Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium
Signe Hässler, Delphine Bachelet, Julianne Duhaze, Natacha Szely, Aude Gleizes, Salima Hacein-Bey Abina, Orhan Aktas, Michael Auer, Jerôme Avouac, Mary Birchler, Yoram Bouhnik, Olivier Brocq, Dorothea Buck-Martin, Guillaume Cadiot, Franck Carbonnel, Yehuda Chowers, Manuel Comabella, Tobias Derfuss, Niek De Vries, Naoimh Donnellan, Abiba Doukani, Michael Guger, Hans-Peter Hartung, Eva Kubala Havrdova, Bernhard Hemmer, Tom Huizinga, Kathleen Ingenhoven, Poul Erik Hyldgaard-Jensen, Elizabeth C. Jury, Michael Khalil, Bernd Kieseier, Anna Laurén, Raija Lindberg, Amy Loercher, Enrico Maggi, Jessica Manson, Claudia Mauri, Badreddine Mohand Oumoussa, Xavier Montalban, Maria Nachury, Petra Nytrova, Christophe Richez, Malin Ryner, Finn Sellebjerg, Claudia Sievers, Dan Sikkema, Martin Soubrier, Sophie Tourdot, Caroline Trang, Alessandra Vultaggio, Clemens Warnke, Sebastian Spindeldreher, Pierre Dönnes, Timothy P. Hickling, Agnès Hincelin Mery, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Xavier Mariette, Marc Pallardy, Philippe Broët, ABIRISK consortium
Abstract
Abstract
Background
The efficacy of biopharmaceutical products (BPs) in treating autoimmune diseases is limited by the development of antidrug antibodies (ADAs) in a subset of patients. However, our understanding of patient-related factors influencing ADA occurrence is still limited.
Introduction
Biopharmaceutical products (BPs) encompass a diverse range of therapeutics used for the treatment of autoimmune diseases and cancer. They include replacement factors, cytokines, monoclonal antibodies, fusion proteins, and protein-drug conjugates. The use of BPs has significantly improved the treatment outcomes for these conditions.
Materials and methods
Study design and patient characteristics
This study recruited patients from three multicentric prospective studies conducted across 12 European and associated countries, with 50 participating sites as part of the ABIRISK EU consortium. Patients provided written informed consent for both the clinical and genetic studies in accordance with the Declaration of Helsinki principles. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline.
Discussion
The consistent pattern of ADA production across different BPs, the heightened immunogenicity in autoimmune disease patients, and the immune hyperresponsiveness observed in these diseases suggest common immunogenetic pathways underlying ADA development. Through bioclinical survival analyses in multiple autoimmune diseases treated with various BPs, this study identified new clinical and genetic factors associated with ADA development, including antibiotics, infections, a CXCL12 genetic variant, and CXCL12 serum protein levels. Additionally, previously identified ADA-associated factors such as tobacco smoking, immunosuppressants, and the HLA DQA1*05 allele were confirmed in this study.
Citation: Hässler S, Bachelet D, Duhaze J, Szely N, Gleizes A, Hacein-Bey Abina S, et al. (2020) Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium. PLoS Med 17(10): e1003348. https://doi.org/10.1371/journal.pmed.1003348
Academic Editor: Sebastien Viatte, Arthritis Research UK Epidemiology Unit, UNITED KINGDOM
Received: January 24, 2020; Accepted: September 18, 2020; Published: October 30, 2020.
Copyright: © 2020 Hässler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data analyzed in this study were collected in the context of the ABIRISK project by ABIRISK partners. In order to be compliant with the European General Data Protection Regulation law on personal data, the clinical and the genetic data of this study cannot be publicly accessible. Access to the data set underlying the findings can be obtained by interested researchers upon request to the ABIRISK Sustainability Scientific Committee at [email protected].
