title: Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients.
abstract: Drug interference complicates assessment of immunogenicity of biologicals and results in an underestimation of anti-drug antibody (ADA) formation. Drug-tolerant assays have the potential to overcome such limitations. However, to which extent drug-tolerant assays provide an unbiased picture of the antibody response to a biological is unknown. In this study, we compared the measurement of ADA to adalimumab in 94 consecutive adalimumab-treated rheumatoid arthritis patients using the traditional antigen binding test (ABT) and four different drug-tolerant assays, the Ph-shift anti-Idiotype Antigen binding test (PIA) and three newly developed assays for this study: an acid-dissociation radioimmunoassay (ARIA), a temperature-shift radioimmunoassay (TRIA) and an electrochemoluminescence-based assay (ECL). Our results indicate that drug-tolerant assays provide a fairly consistent view on the antibody formation: quantitatively, the results from all four assays correlate well (Spearman r > 0.9). However, the percentage of ADA-positive patients ranges from 51 to 66% between assays, with the ARIA identifying the highest number of patients as positive. These differences are largely due to patients making low amounts of ADA; if ADA levels were above ca. 100 AU/ml, a patient was identified as positive in all four assays. Adalimumab concentrations were significantly lower in ADA-positive samples. Taken together, the results indicate that these different drug-tolerant assays provide a similar and reasonably consistent view on ADA responses, which however, breaks down at the lower end of the detectable range, and highlight that ADA is best reported quantitatively. Furthermore, if an even more sensitive drug-tolerant assay could be developed, one would probably find additional positive samples that will predominantly contain very low levels of ADA.
authors: Sanquin Research, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands; Sanquin Diagnostic Services, Amsterdam, The Netherlands. Electronic address: k.bloem@sanquin.nl.
authors: Karien
authors: K
authors: Bloem
authors: Sanquin Diagnostic Services, Amsterdam, The Netherlands.
authors: Astrid
authors: A
authors: van Leeuwen
authors: Sanquin Diagnostic Services, Amsterdam, The Netherlands.
authors: Gerrit
authors: G
authors: Verbeek
authors: Jan van Breemen Research Institute/Reade, Amsterdam, The Netherlands.
authors: Michael T
authors: MT
authors: Nurmohamed
authors: Sanquin Research, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands; Jan van Breemen Research Institute/Reade, Amsterdam, The Netherlands.
authors: Gerrit Jan
authors: GJ
authors: Wolbink
authors: Sanquin Diagnostic Services, Amsterdam, The Netherlands.
authors: Desiree
authors: D
authors: van der Kleij
authors: Sanquin Research, Amsterdam, The Netherlands; Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands.
authors: Theo
authors: T
authors: Rispens
mesh_terms: D000068879:Adalimumab; D000906:Antibodies / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000627:therapeutic use*; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D015331:Cohort Studies; D004361:Drug Tolerance; D006801:Humans; D011863:Radioimmunoassay
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000941:Antigens; D000068879:Adalimumab
keywords: Adalimumab; Anti-drug antibodies (ADA); Drug interference; Drug-tolerant assay; Electrochemoluminescence; Radioimmunoassay