Mytych Daniel T, Hock M Benjamin, Kroenke Mark, Jawa Vibha, Kaliyaperumal Arunan, Zhou Yanchen
Medical Sciences-Clinical Immunology, Amgen, Inc., 1 Amgen Center Drive, Thousand Oaks, California, 91320, USA.
Merck, 2000 Galloping Hill Road, Kenilworth, New Jersey, 07033, USA.
AAPS J. 2017 May;19(3):599-602. doi: 10.1208/s12248-017-0059-7. Epub 2017 Feb 28.
With more than 100 therapeutic proteins (TP) approved since the first EMA guidance on immunogenicity in 2007, a vast amount of clinical experience with a variety of therapeutic proteins has been gained. This has provided data on anti-drug antibodies (ADA) and their observed clinical impact, or lack thereof. It has become evident that not all ADA responses are clinically relevant. The current "standard practice" is to test for ADA in all patients on every study. It is essential that we acknowledge the immunogenicity data gained from marketed TPs and that options for immunogenicity testing reflect this information. Improvements in bioanalytical support throughout the drug development process will eliminate extraneous, non-impactful practices. We propose that low-risk therapeutic proteins could be supported with an event-driven ("collect-and-hold") immunogenicity testing strategy throughout early phases of the clinical program. In the absence of an event, only pivotal studies (where ADA incidence and impact can be decisively assessed) would include default ADA testing. In keeping with the "standard practice," immunogenicity risk assessment must be an on-going and real-time evaluation. This approach has the potential to deliver meaningful, clinically relevant immunogenicity results while maintaining an emphasis on patient safety.
自2007年欧洲药品管理局（EMA）发布首份关于免疫原性的指南以来，已有100多种治疗性蛋白质（TP）获得批准，积累了大量关于各种治疗性蛋白质的临床经验。这提供了有关抗药物抗体（ADA）及其观察到的临床影响（或缺乏临床影响）的数据。显然，并非所有ADA反应都具有临床相关性。当前的“标准做法”是在每项研究中对所有患者进行ADA检测。我们必须承认从已上市的TP中获得的免疫原性数据，并且免疫原性检测的选择应反映这些信息。在整个药物开发过程中改进生物分析支持将消除无关紧要、没有影响的做法。我们建议，在临床项目的早期阶段，低风险治疗性蛋白质可以采用事件驱动的（“收集并保留”）免疫原性检测策略。在没有事件发生的情况下，只有关键研究（可以决定性地评估ADA发生率和影响）才会进行默认的ADA检测。与“标准做法”一致，免疫原性风险评估必须是持续的实时评估。这种方法有可能在强调患者安全的同时，提供有意义的、与临床相关的免疫原性结果。
