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Volumn 5, Issue 3, 2011, Pages 183-194

The role of monoclonal antibodies in the treatment of severe asthma

Author keywords

asthma management; monoclonal antibodies; severe asthma

Indexed keywords

ADALIMUMAB; ALLERGEN; AMG 317; BENRALIZUMAB; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; C REACTIVE PROTEIN; CERTOLIZUMAB PEGOL; CHOLINERGIC RECEPTOR BLOCKING AGENT; CHROMONE DERIVATIVE; CORTICOSTEROID; CREATINE KINASE; DACLIZUMAB; ENOKIZUMAB; ETANERCEPT; GOLIMUMAB; IMMUNOGLOBULIN E; INFLIXIMAB; KELIXIMAB; LEUKOTRIENE RECEPTOR BLOCKING AGENT; LUMILIXIMAB; MEPOLIZUMAB; MONOCLONAL ANTIBODY; OMALIZUMAB; PASCOLIZUMAB; PLACEBO; RESLIZUMAB; STEROID; THEOPHYLLINE; UNCLASSIFIED DRUG;

EID: 79957864313     PISSN: 17534658     EISSN: 17534666     Source Type: Journal    
DOI: 10.1177/1753465811400489     Document Type: Review
Times cited : (9)

References (58)
  • 1
    • 29544432432 scopus 로고    scopus 로고
    • The “black box” warning and allergy drugs
    • Aaronson D.W. (2006) The “black box” warning and allergy drugs. J Allergy Clin Immunol 117: 40–44.
    • (2006) J Allergy Clin Immunol , vol.117 , pp. 40-44
    • Aaronson, D.W.1
  • 5
    • 20044368243 scopus 로고    scopus 로고
    • The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma
    • Bousquet J. Cabrera P. Berkman N. Buhl R. Holgate S. Wenzel S. (2005) The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy 60: 302–308.
    • (2005) Allergy , vol.60 , pp. 302-308
    • Bousquet, J.1    Cabrera, P.2    Berkman, N.3    Buhl, R.4    Holgate, S.5    Wenzel, S.6
  • 6
    • 77953195601 scopus 로고    scopus 로고
    • Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice
    • Brightbill H.D. Jeet S. Lin Z. Yan D. Zhou M. Tan M. (2010) Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice. J Clin Invest 120: 2218–2229.
    • (2010) J Clin Invest , vol.120 , pp. 2218-2229
    • Brightbill, H.D.1    Jeet, S.2    Lin, Z.3    Yan, D.4    Zhou, M.5    Tan, M.6
  • 7
    • 38149091442 scopus 로고    scopus 로고
    • Targeting TNF-alpha: a novel therapeutic approach for asthma
    • quiz 11-12
    • Brightling C. Berry M. Amrani Y. (2008) Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol 121: 5–10, quiz 11-12.
    • (2008) J Allergy Clin Immunol , vol.121 , pp. 5-10
    • Brightling, C.1    Berry, M.2    Amrani, Y.3
  • 8
    • 0034907372 scopus 로고    scopus 로고
    • Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma
    • Busse W. Corren J. Lanier B.Q. McAlary M. Fowler-Taylor A. Cioppa G.D. (2001) Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 108: 184–190.
    • (2001) J Allergy Clin Immunol , vol.108 , pp. 184-190
    • Busse, W.1    Corren, J.2    Lanier, B.Q.3    McAlary, M.4    Fowler-Taylor, A.5    Cioppa, G.D.6
  • 9
    • 57349179165 scopus 로고    scopus 로고
    • Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial
    • Busse W.W. Israel E. Nelson H.S. Baker J.W. Charous B.L. Young D.Y. (2008) Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 178: 1002–1008.
    • (2008) Am J Respir Crit Care Med , vol.178 , pp. 1002-1008
    • Busse, W.W.1    Israel, E.2    Nelson, H.S.3    Baker, J.W.4    Charous, B.L.5    Young, D.Y.6
  • 10
    • 77952683218 scopus 로고    scopus 로고
    • 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
    • Busse W.W. Katial R. Gossage D. Sari S. Wang B. Kolbeck R. (2010) 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 125: 1237–1244 e1232.
