7.PubMedCrossRef

14.

Chanez P, Wenzel SE, Anderson GP, et al. Severe asthma in adults: what are the important questions? J Allergy Clin Immunol. 2007;119(6):1337–48.PubMedCrossRef

15.

Currie GP, Douglas JG, Heaney LG. Difficult to treat asthma in adults. BMJ. 2009;338:b494.PubMedCrossRef

16.

Polosa R, Benfatto GT. Managing patients with chronic severe asthma: rise to the challenge. Eur J Intern Med. 2009;20(2):114–24.PubMedCrossRef

17.

Morjaria JB, Polosa R. Recommendation for optimal management of severe refractory asthma. J Asthma Allergy. 2010;3:43–56.PubMedCrossRef

18.

Scheinberg DA, Chapman PB. Therapeutic applications of monoclonal antibodies for human disease. In: Birch JR, Lennox ES, editors. Monoclonal antibodies, principles and practice. New York: Wiley-Liss; 1995. p. 45–105.

19.

Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205–17.PubMedCrossRef

20.

Corne J, Djukanovic R, Thomas L, et al. The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics. J Clin Invest. 1997;99(5):879–87.PubMedCrossRef

21.

Presta L, Shields R, O’Connell L, et al. The binding site on human immunoglobulin E for its high affinity receptor. J Biol Chem. 1994;269(42):26368–73.PubMed

22.

Shields RL, Whether WR, Zioncheck K, et al. Inhibition of allergic reactions with antibodies to IgE. Int Arch Allergy Immunol. 1995;107(1–3):308–12.PubMedCrossRef

23.

Polosa R, Holgate ST. Omalizumab and severe allergic asthma. Oxford: Clinical Publishing; 2009. 52 pp.

24.

Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev. 2006;2:CD003559.PubMed

25.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126456.htm.

26.

Morjaria JB, Polosa R. Off-label use of omalizumab in non-asthma conditions: new opportunities. Expert Rev Respir Med. 2009;3(3):299–308.PubMedCrossRef

27.

Ohta K, Miyamoto T, Amagasaki T, Yamamoto M. Efficacy and safety of omalizumab in an Asian population with moderate-to-severe persistent asthma. Respirology. 2009;14(8):1156–65.PubMedCrossRef

28.

•• Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009;124(6):1210–6. This was a clinical trial demonstrating the efficacy of omalizumab in children with moderate to severe uncontrolled atopic asthma. PubMedCrossRef

29.

Massanari M, Milgrom H, Pollard S, et al. Adding omalizumab to the therapy of adolescents with persistent uncontrolled moderate-severe allergic asthma. Clin Pediatr (Phila). 2009;48(8):859–65.CrossRef

30.

Hayashi N, Tsukamoto Y, Sallas WM, Lowe PJ. A mechanism-based binding model for the population pharmacokinetics and pharmacodynamics of omalizumab. Br J Clin Pharmacol. 2007;63(5):548–61.PubMedCrossRef

31.

Meno-Tetang GM, Lowe PJ. On the prediction of the human response: a recycled mechanistic pharmacokinetic/pharmacodynamic approach. Basic Clin Pharmacol Toxicol. 2005;96(3):182–92.PubMedCrossRef

32.

Slavin RG, Ferioli C, Tannenbaum SJ, Martin C, Blogg M, Lowe PJ. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J Allergy Clin Immunol. 2009;123(1):107–13. e3.PubMedCrossRef

33.

Lowe PJ, Tannenbaum S, Gautier A, Jimenez P. Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma. Br J Clin Pharmacol. 2009;68(1):61–76.PubMedCrossRef

34.

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (updated 2009); Available at: http://www.ginasthma.org.

35.

Domingo C, Moreno A, Jose Amengual M, Monton C, Suarez D, Pomares X. Omalizumab in the management of oral corticosteroid-dependent IGE-mediated asthma patients. Curr Med Res Opin. 2011;27(1):45–53.PubMedCrossRef

36.

Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005;109(2):135–42.CrossRef

37.

Morjaria JB, Malerba M, Polosa R. Biologic and pharmacologic therapies in clinical development for the inflammatory response in COPD. Drug Discov Today. 2010;15(9–10):396–405.PubMedCrossRef

38.

Cazzola M, Polosa R. Anti-TNF-alpha and Th1 cytokine-directed therapies for the treatment of asthma. Curr Opin Allergy Clin Immunol. 2006;6(1):43–50.PubMedCrossRef

39.

Howarth PH, Babu KS, Arshad HS, Lau LC, Buckley MG, McConnell W, et al. Tumour Necrosis Factor (TNF{alpha}) as a novel therapeutic target in symptomatic corticosteroid-dependent asthma. Thorax. 2005;60:1012–8.PubMedCrossRef

40.

Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006;354(7):697–708.PubMedCrossRef

41.

• Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised placebo-controlled trial. Thorax. 2008;63:584–91. This was a DBPC study showing the lack of objective parameter improvements with etanercept use. PubMedCrossRef

42.

