Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy
Christian Lupinek, Kurt Derfler, Silvia Lee, Thomas Prikoszovich, Oliver Movadat, Eva Wollmann, Carolin Cornelius, Milena Weber, Renate Fröschl, Regina Selb, Katharina Blatt, Dubravka Smiljkovic, Volker Schoder, René Cervenka, Thomas Plaichner, Gottfried Stegfellner, Hans Huber, Rainer Henning, Justyna Kozik-Jaromin, Thomas Perkmann, Verena Niederberger, Ventzislav Petkov, Peter Valent, Adelheid Gauly, Hans Peter Leinenbach, Ingrid Uhlenbusch-Koerwer, Rudolf Valenta, Christian Lupinek, Kurt Derfler, Silvia Lee, Thomas Prikoszovich, Oliver Movadat, Eva Wollmann, Carolin Cornelius, Milena Weber, Renate Fröschl, Regina Selb, Katharina Blatt, Dubravka Smiljkovic, Volker Schoder, René Cervenka, Thomas Plaichner, Gottfried Stegfellner, Hans Huber, Rainer Henning, Justyna Kozik-Jaromin, Thomas Perkmann, Verena Niederberger, Ventzislav Petkov, Peter Valent, Adelheid Gauly, Hans Peter Leinenbach, Ingrid Uhlenbusch-Koerwer, Rudolf Valenta
Abstract
Background: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE.
Objective: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes.
Methods: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014.
Results: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids.
Conclusions: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.
Keywords: Allergy; Asthma; IgE; IgEnio; Immunoadsorption.
Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
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References
- Banerjee S., Resch Y., Chen K.-W., Swoboda I., Focke-Tejkl M., Blatt K., Novak N., Wickman M., van Hage M., Ferrara R., Mari A., Purohit A., Pauli G., Sibanda E.N., Ndlovu P., Thomas W.R., Krzyzanek V., Tacke S., Malkus U., Valent P., Valenta R., Vrtala S. Der p 11 is a major allergen for house dust mite-allergic patients suffering from atopic dermatitis. J. Invest. Dermatol. 2015;135:102–109.
- Bazaral M., Hamburger R.N. Standardization and stability of immunoglobulin E (IgE) J. Allergy Clin. Immunol. 1972;49:189–191.
- Bel E.H., Wenzel S.E., Thompson P.J., Prazma C.M., Keene O.N., Yancey S.W., Ortega H.G., Pavord I.D., Investigators S., Gibson P., Sajkov D., Thompson P., Laviolette M., Lemiere C., Nair P., Bystron J., Chlumsky J., Kindlova A., Kolek V., Pauk N., Aubier M., Bourdin A., De Blay F., Donazzolo Y., Magnan A., Ballenberger S., Beck E., Hoffmann M., Korn S., Kornmann O., Ludwig-Sengpiel A., Rolke M., Schroeder-Babo W., Hernandez-Colin D.D., Bel E.H.D., ten Brinke A., Mroz R., Pulka G., Howarth P., Mortimer K., Pavord I., Spencer D., Castro M., Chupp G., Katial R., Meltzer S., Wenzel S. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 2014;371:1189–1197.
- BTS . British Thoracic Society, Scottish Intercollegiate Guidelines Network (SIGN); 2010. British Guideline on the Management of Asthma. SIGN Guideline 101. 2008. [Online] Available from:
- Bundesärztekammer . Bundesärztekammer (BÄK), Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF); 2009. Nationale Versorgungsleitlinie Asthma–Langfassung. [Online] Available from:
- Dahdah L., Ceccarelli S., Amendola S., Campagnano P., Cancrini C., Mazzina O., Fiocchi A. IgE immunoadsorption knocks down the risk of food-related anaphylaxis. Pediatrics. 2015;136:e1617–e1620.
- Davila I., Valero A., Entrenas L.M., Valveny N., Herraez L., Group, S. S Relationship between serum total IgE and disease severity in patients with allergic asthma in Spain. J. Investig. Allergol. Clin. Immunol. 2015;25:120–127.
- EMA . European Medicines Agency; 2015. Xolair (Omalizumab) [Online] Available from:
- FDA . Food and Drug Administration; 2015. Xolair Prescribing Information. [Online] Available from:
- FMC . Fresenius Medical Care Deutschland GmbH; 2014. Extracorporeal SPecific IgE Removal From the Plasma of Allergic Asthma Patients (ESPIRA-study) [Online] Available from:
- Gauvreau G.M., O'Byrne P.M., Boulet L.-P., Wang Y., Cockcroft D., Bigler J., FitzGerald J.M., Boedigheimer M., Davis B.E., Dias C., Gorski K.S., Smith L., Bautista E., Comeau M.R., Leigh R., Parnes J.R. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 2014;370:2102–2110.
- GCP . ISO; 2011. Clinical Investigation of Medical Devices for Human Subjects - Good Clinical Practice. [Online] Available from:
- Gergen P.J., Arbes S.J., Jr., Calatroni A., Mitchell H.E., Zeldin D.C. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005–2006. J. Allergy Clin. Immunol. 2009;124:447–453.