    • (2010) J Allergy Clin Immunol , vol.125 , pp. 1237-1244 e1232
    • Busse, W.W.1    Katial, R.2    Gossage, D.3    Sari, S.4    Wang, B.5    Kolbeck, R.6
  • 12
    • 0000898623 scopus 로고    scopus 로고
    • The pharmacological basis of anti-IgE therapy
    • Chang T.W. (2000) The pharmacological basis of anti-IgE therapy. Nat Biotechnol 18: 157–162.
    • (2000) Nat Biotechnol , vol.18 , pp. 157-162
    • Chang, T.W.1
  • 14
    • 33846464598 scopus 로고    scopus 로고
    • Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection
    • Cruz A.A. Lima F. Sarinho E. Ayre G. Martin C. Fox H. (2007) Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy 37: 197–207.
    • (2007) Clin Exp Allergy , vol.37 , pp. 197-207
    • Cruz, A.A.1    Lima, F.2    Sarinho, E.3    Ayre, G.4    Martin, C.5    Fox, H.6
  • 15
    • 0020606965 scopus 로고
    • Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation
    • Depper J.M. Leonard W.J. Robb R.J. Waldmann T.A. Greene W.C. (1983) Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation. J Immunol 131: 690–696.
    • (1983) J Immunol , vol.131 , pp. 690-696
    • Depper, J.M.1    Leonard, W.J.2    Robb, R.J.3    Waldmann, T.A.4    Greene, W.C.5
  • 16
    • 36849070537 scopus 로고    scopus 로고
    • Cytokines and growth factors in airway remodeling in asthma
    • Doherty T. Broide D. (2007) Cytokines and growth factors in airway remodeling in asthma. Curr Opin Immunol 19: 676–680.
    • (2007) Curr Opin Immunol , vol.19 , pp. 676-680
    • Doherty, T.1    Broide, D.2
  • 18
    • 32644459549 scopus 로고    scopus 로고
    • Inhibition of tumor necrosis factor alpha for refractory asthma
    • Erzurum S.C. (2006) Inhibition of tumor necrosis factor alpha for refractory asthma. N Engl J Med 354: 754–758.
    • (2006) N Engl J Med , vol.354 , pp. 754-758
    • Erzurum, S.C.1
  • 19
    • 85047693849 scopus 로고    scopus 로고
    • Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics
    • Flood-Page P. Menzies-Gow A. Phipps S. Ying S. Wangoo A. Ludwig M.S. (2003) Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 112: 1029–1036.
    • (2003) J Clin Invest , vol.112 , pp. 1029-1036
    • Flood-Page, P.1    Menzies-Gow, A.2    Phipps, S.3    Ying, S.4    Wangoo, A.5    Ludwig, M.S.6
  • 22
  • 25
    • 0036379740 scopus 로고    scopus 로고
    • Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma
    • Hart T.K. Blackburn M.N. Brigham-Burke M. Dede K. Al-Mahdi N. Zia-Amirhosseini P. (2002) 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) Clin Exp Immunol , vol.130 , pp. 93-100
    • Hart, T.K.1    Blackburn, M.N.2    Brigham-Burke, M.3    Dede, K.4    Al-Mahdi, N.5    Zia-Amirhosseini, P.6
  • 26
    • 0141570710 scopus 로고    scopus 로고
    • Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma
    • Hochhaus G. Brookman L. Fox H. Johnson C. Matthews J. Ren S. (2003) Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med Res Opin 19: 491–498.
    • (2003) Curr Med Res Opin , vol.19 , pp. 491-498
    • Hochhaus, G.1    Brookman, L.2    Fox, H.3    Johnson, C.4    Matthews, J.5    Ren, S.6
  • 27
    • 28244479315 scopus 로고    scopus 로고
    • Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma
    • Howarth P.H. Babu K.S. Arshad H.S. Lau L. Buckley M. McConnell W. (2005) Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60: 1012–1018.
