Development of assays to reliably identify and characterize anti-drug antibodies (ADAs) depends on positive control anti-idiotype (anti-id) reagents, which are used to demonstrate that the standards recommended by regulatory authorities are met. This work employs a set of therapeutic antibodies under clinical development and their corresponding anti-ids to investigate how different positive control reagent properties impact ADA assay development. Positive controls exhibited different response profiles and apparent assay analytical sensitivity values depending on assay format. Neither anti-id affinity for drug, nor sensitivity in direct immunoassays related to sensitivity in ADA assays. Anti-ids were differentially able to detect damage to drug conjugates used in bridging assays and were differentially drug tolerant. These parameters also failed to relate to assay sensitivity, further complicating selection of anti-ids for use in ADA assay development based on functional characteristics. Given this variability among anti-ids, alternative controls that could be employed across multiple antibody drugs were investigated as a more uniform means to define ADA detection sensitivity across drug products and assay protocols, which could help better relate assay results to clinical risks of ADA responses. Overall, this study highlights the importance of positive control selection to reliable detection and clinical interpretation of the presence and magnitude of ADA responses.

中文翻译：

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阳性对照的选择及其对抗药物抗体测定性能的影响

可靠地识别和表征抗药物抗体 (ADA) 的检测方法的开发取决于阳性对照抗独特型 (抗 id) 试剂，这些试剂用于证明符合监管机构推荐的标准。这项工作采用了一组正在临床开发的治疗性抗体及其相应的抗 ids 来研究不同的阳性对照试剂特性如何影响 ADA 检测开发。根据测定形式，阳性对照表现出不同的响应曲线和表观测定分析灵敏度值。抗 id 对药物的亲和力以及直接免疫测定中的敏感性均不与 ADA 测定中的敏感性相关。抗 ids 能够不同地检测桥接测定中使用的药物缀合物的损伤，并且具有不同的药物耐受性。这些参数也未能与检测灵敏度相关，使得根据功能特征选择用于 ADA 检测开发的抗 ids 进一步复杂化。鉴于抗 ids 之间的这种差异，研究了可用于多种抗体药物的替代对照，作为定义跨药品和检测方案的 ADA 检测灵敏度的更统一方法，这有助于更好地将检测结果与 ADA 反应的临床风险联系起来。总体而言，本研究强调了阳性对照选择对于可靠检测和临床解释 ADA 反应的存在和程度的重要性。