| 1. |
- Bachelet, Delphine, et al.
(författare)
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Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis : A Collaborative Cohort Analysis
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:11
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Tidskriftsartikel (refereegranskat)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 (IFN beta)-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, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-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 IFN beta 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 IFN beta 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 IFN beta. 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.
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| 2. |
- Faustini, Francesca, et al.
(författare)
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First exposure to rituximab is associated to high rate of anti-drug antibodies in systemic lupus erythematosus but not in ANCA-associated vasculitis
- 2021
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Ingår i: Arthritis Research & Therapy. - : BMC. - 1478-6362. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Anti-drug antibodies (ADAs) can impact on the efficacy and safety of biologicals, today used to treat several chronic inflammatory conditions. Specific patient groups may be more prone to develop ADAs. Rituximab is routinely used for ANCA-associated vasculitis (AAV) and as off-label therapy for systemic lupus erythematosus (SLE), but data on occurrence and predisposing factors to ADAs in these diseases is limited. Objectives To elucidate the rate of occurrence, and risk factors for ADAs against rituximab in SLE and AAV. Methods ADAs were detected using a bridging electrochemiluminescent (ECL) immunoassay in sera from rituximab-naive (AAV; n = 41 and SLE; n = 62) and rituximab-treated (AAV; n = 22 and SLE; n = 66) patients. Clinical data was retrieved from medical records. Disease activity was estimated by the SLE Disease Activity Index-2000 (SLEDAI-2 K) and the Birmingham Vasculitis Activity Score (BVAS). Results After first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients. Samples were obtained at a median (IQR) time of 5.5 (3.7-7.0) months (AAV), and 6.0 (5.0-7.0) months (SLE). ADA-positive SLE individuals were younger (34.0 (25.9-40.8) vs 44.3 (32.7-56.3) years, p = 0.002) and with more active disease (SLEDAI-2 K 14.0 (10.0-18.5) vs. 8.0 (6.0-14), p = 0.0017) and shorter disease duration (4.14 (1.18-10.08) vs 9.19 (5.71-16.93), p = 0.0097) compared to ADA-negative SLE. ADAs primarily occurred in nephritis patients, were associated with anti-dsDNA positivity but were not influenced by concomitant use of corticosteroids, cyclophosphamide or previous treatments. Despite overall reduction of SLEDAI-2 K (12.0 (7.0-16) to 4.0 (2.0-6.7), p < 0.0001), ADA-positive individuals still had higher SLEDAI-2 K (6.0 (4.0-9.0) vs 4.0 (2.0-6.0), p = 0.004) and their B cell count at 6 months follow-up was higher (CD19 + % 4.0 (0.5-10.0) vs 0.5 (0.4-1.0), p = 0.002). At retreatment, two ADA-positive SLE patients developed serum sickness (16.7%), and three had infusion reactions (25%) in contrast with one (5.2%) serum sickness in the ADA-negative group. Conclusions In contrast to AAV, ADAs were highly prevalent among rituximab-treated SLE patients already after the first course of treatment and were found to effect on both clinical and immunological responses. The high frequency in SLE may warrant implementations of ADA screening before retreatment and survey of immediate and late-onset infusion reactions.
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| 3. |
- Jensen, Poul Erik H., et al.
(författare)
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Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis : Results from the ABIRISK prospective cohort study
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 326, s. 19-27
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Tidskriftsartikel (refereegranskat)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.
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| 4. |
- Link, Jenny, et al.
(författare)
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Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe : A descriptive study of test results
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFN beta) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFN beta preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFN beta-1a subcutaneous (s.c.) and IFN beta-1b s.c. in favor of the least immunogenic preparation IFN beta-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFN beta-1b-Extavia s. c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFN beta-1a i. m. (1.41 and 2.27 years), IFN beta-1b-Betaferon s. c. (2.51 and 1.96 years) and IFN beta-1a s. c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFN beta ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.
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| 5. |
- Ryner, Malin
(författare)
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Anti-drug antibodies in patients with multiple sclerosis
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is an inflammatory disease affecting the brain and spinal cord and it is the main cause of neurological disability among young adults. Recombinant interferon beta (IFNβ) and natalizumab are commonly used disease-modifying drugs that reduce disease severity. Even though these treatments show beneficial clinical effects they are associated with the development of anti-drug antibodies (ADAs), which at high titer levels reduce drug efficacy. Although ADAs are known to adversely affect the clinical effect of the treatment on a group level, the treatment response in individual patients is less characterized. In addition, it is unknown why only a subgroup of treated MS patients develops ADAs. The objective of this thesis was to identify biologically relevant ADA titer cut-points that can be used to predict treatment response and persistence of ADAs in individual patients, and to investigate if genetic and immunological factors influence the development of ADAs in MS patients. MS patients analyzed for the presence of ADAs against IFNβ or natalizumab in the routine NAb laboratory at Karolinska Institutet were included in this project. In Sweden, NAb monitoring became clinical practice in 2003 and during 2003-2004 the overall seroprevalence of neutralizing antibodies (NAbs) against IFNβ was 32%. When the NAb seroprevalence was analyzed five years later, in 2009-2010, the overall frequency of NAb-positive patients had decreased significantly to 19%. Importantly, the greatest reduction was observed in patients with high NAb titers (study I). By correlating the in vivo IFNβ bioactivity with patients’ NAb titers we identified that a NAb titer of 150 TRU/ml is a biologically functional cut-point for treatment response, since titers above 150 TRU/ml completely block IFNβ bioactivity (study II). Furthermore, characterization of ADA responses in natalizumab-treated patients revealed that the level of total anti-natalizumab antibodies in a first positive sample can be used to predict patients at risk of becoming persistently antibody positive (study V). It is known that factors such as protein modifications and/or impurities impact the immunogenicity of IFNβ, which can explain the variation in NAb positivity between IFNβ preparations. In addition, since only a subgroup of IFNβ-treated patients develops NAbs, patient-related factors are likely to influence the immunogenicity of IFNβ. In study III, we hypothesized that MS patients with and without intrathecal production of oligoclonal IgG bands (OCB) have different propensities to induce humoral immune responses. The presence of OCB was found to be associated with NAb development, and this risk was confined to NAbs against IFNβ-1a. From these results we proposed that MS patients with and without OCB differ immunologically, potentially influenced by distinct human leukocyte antigen (HLA) alleles. The role of HLA in the immunogenicity of IFNβ was further investigated in study IV, in which we found that HLA-DRB1*15 carriage was associated with increased risk of developing NAbs. Stratification on type of IFNβ preparation showed that HLA-DRB1*15 increased the risk of NAbs against IFNβ-1a, while HLA-DRB1*04 increased the risk of NAbs against IFNβ-1b, indicating that there is an IFNβ preparation-specific genetically determined risk to develop NAbs. Overall, these results can be used to assist when making decisions about whether treatment should be discontinued or not. In addition, the identification of factors contributing to the immunogenicity of protein therapeutics can increase our understanding of the immunological mechanisms leading to ADA responses, possibly resulting in less immunogenic drugs in the future.
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