    • (2005) Thorax , vol.60 , pp. 1012-1018
    • Howarth, P.H.1    Babu, K.S.2    Arshad, H.S.3    Lau, L.4    Buckley, M.5    McConnell, W.6
  • 28
    • 20044362008 scopus 로고    scopus 로고
    • 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
    • Humbert M. Beasley R. Ayres J. Slavin R. Hebert J. Bousquet J. (2005) 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) Allergy , vol.60 , pp. 309-316
    • Humbert, M.1    Beasley, R.2    Ayres, J.3    Slavin, R.4    Hebert, J.5    Bousquet, J.6
  • 29
    • 0025270366 scopus 로고
    • Anti-Tac-H, a humanized antibody to the interleukin 2 receptor with new features for immunotherapy in malignant and immune disorders
    • Junghans R.P. Waldmann T.A. Landolfi N.F. Avdalovic N.M. Schneider W.P. Queen C. (1990) Anti-Tac-H, a humanized antibody to the interleukin 2 receptor with new features for immunotherapy in malignant and immune disorders. Cancer Res 50: 1495–1502.
    • (1990) Cancer Res , vol.50 , pp. 1495-1502
    • Junghans, R.P.1    Waldmann, T.A.2    Landolfi, N.F.3    Avdalovic, N.M.4    Schneider, W.P.5    Queen, C.6
  • 31
    • 67249158818 scopus 로고    scopus 로고
    • Establishment of humanized anti-interleukin-5 receptor alpha chain monoclonal antibodies having a potent neutralizing activity
    • Koike M. Nakamura K. Furuya A. Iida A. Anazawa H. Takatsu K. (2009) Establishment of humanized anti-interleukin-5 receptor alpha chain monoclonal antibodies having a potent neutralizing activity. Hum Antibodies 18: 17–27.
    • (2009) Hum Antibodies , vol.18 , pp. 17-27
    • Koike, M.1    Nakamura, K.2    Furuya, A.3    Iida, A.4    Anazawa, H.5    Takatsu, K.6
  • 32
    • 77952733788 scopus 로고    scopus 로고
    • MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function
    • Kolbeck R. Kozhich A. Koike M. Peng L. Andersson C.K. Damschroder M.M. (2010) MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol 125: 1344–1353 e1342.
    • (2010) J Allergy Clin Immunol , vol.125 , pp. 1344-1353 e1342
    • Kolbeck, R.1    Kozhich, A.2    Koike, M.3    Peng, L.4    Andersson, C.K.5    Damschroder, M.M.6
  • 33
    • 0032480574 scopus 로고    scopus 로고
    • Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma
    • Kon O.M. Sihra B.S. Compton C.H. Leonard T.B. Kay A.B. Barnes N.C. (1998) Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet 352: 1109–1113.
    • (1998) Lancet , vol.352 , pp. 1109-1113
    • Kon, O.M.1    Sihra, B.S.2    Compton, C.H.3    Leonard, T.B.4    Kay, A.B.5    Barnes, N.C.6
  • 34
    • 70349542893 scopus 로고    scopus 로고
    • Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany
    • Korn S. Thielen A. Seyfried S. Taube C. Kornmann O. Buhl R. (2009) Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany. Respir Med 103: 1725–1731.
    • (2009) Respir Med , vol.103 , pp. 1725-1731
    • Korn, S.1    Thielen, A.2    Seyfried, S.3    Taube, C.4    Kornmann, O.5    Buhl, R.6
  • 35
    • 6644229440 scopus 로고    scopus 로고
    • Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response
    • Leckie M.J. ten Brinke A. Khan J. Diamant Z. O'Connor B.J. Walls C.M. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356: 2144–2148.