- GINA . Global Initiative for Asthma (GINA); 2007. The Global Strategy for Asthma Management and Prevention. [Online] Available from:
- Hauswirth A.W., Natter S., Ghannadan M., Majlesi Y., Schernthaner G.H., Sperr W.R., Buhring H.J., Valenta R., Valent P. Recombinant allergens promote expression of CD203c on basophils in sensitized individuals. J. Allergy Clin. Immunol. 2002;110:102–109.
- Heinzerling L., Mari A., Bergmann K.C., Bresciani M., Burbach G., Darsow U., Durham S., Fokkens W., Gjomarkaj M., Haahtela T., Bom A.T., Wohrl S., Maibach H., Lockey R. The skin prick test - European standards. Clin. Transl. Allergy. 2013;3:3.
- Holgate S.T. Innate and adaptive immune responses in asthma. Nat. Med. 2012;18:673–683.
- Holgate S.T. New strategies with anti-IgE in allergic diseases. World Allergy Organ. J. 2014;7:17.
- Humbert M., Busse W., Hanania N.A., Lowe P.J., Canvin J., Erpenbeck V.J., Holgate S. Omalizumab in asthma: an update on recent developments. J. Allergy Clin. Immunol. Pract. 2014;2(525–36):e1.
- Jardieu P.M., Fick R.B., Jr. IgE inhibition as a therapy for allergic disease. Int. Arch. Allergy Immunol. 1999;118:112–115.
- Juniper E.F., O'Byrne P.M., Guyatt G.H., Ferrie P.J., King D.R. Development and validation of a questionnaire to measure asthma control. Eur. Respir. J. 1999;14:902–907.
- Kasperkiewicz M., Schmidt E., Frambach Y., Rose C., Meier M., Nitschke M., Falk T.M., Reich K., Ludwig R.J., Zillikens D. Improvement of treatment-refractory atopic dermatitis by immunoadsorption: a pilot study. J. Allergy Clin. Immunol. 2011;127 267–70, 270 e1–6.
- Kasperkiewicz M., Sufke S., Schmidt E., Zillikens D. IgE-specific immunoadsorption for treatment of recalcitrant atopic dermatitis. JAMA Dermatol. 2014;150:1350–1351.
- Kerzel S., Zemlin M., Rogosch T., Ollert M., Renz H., Klaus G., Maier R.F. Plasmapheresis prior to omalizumab administration in a 15-year-old boy with severe asthma and very high IgE levels: sustained effect over 2 years. Klin. Padiatr. 2011;223:356–359.
- Konradsen J.R., Fujisawa T., van Hage M., Hedlin G., Hilger C., Kleine-Tebbe J., Matsui E.C., Roberts G., Ronmark E., Platts-Mills T.A.E. Allergy to furry animals: new insights, diagnostic approaches, and challenges. J. Allergy Clin. Immunol. 2015;135:616–625.
- Lupinek C., Roux K.H., Laffer S., Rauter I., Reginald K., Kneidinger M., Blatt K., Ball T., Pree I., Jahn-Schmid B., Allam J.P., Novak N., Drescher A., Kricek F., Valent P., Englund H., Valenta R. Trimolecular complex formation of IgE, FcεRI, and a recombinant nonanaphylactic single-chain antibody fragment with high affinity for IgE. J. Immunol. 2009;182:4817–4829.
- Manise M., Bakayoko B., Schleich F., Corhay J.L., Louis R. IgE mediated sensitisation to aeroallergens in an asthmatic cohort: relationship with inflammatory phenotypes and disease severity. Int. J. Clin. Pract. 2016;70:596–605.
- Midoro-Horiuti T., Nouno S., Seino Y. Skin tests of pollen grains of taxodiaceae and cupressaceae in children with bronchial asthma. Acta Paediatr. Jpn. 1992;34:501–504.
- Molimard M., Buhl R., Niven R., Le Gros V., Thielen A., Thirlwell J., Maykut R., Peachey G. Omalizumab reduces oral corticosteroid use in patients with severe allergic asthma: real-life data. Respir. Med. 2010;104:1381–1385.
- Mudde G.C., Van Reijsen F.C., Boland G.J., de Gast G.C., Bruijnzeel P.L., Bruijnzeel-Koomen C.A. Allergen presentation by epidermal Langerhans' cells from patients with atopic dermatitis is mediated by IgE. Immunology. 1990;69:335–341.
- NHLBI . National Heart, Lung and Blood Institute (NHLBI); 2007. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Full Report 2007. [Online] Available from:
- Niederberger V., Ring J., Rakoski J., Jager S., Spitzauer S., Valent P., Horak F., Kundi M., Valenta R. Antigens drive memory IgE responses in human allergy via the nasal mucosa. Int. Arch. Allergy Immunol. 2007;142:133–144.
- O'Byrne P.M., Tworek D. Timing is everything: targeting IgE to reduce asthma exacerbation risk. J. Allergy Clin. Immunol. 2015;136:1486–1487.