• Holgate ST, Noonan M, Chanez P, et al. Efficacy/safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2010 Nov 25 (Epub ahead of print). This was a large DBPC study reporting no improvements on any parameters of asthma assessment with use of etanercept. However, it also reported no safety concerns.

43.

• 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(7):549–58. This was a large DBPC study showing not only no clinical improvements in individuals treated with golimumab but also high numbers of serious adverse events. PubMedCrossRef

44.

Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147–74.PubMedCrossRef

45.

Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood. 1992;79(12):3101–9.PubMed

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.PubMedCrossRef

47.

Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med. 2003;167(2):199–204.PubMedCrossRef

48.

Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356(9248):2144–8.PubMedCrossRef

49.

•• Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84. This was a small but relevant study demonstrating the efficacy and safety of mepolizumab in oral corticosteroid-dependent, sputum eosinophilic asthmatics. PubMedCrossRef

50.

•• Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93. This was an important study reporting that mepolizumab reduces asthma exacerbations and improves quality of life in refractory eosinophilic asthma. PubMedCrossRef

51.

Polosa R, Morjaria J. Immunomodulatory and biologic therapies for severe refractory asthma. Respir Med. 2008;102(11):1499–510.PubMedCrossRef

52.

http://clinicaltrials.gov/ct2/show/NCT01000506?term=mepolizumab+AND+asthma&rank=1.

53.

Holgate ST, Polosa R. Treatment strategies for allergy and asthma. Nat Rev Immunol. 2008;8(3):218–30.PubMedCrossRef

54.

Kon OM, Sihra BS, Loh LC, et al. The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur Respir J. 2001;18(1):45–52.PubMedCrossRef

55.

Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB, Barnes NC. Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet. 1998;352(9134):1109–13.PubMedCrossRef

56.

Azzawi M, Johnston PW, Majumdar S, Kay AB, Jeffery PK. T lymphocytes and activated eosinophils in airway mucosa in fatal asthma and cystic fibrosis. Am Rev Respir Dis. 1992;145(6):1477–82.PubMed

57.

Kon OM, Kay AB. Anti-T cell strategies in asthma. Inflamm Res. 1999;48(10):516–23.PubMedCrossRef

58.

Park CS, Lee SM, Chung SW, Uh S, Kim HT, Kim YH. Interleukin-2 and soluble interleukin-2 receptor in bronchoalveolar lavage fluid from patients with bronchial asthma. Chest. 1994;106(2):400–6.PubMedCrossRef

59.

Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med. 2008;178(10):1002–8.PubMedCrossRef

60.

Grunig G, Warnock M, Wakil AE, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998;282(5397):2261–3.PubMedCrossRef

61.

Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282(5397):2258–61.PubMedCrossRef

62.

Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol. 2003;111(4):677–90. quiz 91.PubMedCrossRef

63.

Rolling C, Treton D, Pellegrini S, Galanaud P, Richard Y. IL4 and IL13 receptors share the gamma c chain and activate STAT6, STAT3 and STAT5 proteins in normal human B cells. FEBS Lett. 1996;393(1):53–6.PubMedCrossRef

64.

Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370(9596):1422–31.PubMedCrossRef

65.

http://clinicaltrials.gov/ct2/show/NCT00801853?term=Aerovant+AND+asthma&rank=1.

66.

• Corren J, Busse W, Meltzer EO, et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Am J Respir Crit Care Med. 2010;181(8):788–96. This was a large study reporting the safety of AMG 317. Although there was no significant differences in any of the end points measured, it was thought to be clinically efficacious in patients with maximal symptoms. PubMedCrossRef

67.

Krishnamoorthy N, Oriss TB, Paglia M, et al. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat Med. 2008;14(5):565–73.PubMedCrossRef

68.

Reber L, Da Silva CA, Frossard N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol. 2006;533(1–3):327–40.PubMedCrossRef

69.

Chung KF, Hew M, Score J, et al. Cough and hypereosinophilia due to FIP1L1-PDGFRA fusion gene with tyrosine kinase activity. Eur Respir J. 2006;27(1):230–2.PubMedCrossRef

70.

Ingram JL, Bonner JC. EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases. Curr Mol Med. 2006;6(4):409–21.PubMedCrossRef

71.

Hahn KA, Ogilvie G, Rusk T, et al. Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Intern Med. 2008;22(6):1301–9.PubMedCrossRef

72.

Humbert M, de Blay F, Garcia G, et al. Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy. 2009;64(8):1194–201.PubMedCrossRef

73.

http://www.fp7-consulting.be/en/ubiopred/. 2008.

Title: Monoclonal Antibodies for the Treatment of Severe Asthma
Authors: Salvatore Clienti
Jaymin B. Morjaria
Elisa Basile
Riccardo Polosa
Publication date: 01-06-2011
Publisher: Current Science Inc.
Published in: Current Allergy and Asthma Reports / Issue 3/2011
Print ISSN: 1529-7322
Electronic ISSN: 1534-6315
DOI: https://doi.org/10.1007/s11882-011-0184-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Monoclonal Antibodies for the Treatment of Severe Asthma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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