    • (2000) Lancet , vol.356 , pp. 2144-2148
    • Leckie, M.J.1    ten Brinke, A.2    Khan, J.3    Diamant, Z.4    O'Connor, B.J.5    Walls, C.M.6
  • 36
    • 76749136238 scopus 로고    scopus 로고
    • Immunomodulator therapy: monoclonal antibodies, fusion proteins, cytokines, and immunoglobulins
    • Lee S.J. Chinen J. Kavanaugh A. (2010) Immunomodulator therapy: monoclonal antibodies, fusion proteins, cytokines, and immunoglobulins. J Allergy Clin Immunol 125(2 Suppl.2): S314's323.
    • (2010) J Allergy Clin Immunol , vol.125 , Issue.2 , pp. S314-S323
    • Lee, S.J.1    Chinen, J.2    Kavanaugh, A.3
  • 37
    • 36749043895 scopus 로고    scopus 로고
    • Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma
    • Limb S.L. Starke P.R. Lee C.E. Chowdhury B.A. (2007) Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol 120: 1378–1381.
    • (2007) J Allergy Clin Immunol , vol.120 , pp. 1378-1381
    • Limb, S.L.1    Starke, P.R.2    Lee, C.E.3    Chowdhury, B.A.4
  • 39
    • 67650434286 scopus 로고    scopus 로고
    • Immunomodulators in the treatment of asthma
    • Long A.A. (2009a) Immunomodulators in the treatment of asthma. Allergy Asthma Proc 30: 109–119.
    • (2009) Allergy Asthma Proc , vol.30 , pp. 109-119
    • Long, A.A.1
  • 40
    • 77951535660 scopus 로고    scopus 로고
    • Monoclonal antibodies and other biologic agents in the treatment of asthma
    • Long A.A. (2009b) Monoclonal antibodies and other biologic agents in the treatment of asthma. MAbs 1: 237–246.
    • (2009) MAbs , vol.1 , pp. 237-246
    • Long, A.A.1
  • 41
    • 34548762411 scopus 로고    scopus 로고
    • Monoclonal antibodies in Pediatrics: use in prevention and treatment
    • Martin-Mateos M. (2007) Monoclonal antibodies in Pediatrics: use in prevention and treatment. Allergologia Immunopathologia 35: 145–150.
    • (2007) Allergologia Immunopathologia , vol.35 , pp. 145-150
    • Martin-Mateos, M.1
  • 42
    • 0036721711 scopus 로고    scopus 로고
    • IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production
    • McDyer J.F. Li Z. John S. Yu X. Wu C.Y. Ragheb J.A. (2002) IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production. J Immunol 169: 2736–2746.
    • (2002) J Immunol , vol.169 , pp. 2736-2746
    • McDyer, J.F.1    Li, Z.2    John, S.3    Yu, X.4    Wu, C.Y.5    Ragheb, J.A.6
  • 44
    • 0033599043 scopus 로고    scopus 로고
    • Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group
    • Milgrom H. Fick R.B. Jr Su J.Q. Reimann J.D. Bush R.K. Watrous M.L. (1999) Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med 341: 1966–1973.
    • (1999) N Engl J Med , vol.341 , pp. 1966-1973
    • Milgrom, H.1    Fick, R.B.2    Su, J.Q.3    Reimann, J.D.4    Bush, R.K.5    Watrous, M.L.6
  • 45
    • 47049130758 scopus 로고    scopus 로고
    • The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial
    • Morjaria J.B. Chauhan A.J. Babu K.S. Polosa R. Davies D.E. Holgate S.T. (2008) The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 63: 584–591.
    • (2008) Thorax , vol.63 , pp. 584-591
    • Morjaria, J.B.1    Chauhan, A.J.2    Babu, K.S.3    Polosa, R.4    Davies, D.E.5    Holgate, S.T.6
  • 48
    • 25844461664 scopus 로고    scopus 로고
    • Anti-CD23 monoclonal antibody, lumiliximab, inhibited allergen-induced responses in antigen-presenting cells and T cells from atopic subjects
    • Poole J.A. Meng J. Reff M. Spellman M.C. Rosenwasser L.J. (2005) Anti-CD23 monoclonal antibody, lumiliximab, inhibited allergen-induced responses in antigen-presenting cells and T cells from atopic subjects. J Allergy Clin Immunol 116: 780–788.
