Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.
Methods and Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.
Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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.