COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy

Abstract

Background: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).

Objective: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.

Methods: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test.

Results: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5).

Conclusion: C4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.

Trial registration: ClinicalTrials.gov NCT02496468 NCT02419274.

Conflict of interest statement

Conflict of interest: M. Weckmann reports grants from Federal Ministry for Education and Research (BMBF), University of Lübeck (E42-2012 and JC01-2016) and German Academic Exchange Service (56266000), during the conduct of the study. Conflict of interest: T. Bahmer has nothing to disclose. Conflict of interest: J.M. Sand is a full-time employee of Nordic Bioscience. Conflict of interest: S. Rank Rønnow is employed by Nordic Bioscience, and has received grants from Innovation Foundation, during the conduct of the study. Conflict of interest: M. Pech has nothing to disclose. Conflict of interest: C. Vermeulen has nothing to disclose. Conflict of interest: A. Faiz has nothing to disclose. Conflict of interest: D.J. Leeming is a stockholder and full-time employee of Nordic Bioscience A/S. Conflict of interest: M.A. Karsdal is a stockholder and full-time employee of Nordic Bioscience. Conflict of interest: L. Lunding has nothing to disclose. Conflict of interest: B.G.G. Oliver has nothing to disclose. Conflict of interest: M. Wegmann has nothing to disclose. Conflict of interest: G. Ulrich-Merzenich reports grants for research and meeting attendance from Novartis AG, during the conduct of the study; and has a patent EPC 18185472.0-1118 pending. Conflict of interest: U.R. Juergens has nothing to disclose. Conflict of interest: J. Duhn has nothing to disclose. Conflict of interest: Y. Laumonnier has nothing to disclose. Conflict of interest: O. Danov has nothing to disclose. Conflict of interest: K. Sewald has nothing to disclose. Conflict of interest: U. Zissler reports grants and personal fees from Federal Ministry for Education and Research of Germany, during the conduct of the study. Conflict of interest: M. Jonker has nothing to disclose. Conflict of interest: I. König has nothing to disclose. Conflict of interest: G. Hansen is a consultant for Novartis and Sanofi. Conflict of interest: E. von Mutius received consultancy fees from European Commission, Tampereen Yliopisto, University of Edinburgh, Nestec S.A., University of Veterinary Medicine, Vienna, Chinese University of Hongkong, Research Center Borstel – Leibniz Lung Center, OM Pharma S.A., Pharmaventures Ltd, Peptinnovate Ltd, Turun Yliopisto, Helsingin Yliopisto, Chinese University of Hongkong, Imperial College London, Universiteit Utrecht, Universität Salzburg, Österreichische Gesellschaft f. Allergologie u. Immunologie, HiPP GmbH & Co KG; received fees for speaking from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), The American Academy of Allergy Asthma and Immunology, British Society for Immunology, Medical University of Vienna, Schweizerisches Institiut für Allergie- und Asthmaforschung, Howard Hughes Medical Institute, University Hospital Erlangen, Margaux Orange, Deutsche Akademie der Naturforscher Leopoldina e.V., Hannover Medical School, American Thoracic Society, Inc., European Academy of Allergy and Clinical Immunology, Mundipharma Deutschland GmbH & Co. KG, DOC Congress SRL, ITÄ-Suomen Yliopisto, Interplan – Congress, Meeting & Event Management AG, INC, Ökosoziales Forum Oberösterreich, Imperial College London, WMA Kongress GmbH, University Hospital rechts der Isar, European Respiratory Society, HAL Allergie GmbH, PersonalGenomes.org, Nestlé Deutschland AG, Universitätsklinikum Aachen, SIAF – Swiss Institute of Allergy and Asthma Research, Deutsche Pharmazeutische Gesellschaft e.V., Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf e.V., Pneumologie Developpement, Mondial Congress & Events GmbH & Co. KG, Volkswagen Stiftung, Boehringer Ingelheim International GmbH, Hanson Wade Ltd, DSI Dansk Borneastma Center; received author honoraria from Elsevier Ltd, Springer-Verlag GmbH, Schattauer GmbH, Georg Thieme Verlag, Springer Medizin Verlag GmbH; is on the editorial board of the New England Journal of Medicine; and has a patent Application number LU101064, Barn dust extract for the prevention and treatment of diseases pending; a patent Publication number EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to Protectimmun GmbH; a patent Publication number EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases licensed to Protectimmun GmbH; a patent Publication number EP1637147: Stable dust extract for allergy protection licensed to Protectimmun GmbH; and a patent Publication number EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to Protectimmun GmbH. Conflict of interest: O. Fuchs is a consultant for Menarini and Vifor; has received speaker's fees from Vertex, aha! Allergy Centre Switzerland, Menarini, Novartis, Medical Tribune Switzerland, German Society of Paediatric Allergology and ALK; and has received travel support from Milupa/Nutricia, Stallergenes Greer and Bencard. Conflict of interest: A-M. Dittrich has nothing to disclose. Conflict of interest: B. Schaub reports grants from DFG, BMBF and EU, outside the submitted work. Conflict of interest: C. Happle has nothing to disclose. Conflict of interest: K.F. Rabe received grants from Boehringer Ingelheim and personal fees from AstraZeneca, Novartis, Sanofi, Regeneron, Roche and Chiesi Pharmaceuticals. Conflict of interest: M. van de Berge reports grants paid to university from GlaxoSmithKline, AstraZeneca and Genentech, outside the submitted work. Conflict of interest: J.K. Burgess reports grants from National Health and Medical Research Council, Australia, University of Groningen and European Union, during the conduct of the study. Conflict of interest: M.V. Kopp reports grants from Federal Ministry of Research and Education (BMBF), during the conduct of the study; personal fees from ALK-Abello, Allergopharma, Boehringer Ingelheim, Chiesi, Glaxo, Infectopharm, Meda, Sanofi-Aventis, Leti Pharma, Novartis and Vertex, outside the submitted work.

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