Funding: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. [115303], resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. BH received support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). The biobank of the Department of Neurology as part of the Joint Biobank Munich in the framework of the German Biobank Node supported the study. OA received grants from the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF). TD’s institution received grants from the Swiss National Research Foundation, University of Basel, and Swiss MS Society. EKH and PN were supported by the Czech Ministry of Education research project PROGRES Q27/LF1 and MSMT-35199/2012-32. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SH, DB, JD, NS, AG, MB, DBM, NDV, ND, AD, SHBH, HPH, KI, PEHJ, ECJ, BK, AL, RL, AL, EM, CM, BMO, MR, FS, CS, DS, PD, AHM, MP, and PB declare no conflict of interest. OA reports grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, Teva and Viela Bio, and personal fees from Almirall, MedImmune, Merck Serono, and Roche. MA received speaker honoraria and/or travel grants from Biogen, Novartis, Merck Serono, and Sanofi. JA has served on scientific advisory boards for Roche, BMS, Abbvie, Nordic, Boerhinger, and Sanofi-Genzyme; he has received speaking honoraria from Pfizer, MSD, BMS, and Novartis; and he has received research grants from BMS and Pfizer. YB received speaker honoraria from Abbvie, Biogaran, Biogen, Boehringer Ingelheim, Ferring, Fresenius Kabi, Gilead, Hospira, Janssen, Lilly, Mayoli Spindler, Merck, MSD, Norgine, Pfizer, Roche, Sandoz, Sanofi, Shire, Takeda, and UCB. OB has received institutional fees for consultancy or lectures from Wyeth/Pfizer, AbBVIE, Roche, Chugai, Shering Plough, UCB, Swedish Orphan, Genevrier, Smith & Nephew, BMS, MSD, Celgene, novartis, Janssen, Sanofi, and Lilly. GC participated in advisory boards with AAA, Kéocyt, Ipsen, Novartis, Pfizer; he received honoraria for lectures from Ferring, Abbvie, Janssen,Biogen, Amgen, and Sandoz. YC has received institutional fees for consultancy or lectures from Abbvie, Celtrion, Getting, Pfizer, and Takeda. He received research grants from Takeda and Abbvie. MC has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. TD’s institution received compensation for his talks and his consultation services on Advisory Boards or Steering Committees of Novartis Pharma, Merck, Biogen, GeNeuro, Mitsubishi Pharma, MedDay, Roche, Actelion, Celgene, and Genzyme; his institution received research support from Biogen, Novartis, and Roche. MG received support and honoraria for research, consultation, lectures and education from Almirall, Bayer, Biogen, Celgene, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi Aventis, Shire and TEVA ratiopharm. EKH: honoraria/research support from Biogen, Merck Serono, Novartis, Roche, and Teva; advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme. BH has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Desitin; he holds part of two patents, one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. TH is a member of the Editorial Board of PLOS Medicine. MK has received funding for travel and speaker honoraria from Bayer, Novartis, Merck, Biogen, Roche, and Teva ratiopharm; serves on scientific advisory boards for Biogen, Merck, and Roche; and received a research grant from Teva ratiopharm. JM has received an unrestricted research grant from Pfizer. XM has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall, and Roche. MN has received speaking honoraria from Abbvie, Adacyte, Amgen, Biogen, Ferring, Janssen, MSD, and Takeda. PN has received speaking honoraria from Biogen, Novartis, and Roche. CR has received speaking honoraria from Abbvie, Amgen, Astra Zeneca, Janssen, Glenmark, GSK, Lilly, Nordic Pharma, Novartis, Pfizer, and UCB. MS received speaker honoraria and/or travel grants from Roche, Chugai, Abbvie, BMS, UCB, Pfizer, Novartis, Janssen, Amgen, Biogen, laboratoires Fresenius, Lilly France, Medac, MSD, Sandoz, and Janssen. CT has received speaking honoraria from Abbvie, Ferring, Janssen, MSD, and Takeda. AV has received fee for lectures and advisory board from GSK, Novartis, and AstraZeneca in the last two years. CW has received institutional fees for consultancy, speaking, or research from Novartis, Biogen, Sanofi-Genzyme and Roche. SS is a former employee and has stocks and/or stock options in Novartis. TPH is an employee and shareholder of Pfizer Inc. MA has served on scientific advisory boards for Pfizer, Janssen, Celgene, Genentech/Roche, Takeda, Abbvie, MSD, Ferring, Falk, Mayoli, Tillots, Biogen, and Amgen. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis Pharma, and Roche. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders). AFH has received speaker's fees from Pfizer, Biogen, Merck-Serono, and Sanofi-Genzyme. She has served as prinicipal investigator for projects, or received unrestricted research support from, Biogen Idec and Pfizer. XM has served on scientific advisory boards for BMS, GSK, Janssen, Novartis, Pfizer, and UCB.
Abbreviations: ABIRISK, Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK; ADA, antidrug antibody; aHR, adjusted hazard ratio; AMP, Adenosine MonoPhosphate; ASB7, Ankyrin repeat and SOCS box protein 7; ATC2, Anatomic Therapeutic Chemical level 2; BAb, binding antibody; BAFF, B-cell–activating factor; BMI, body mass index; BP, biopharmaceutical product; CD20, Cluster of Differentiation 20; CI, confidence interval; DNA1, Dynein intermediate chain 1, axonemal (gene); eCRF, electronic Case Report Form; ELISA, enzyme-linked immunosorbent assay; eQTL, expression Quantitative Trait Loci; FDR, false discovery rate; G-CSF, Granulocyte Colony-Stimulating Factor; HLA, Human Leukocyte Antigen; HLGT, High-Level Group Term; HR, hazard ratio; IBD, inflammatory bowel disease; ICI, Immune Checkpoint Inhibitor; IFN, interferon; IL, interleukin; IM, intramuscular(ly); LLT, Lowest-Level Term; mAb, monoclonal Antibody; MAF, Minor Allele Frequency; MPA, Medical Product Agency; MS, multiple sclerosis; MSD, MesoScale Discovery; MTX, methotrexate; NAb, Neutralizing Antibody; PANTS, Personalizing anti-TNF Therapy in Crohn’s disease; PC, positive control; PRDM2, PR domain zinc finger protein 2; PT, Preferred Term; RA, rheumatoid arthritis; RORγ, RAR-related orphan receptor gamma; SC, subcutaneous(ly); SD, standard deviation; SNP, Single-Nucleotide Polymorphism; SOC, System Organ Class; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; TLR5, Toll-Like Receptor 5; TNF, tumor necrosis factor.
