Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis

Abstract

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNβ)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9–8.4 and pooled HR = 8.7, 95% CI 6.6–11.4 respectively). Patients older than 50 years at start of IFNβ therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4–2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1–1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNβ in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1–2.4 and HR = 2.4, 95% CI 1.5–3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0–1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0–2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNβ. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

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

“…However, another study on 37 MS patients treated with IFN-beta did not find an association of cotinine, a smoke nicotine metabolite, with ADAs [ 33 ]. We previously found sex to be associated with immunogenicity in MS patients [ 34 ], but the sex at increased risk was females for natalizumab and males for IFN-beta, suggesting that BP-specific mechanisms of immunogenicity were involved. Heterogeneity might in part account for the absence of this association in the present study, together with the lower number of patients of the cohort and thereby lower power to identify factors with a small effect size.…”

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients

“…The finding that the NZM-LC FR2-CDR2 peptide is naturally presented in the context of the HLA-DRB1*07 and DRB1*14/16 alleles of the two patients, together with the prediction of its binding to different alleles, including DRB1*13, suggests that this peptide is a major source of T cell help driving the anti-idiotypic B cell response to NZM. This may explain the high frequency of MS patients producing ADAs to NZM 3,4 and offers the possibility for the deimmunization of the drug for a more safe treatment. Structured-guided mutagenesis and experimental tests suggest that a little amendment of only three residues of the CDR2 of the NZM light chain may be sufficient to remove the immunogenic T cell epitope without interfering with the interaction of NZM with its target.…”

A test for comparing current status survival data with crossing hazard functions and its application to immunogenicity of biotherapeutics

“…In our immunogenicity study and using our proposed test, we identify a significant association between gender and ADAs occurrence. This finding is in accordance with what has been shown in other European cohorts . We may hypothesize that the observed crossing effect of gender might be due to the interplay between gender and a latent factor such as oral contraception.…”

“…We did not find a significant effect for age. However, with a larger sample size, we may expect to see a significant effect as it was observed in other cohorts . On the basis of these results, we should emphasize that using the proposed test provides new findings that would have been overlooked by only considering results from the classical tests.…”