Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients

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 an...

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Published in:	Journal of immunological methods Vol. 418; pp. 29 - 38
Main Authors:	Bloem, Karien, van Leeuwen, Astrid, Verbeek, Gerrit, Nurmohamed, Michael T., Wolbink, Gerrit Jan, van der Kleij, Desiree, Rispens, Theo
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-03-2015
Subjects:	Adalimumab Anti-drug antibodies (ADA) Antibodies - immunology Antibodies, Monoclonal, Humanized - immunology Antibodies, Monoclonal, Humanized - therapeutic use Antigen-Antibody Reactions Antigens - immunology Arthritis, Rheumatoid - drug therapy Arthritis, Rheumatoid - immunology Cohort Studies Drug interference Drug Tolerance Drug-tolerant assay Electrochemoluminescence Humans Radioimmunoassay Anti-drug antibodies (ADA) ADL PIA ECL Drug interference TRIA ABT Electrochemoluminescence Radioimmunoassay ARIA Drug-tolerant assay Adalimumab ADA
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Summary:	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. 100AU/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. •We developed three new drug tolerant assays for the detection of anti-drug antibodies.•In a major portion of the patient samples anti-drug antibodies are detected.•The four drug tolerant assays tested correlate well.•The consistent results of the assays break down at the lower end of the detectable range.•This highlights that anti-drug antibodies are best reported quantitatively.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1759 1872-7905
DOI:	10.1016/j.jim.2015.01.007