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Determining the immunogenic potential of a therapeutic antibody is a regulatory requirement during clinical development since anti-drug antibodies (ADA) can cause undesirable effects, ranging from loss of drug exposure and efficacy to serious adverse events. Justine Brose and her colleagues at Novimmune SA, Geneva, Switzerland evaluated four platforms to determine which platform and sample pre-treatment procedures could deliver a fit-for-purpose assay for ADA analysis to determine the immunogenicity of the therapeutic antibody Novimab. Of the platforms tested (ELISA and Gyrolab, Meso Scale Discovery, and AlphaLISA platforms) only Gyrolab and MSD platforms met all of their pre-specified assay requirements.
The ADA assay evaluated by the team at Novimmune was a bridging assay, a typical assay for this application where the ADA bridges two molecules of labeled therapeutic drug – one functioning as a capture reagent and the other as a detection reagent (see original reference). In addition to testing the performance of the four technology platforms, the team also studied two common types of interference in these assays: (1) therapeutic drug in the clinical sample binds ADA and prevents detection, which leads to a false negative, and (2) target interference where multimeric forms of soluble target bridge the capture and detection reagent and give a false positive. The team therefore tested the effect of sample pre-treatment steps aimed at reducing this interference: acid dissociation and immunodepletion to combat drug interference and target interference, respectively.
The extensive evaluation, based on performance in terms of sensitivity, inter-assay variability, inter-donor variability, and drug and target tolerance led to the conclusion that only Gyrolab and MSD platforms met the team’s needs for a fit-for-purpose assay. The best sensitivity and drug tolerance was obtained by pre-treating samples with acid dissociation, followed by analysis on the Gyrolab platform, which also delivered results with low inter-assay variation. Target depletion raised the target tolerance to an acceptable level.
The authors summarized, “This study highlights the usefulness of evaluating the performance of different assay platforms at an early stage in the assay development process to aid in the selection of the best fit-for-purpose technology platform and sample pre-treatment steps, to support individual clinical trial programs. As part of this selection process it is also very important to consider additional practical factors including available clinical sample volume and data turnaround times to guide appropriate selection.”
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