Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study

Poul Erik H Jensen; Clemens Warnke; Kathleen Ingenhoven; Luca Piccoli; Marcia Gasis; Christina Hermanrud; Blanca M Fernandez-Rodriguez; Malin Ryner; Daniel Kramer; Jenny Link; Ryan Ramanujam; Michael Auer; Dorothea Buck; Verena Grummel; Elisa Bertotti; Nicolas Fissolo; Begoña Oliver-Martos; Petra Nytrova; Michael Khalil; Michael Guger; Sandra Rathmaier; Claudia Sievers-Stober; Raija L P Lindberg; Signe Hässler; Delphine Bachelet; Orhan Aktas; Naoimh Donnellan; Andy Lawton; Bernhard Hemmer; Eva Kubala Havrdova; Bernd Kieseier; Hans-Peter Hartung; Manuel Comabella; Xavier Montalban; Tobias Derfuss; Finn Sellebjerg; Pierre Dönnes; Marc Pallardy; Sebastian Spindeldreher; Philippe Broët; Florian Deisenhammer; Anna Fogdell-Hahn; Per Soelberg Sorensen; ABIRISK Consortium

doi:10.1016/j.jneuroim.2018.11.002

Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study

J Neuroimmunol. 2019 Jan 15:326:19-27. doi: 10.1016/j.jneuroim.2018.11.002. Epub 2018 Nov 7.

Authors

Poul Erik H Jensen¹, Clemens Warnke², Kathleen Ingenhoven³, Luca Piccoli⁴, Marcia Gasis⁵, Christina Hermanrud⁶, Blanca M Fernandez-Rodriguez⁷, Malin Ryner⁸, Daniel Kramer⁹, Jenny Link¹⁰, Ryan Ramanujam¹¹, Michael Auer¹², Dorothea Buck¹³, Verena Grummel¹⁴, Elisa Bertotti¹⁵, Nicolas Fissolo¹⁶, Begoña Oliver-Martos¹⁷, Petra Nytrova¹⁸, Michael Khalil¹⁹, Michael Guger²⁰, Sandra Rathmaier²¹, Claudia Sievers-Stober²², Raija L P Lindberg²³, Signe Hässler²⁴, Delphine Bachelet²⁵, Orhan Aktas²⁶, Naoimh Donnellan²⁷, Andy Lawton²⁸, Bernhard Hemmer²⁹, Eva Kubala Havrdova³⁰, Bernd Kieseier³¹, Hans-Peter Hartung³², Manuel Comabella³³, Xavier Montalban³⁴, Tobias Derfuss³⁵, Finn Sellebjerg³⁶, Pierre Dönnes³⁷, Marc Pallardy³⁸, Sebastian Spindeldreher³⁹, Philippe Broët⁴⁰, Florian Deisenhammer⁴¹, Anna Fogdell-Hahn⁴², Per Soelberg Sorensen⁴³; ABIRISK Consortium