- Ortega H.G., Liu M.C., Pavord I.D., Brusselle G.G., FitzGerald J.M., Chetta A., Humbert M., Katz L.E., Keene O.N., Yancey S.W., Chanez P., Investigators M., Ardusso L., De Salvo M., Raso E., Rey L., Rodriguez A., Scherbovsky P.S., Wehbe L., Bardin P., Gibson P., Robinson P., Sajkov D., Thompson P., Brusselle G., Dupont L., Louis R., Michel O., Bergeron C., Bhutani M., FitzGerald J.M., Houle P.-A., Killian K., Killorn P., Laviolette M., Leigh R., Lemiere C., Martin J., Pek B., Sharma S., Bisbal C., Patricio M., Saavedra R., Silva Orellana R., Vargas S., Bourdin A., Chanez P., Deschildre A., Devouassoux G., Humbert M., Paganin F., Verdier S., Wallaert B., Ballenberger S., Beck E., Ehlers M., Foerster K., Hofmann S., Illies G., Keller C., Korn S., Kornmann O., Rolke M., Schroeder-Babo W., Zielen S., Baglioni S., Canonica G.W., Chetta A., Foschino Barbaro M., Idotta G., Mereu C., Paggiaro P., Sofia M., Agnese S.A., Fukushima Y., Haida M., Harada T., Hataji O., Hozawa S., Kaneko N., Kato M., Kikuchi K., Kinoshita M., Kishaba T., Matsumoto M., Matsuoka H., Mori M., Nakatani Y., Odajima H., Oki K., Saito T., Ekino H., Shimoda T., Tohyama K., Tsuburai T., Tsuda T., Yamazaki Y., Choi B.W., Jung K.-S., Kim M.-K. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 2014;371:1198–1207.
- Pawankar R., Canonica G.W., Holgate S.T., Lockey R.F. Allergic diseases and asthma: a major global health concern. Curr. Opin. Allergy Clin. Immunol. 2012;12:39–41.
- Pollart S.M., Chapman M.D., Fiocco G.P., Rose G., Platts-Mills T.A. Epidemiology of acute asthma: IgE antibodies to common inhalant allergens as a risk factor for emergency room visits. J. Allergy Clin. Immunol. 1989;83:875–882.
- Pollart S.M., Reid M.J., Fling J.A., Chapman M.D., Platts-Mills T.A. Epidemiology of emergency room asthma in northern California: association with IgE antibody to ryegrass pollen. J. Allergy Clin. Immunol. 1988;82:224–230.
- Rasband W.S. U. S. National Institutes of Health; Bethesda, Maryland, USA: 1997–2014. ImageJ.
- Reed C.E., Swanson M.C., Agarwal M.K., Yunginger J.W. Allergens that cause asthma. Identification and quantification. Chest. 1985;87:40S–44S.
- Reich K., Deinzer J., Fiege A.K., von Gruben V., Sack A.L., Thraen A., Weisenseel P., Breuer K., Jackle S., Meier M. Panimmunoglobulin and IgE-selective extracorporeal immunoadsorption in patients with severe atopic dermatitis. J. Allergy Clin. Immunol. 2016;137(1882–1884):e6.
- Schäppi G.F., Suphioglu C., Taylor P.E., Knox R.B. Concentrations of the major birch tree allergen Bet v 1 in pollen and respirable fine particles in the atmosphere. J. Allergy Clin. Immunol. 1997;100:656–661.
- Sprenger K.B., Huber K., Kratz W., Henze E. Nomograms for the prediction of patient's plasma volume in plasma exchange therapy from height, weight, and hematocrit. J. Clin. Apher. 1987;3:185–190.
- Suphioglu C., Singh M.B., Taylor P., Bellomo R., Holmes P., Puy R., Knox R.B. Mechanism of grass-pollen-induced asthma. Lancet. 1992;339:569–572.
- Tay T.R., Bosco J., Aumann H., O'Hehir R., Hew M. Elevated total serum immunoglobulin E (> 1000 IU/mL): implications? Intern. Med. J. 2016;46:846–849.
- van der Heijden F.L., Joost van Neerven R.J., van Katwijk M., Bos J.D., Kapsenberg M.L. Serum-IgE-facilitated allergen presentation in atopic disease. J. Immunol. 1993;150:3643–3650.
- Wenzel S., Ford L., Pearlman D., Spector S., Sher L., Skobieranda F., Wang L., Kirkesseli S., Rocklin R., Bock B., Hamilton J., Ming J.E., Radin A., Stahl N., Yancopoulos G.D., Graham N., Pirozzi G. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 2013;368:2455–2466.
- Zink A., Gensbaur A., Zirbs M., Seifert F., Suarez I.L., Mourantchanian V., Weidinger S., Mempel M., Ring J., Ollert M. Targeting IgE in severe atopic dermatitis with a combination of immunoadsorption and omalizumab. Acta Derm. Venereol. 2016;96:72–76.
Source: PubMed