    • (2005) J Allergy Clin Immunol , vol.116 , pp. 780-788
    • Poole, J.A.1    Meng, J.2    Reff, M.3    Spellman, M.C.4    Rosenwasser, L.J.5
  • 51
    • 0028144786 scopus 로고
    • IL-4: a key cytokine in atopy
    • Ricci M. (1994) IL-4: a key cytokine in atopy. Clin Exp Allergy 24: 801–812.
    • (1994) Clin Exp Allergy , vol.24 , pp. 801-812
    • Ricci, M.1
  • 52
    • 0033136728 scopus 로고    scopus 로고
    • Down-regulation of human basophil IgE and FC epsilon RI alpha surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo
    • Saini S.S. MacGlashan D.W. Jr Sterbinsky S.A. Togias A. Adelman D.C. Lichtenstein L.M. (1999) Down-regulation of human basophil IgE and FC epsilon RI alpha surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo. J Immunol 162: 5624–5630.
    • (1999) J Immunol , vol.162 , pp. 5624-5630
    • Saini, S.S.1    MacGlashan, D.W.2    Sterbinsky, S.A.3    Togias, A.4    Adelman, D.C.5    Lichtenstein, L.M.6
  • 53
    • 4944230274 scopus 로고    scopus 로고
    • The safety and pharmacokinetics of SB240683 anti-Il-4 humanized monoclonal antibody) in patients with mild to moderate asthma
    • Shames R.S. Vexler V. Lane N.M. McClellan M. Shi J. Keller S. (2001) The safety and pharmacokinetics of SB240683 anti-Il-4 humanized monoclonal antibody) in patients with mild to moderate asthma. J Allergy Clin Immunol 107: S316's316.
    • (2001) J Allergy Clin Immunol , vol.107 , pp. S316-S316
    • Shames, R.S.1    Vexler, V.2    Lane, N.M.3    McClellan, M.4    Shi, J.5    Keller, S.6
  • 54
    • 38449109458 scopus 로고    scopus 로고
    • Anti-IgE and other antibody targets in asthma
    • Singh J. Kraft M. (2008) Anti-IgE and other antibody targets in asthma. Handb Exp Pharmacol 181: 257–288.
    • (2008) Handb Exp Pharmacol , vol.181 , pp. 257-288
    • Singh, J.1    Kraft, M.2
  • 55
    • 0034881877 scopus 로고    scopus 로고
    • The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics
    • Soler M. Matz J. Townley R. Buhl R. O'Brien J. Fox H. (2001) The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 18: 254–261.
    • (2001) Eur Respir J , vol.18 , pp. 254-261
    • Soler, M.1    Matz, J.2    Townley, R.3    Buhl, R.4    O'Brien, J.5    Fox, H.6
  • 57
    • 77951614830 scopus 로고    scopus 로고
    • Monoclonal antibodies: versatile platforms for cancer immunotherapy
    • Weiner L.M. Surana R. Wang S. (2010) Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10: 317–327.
    • (2010) Nat Rev Immunol , vol.10 , pp. 317-327
    • Weiner, L.M.1    Surana, R.2    Wang, S.3
  • 58
    • 62549084077 scopus 로고    scopus 로고
    • A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma
    • Wenzel S.E. Barnes P.J. Bleecker E.R. Bousquet J. Busse W. Dahlen S.E. (2009) A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 179: 549–558.
    • (2009) Am J Respir Crit Care Med , vol.179 , pp. 549-558
    • Wenzel, S.E.1    Barnes, P.J.2    Bleecker, E.R.3    Bousquet, J.4    Busse, W.5    Dahlen, S.E.6


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