Affiliations

¹ Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: poul.erik.h.jensen@regionh.dk.
² Department of Neurology, University Hospital Köln, Köln, Germany; University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany. Electronic address: clemens.warnke@uk-koeln.de.
³ University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany. Electronic address: Kathleen.Ingenhoven@med.uni-duesseldorf.de.
⁴ Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Bellinzona, Switzerland. Electronic address: luca.piccoli@irb.usi.ch.
⁵ University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany. Electronic address: gasis@hhu.de.
⁶ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: christina.hermanrud@ki.se.
⁷ Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Bellinzona, Switzerland. Electronic address: blanca.fernandez@irb.usi.ch.
⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁹ Sanofi-Aventis Germany, Frankfurt Am Main, Germany. Electronic address: daniel.kramer@sanofi.com.
¹⁰ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: jenny.link@ki.se.
¹¹ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; KTH - Royal Institute of Technology, Stockholm, Sweden. Electronic address: Ryan.Ramanujam@ki.se.
¹² Innsbruck Medical University, Innsbruck, Austria. Electronic address: Michael.Auer@student.i-med.ac.at.
¹³ Department of Neurology, Technische Universität München, Munich, Germany. Electronic address: dorothea.buck@tum.de.
¹⁴ Department of Neurology, Technische Universität München, Munich, Germany. Electronic address: v.grummel@tum.de.
¹⁵ Merck NBE Bioanalytics Ivrea, Colleretto Giacosa, Italy. Electronic address: elisa.bertotti@merckgroup.com.
¹⁶ Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Barcelona, Spain. Electronic address: nicolas.fissolo@vhir.org.
¹⁷ Hospital Regional Universitario de Málaga, Instituto de investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
¹⁸ MS Center, Department of Neurology and Center Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic. Electronic address: Petra.Nytrova@lf1.cuni.cz.
¹⁹ Department of Neurology, Medical University of Graz, Graz, Austria. Electronic address: michael.khalil@medunigraz.at.
²⁰ Clinic for Neurology 2, Kepler University Clinic, Med Campus III, Linz, Austria. Electronic address: Michael.Guger@kepleruniklinikum.at.
²¹ Clinic for Neurology 2, Kepler University Clinic, Med Campus III, Linz, Austria. Electronic address: Sandra.Rathmaier@kepleruniklinikum.at.
²² Departments of Biomedicine and Neurology, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: claudia.sievers-stober@unibas.ch.
²³ Departments of Biomedicine and Neurology, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: Raija.Lindberg@unibas.ch.
²⁴ CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay, University UVSQ, Villejuif, France. Electronic address: signe.hassler@inserm.fr.
²⁵ CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay, University UVSQ, Villejuif, France. Electronic address: delphine.bachelet@inserm.fr.
²⁶ University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany. Electronic address: orhan.aktas@uni-duesseldorf.de.
²⁷ Ipsen Biopharm Ltd., Berkshire, United Kingdom.
²⁸ GlaxoSmithKline R&D, Uxbridge, Middlesex, United Kingdom. Electronic address: andy.m.lawton@gsk.com.
²⁹ Department of Neurology, Technische Universität München, Munich, Germany; Munich Cluster for systems Neurology (SyNergy), Munich, Germany. Electronic address: hemmer@lrz.tu-muenchen.de.
³⁰ MS Center, Department of Neurology and Center Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic. Electronic address: eva.havrdova@lf1.cuni.cz.
³¹ University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany. Electronic address: Bernd.Kieseier@uni-duesseldorf.de.
³² University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany. Electronic address: hans-peter.hartung@uni-duesseldorf.de.
³³ Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Barcelona, Spain. Electronic address: manuel.comabella@vhir.org.
³⁴ Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Barcelona, Spain. Electronic address: xavier.montalban@unic-em.com.
³⁵ Departments of Biomedicine and Neurology, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: Tobias.Derfuss@usb.ch.
³⁶ Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: finn.thorup.sellebjerg@regionh.dk.
³⁷ SciCross AB, Skövde, Sweden. Electronic address: pierre@scicross.com.
³⁸ INSERM UMR 996, Univ. Paris-Sud, Faculty of Pharmacy, Université Paris-Saclay, Châtenay-Malabry, France. Electronic address: marc.pallardy@u-psud.fr.
³⁹ Drug Metabolism Pharmacokinetics-Biologics, Novartis Institutes for Biomedical Research, Basel, Switzerland. Electronic address: sebastian.spindeldreher@novartis.com.
⁴⁰ CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay, University UVSQ, Villejuif, France; Assistance Publique - Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France. Electronic address: philippe.broet@inserm.fr.
⁴¹ Innsbruck Medical University, Innsbruck, Austria. Electronic address: Florian.Deisenhammer@tirol-kliniken.at.
⁴² Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Anna.Fogdell-Hahn@ki.se.
⁴³ Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: Per.Soelberg.Soerensen@regionh.dk.

PMID: 30447419
DOI: 10.1016/j.jneuroim.2018.11.002

Abstract

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.

Keywords: Anti-drug antibodies; Bridging ELISA; Interferon-beta; Luciferase-based bioassay; Multiple sclerosis; Neutralizing antibodies.

Publication types

Comparative Study
Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Neutralizing / blood*
Biological Assay
Enzyme-Linked Immunosorbent Assay
Female
Humans
Immunologic Factors / immunology
Immunologic Factors / therapeutic use
Interferon-beta / immunology
Interferon-beta / therapeutic use
Male
Multiple Sclerosis / blood*
Multiple Sclerosis / drug therapy
Neutralization Tests / methods*

Substances

Antibodies, Neutralizing
Immunologic Factors
Interferon-beta