Lai Ching-Ha, Chen Mu, Fraser Sasha, Wang Jessica, McAfee Sean, Speaks Emma, Simeone Nicholas, Rodriguez Jacqueline, Stefan Colin, DeStefano Lisa, Elango Chinnasamy, Andisik Matthew D, Sumner Giane, Zhao An, Irvin Susan C, Torri Albert, Partridge Michael A
Regeneron Pharmaceuticals, Bioanalytical Sciences, 777 Old Saw Mill River Road, Tarrytown, New York, 10591, USA.
AAPS J. 2024 Dec 12;27(1):11. doi: 10.1208/s12248-024-00993-9.
The ADA testing strategy for protein therapeutics was established almost two decades ago when assay methodologies were rudimentary, and serious immunogenicity-related safety issues had recently been observed with some biotherapeutics. The current testing paradigm employs multiple tiers and stringent cut points to minimize false negatives, reflecting a conservative stance towards ADA analysis. The development of highly sensitive ADA assay platforms and technologies such as humanized or fully human monoclonal antibody (mAb) drugs has put the traditional, resource-intensive 3-tiered testing approach under scrutiny. ADA data from clinical studies for three different mAb programs were re-assessed to explore the feasibility of a simplified 1-tiered ADA testing strategy with a 1% false positive cut point versus the traditional 3-tiered approach. The analysis demonstrated moderate to strong correlations between screening results (signal-to-noise, S/N) and those of confirmation and titer results, with the vast majority of samples (~ 97%) across all studies having the same ADA positive/negative classification with either testing approach. Furthermore, at the subject level, over 92% had the same ADA category (pre-existing, treatment-emergent, treatment-boosted) under both testing approaches. The re-categorized subjects had low titer ADA responses with no observed clinical implications on pharmacokinetics, efficacy, or safety. Finally, the treatment-emergent ADA incidences were comparable between the 1-tiered and 3-tiered approaches. The results demonstrate that the 1-tiered testing strategy is suitable for ADA assessment in these programs and is likely more widely applicable. Additionally, the 1-tiered approach could expedite data delivery and reduce resource needs in clinical development without compromising data quality or clinical interpretation.
蛋白质治疗药物的ADA检测策略大约在二十年前就已确立，当时检测方法还很初级，而且最近在一些生物治疗药物中观察到了与免疫原性相关的严重安全问题。当前的检测模式采用多层级和严格的截断点以尽量减少假阴性，这反映了对ADA分析的保守立场。高灵敏度ADA检测平台和技术的发展，如人源化或全人源单克隆抗体（mAb）药物，使传统的、资源密集型的三层检测方法受到审视。对三个不同mAb项目的临床研究中的ADA数据进行了重新评估，以探索简化的单层ADA检测策略（假阳性截断点为1%）相对于传统三层方法的可行性。分析表明，筛查结果（信噪比，S/N）与确证和效价结果之间存在中度至强相关性，所有研究中绝大多数样本（约97%）采用两种检测方法时的ADA阳性/阴性分类相同。此外，在个体水平上，两种检测方法下超过92%的个体具有相同的ADA类别（既往存在、治疗中出现、治疗后增强）。重新分类的个体ADA效价反应较低，未观察到对药代动力学、疗效或安全性的临床影响。最后，单层和三层方法的治疗中出现的ADA发生率相当。结果表明，单层检测策略适用于这些项目中的ADA评估，并且可能更广泛适用。此外，单层方法可以加快数据交付并减少临床开发中的资源需求，而不会影响数据质量或临床解读。
