Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

Ingenhoven, Kathleen; Kramer, Daniel; Jensen, Poul Erik; Hermanrud, Christina; Ryner, Malin; Deisenhammer, Florian; Pallardy, Marc; Menge, Til; Hartung, Hans‐Peter; Kieseier, Bernd C.; Bertotti, Elisa; Creeke, Paul I.; Fogdell‐Hahn, Anna; Warnke, Clemens

doi:10.3389/fneur.2017.00305

Cited by 8 publications

(4 citation statements)

References 27 publications

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“…Our study was conducted in the first 12 months of BP therapy, during which the occurrence of ADA in patients is the most frequent [16][17][18]. The use of highly sensitive ADA assays validated and performed within ABIRISK central laboratories [7][8][9] improved the power of the analysis by increasing the number of events detected and by allowing an earlier detection of ADA occurrence.…”

Section: Discussionmentioning

confidence: 99%

“…For IFN-beta, binding antibodies (BAbs) were tested with a previously described bridging enzyme-linked immunosorbent assay (ELISA) at the University of Düsseldorf, Department of Neurology, Düsseldorf, Germany, and Neutralizing antibodies (NAbs) were detected with a cell-based luciferase reporter gene assay in Region Hovedstaden Neuroimmunology laboratory, Department of Neurology, Rigshospitalet, Copenhagen, Denmark. Because of the higher sensitivity of the NAb assay, a serum sample was defined as IFN-beta ADA positive if it was either BAb positive or NAb positive (with an NAb titer equal or higher than 320 U/ml) or positive for both criteria [7][8][9]. For adalimumab and infliximab and its biosimilars, BAbs were measured with a chemoluminescence drug-tolerant capture ELISA assay using an MSD (MesoScale Discovery) platform at the INSERM UMR 996, Inflammation, Chemokines and Immunopathology laboratory, Châtenay-Malabry, France.…”

Section: Ada Assaysmentioning

confidence: 99%

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

Hässler¹,

Bachelet²,

Duhazé³

et al. 2020

PLoS Med

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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 w...

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Section: Discussionmentioning

confidence: 99%

Section: Ada Assaysmentioning

confidence: 99%

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

Hässler¹,

Bachelet²,

Duhazé³

et al. 2020

PLoS Med

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“…Serum was tested for both binding (bAbs) and neutralizing (nAbs) ADA. BAbs were measured with an enzyme-linked immunosorbent assay (ELISA) (38) and nAbs were detected by a cell-based luciferase reporter gene assay (39).…”

Section: Ada Detectionmentioning

confidence: 99%

Using Serum Metabolomics to Predict Development of Anti-drug Antibodies in Multiple Sclerosis Patients Treated With IFNβ

et al. 2020

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Background: Neutralizing anti-drug antibodies (ADA) can greatly reduce the efficacy of biopharmaceuticals used to treat patients with multiple sclerosis (MS). However, the biological factors pre-disposing an individual to develop ADA are poorly characterized. Thus, there is an unmet clinical need for biomarkers to predict the development of immunogenicity, and subsequent treatment failure. Up to 35% of MS patients treated with beta interferons (IFNβ) develop ADA. Here we use machine learning to predict immunogenicity against IFNβ utilizing serum metabolomics data. Methods: Serum samples were collected from 89 MS patients as part of the ABIRISK consortium-a multi-center prospective study of ADA development. Metabolites and ADA were quantified prior to and after IFNβ treatment. Thirty patients became ADA positive during the first year of treatment (ADA+). We tested the efficacy of six binary classification models using 10-fold cross validation; k-nearest neighbors, decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions. Results: We were able to predict future immunogenicity from baseline metabolomics data. Lasso logistic regression with/without interactions and support vector machines were the most successful at identifying ADA+ or ADA-cases, respectively. Furthermore, patients who become ADA+ had a distinct metabolic response to IFNβ in the first 3 months, with 29 differentially regulated metabolites. Machine learning algorithms could also predict ADA status based on metabolite concentrations at 3 months. Lasso logistic regressions had the greatest proportion of correct classifications [F1 score (accuracy measure) = 0.808, specificity = 0.913]. Waddington et al. Using Metabolomics to Predict Immunogenicity Finally, we hypothesized that serum lipids could contribute to ADA development by altering immune-cell lipid rafts. This was supported by experimental evidence demonstrating that, prior to IFNβ exposure, lipid raft-associated lipids were differentially expressed between MS patients who became ADA+ or remained ADA-. Conclusion: Serum metabolites are a promising biomarker for prediction of ADA development in MS patients treated with IFNβ, and could provide novel insight into mechanisms of immunogenicity.

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“…Bridging ELISAs have been used to detect ADAs against various biopharmaceuticals and mAb-based drugs; examples include ADA assays for erythropoietin, interferon beta, metuzumab, ADL, infliximab, and eternacept [43,57,62,[70][71][72][73][74][75][76]. A bridging ELISA assay was used to detect antibodies against metuzumab by placing some of this drug on a microtiter plate to capture ADAs against this drug [53].…”

Section: Bridging Elisasmentioning

confidence: 99%

Approaches for the detection and analysis of antidrug antibodies to biopharmaceuticals: A review

Suh

Kyei

Hage

2022

J of Separation Science

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Antibody-based therapeutic agents and other biopharmaceuticals are now used in the treatment of many diseases. However, when these biopharmaceuticals are administrated to patients, an immune reaction may occur that can reduce the drug's efficacy and lead to adverse side-effects. The immunogenicity of biopharmaceuticals can be evaluated by detecting and measuring antibodies that have been produced against these drugs, or antidrug antibodies. Methods for antidrug antibody detection and analysis can be important during the selection of a therapeutic approach based on such drugs and is crucial when developing and testing new biopharmaceuticals. This review examines approaches that have been used for antidrug antibody detection, measurement, and characterization. Many of these approaches are based on immunoassays and antigen binding tests, including homogeneous mobility shift assays. Other techniques that have been used for the analysis of antidrug antibodies are capillary electrophoresis, reporter gene assays, surface plasmon resonance spectroscopy, and liquid chromatographymass spectrometry. The general principles of each approach will be discussed, along with their recent applications with regards to antidrug antibody analysis.

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Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

Cited by 8 publications

References 27 publications

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

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

Using Serum Metabolomics to Predict Development of Anti-drug Antibodies in Multiple Sclerosis Patients Treated With IFNβ

Approaches for the detection and analysis of antidrug antibodies to biopharmaceuticals: A review

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