Büttel I C, Chamberlain P, Chowers Y, Ehmann F, Greinacher A, Jefferis R, Kramer D, Kropshofer H, Lloyd P, Lubiniecki A, Krause R, Mire-Sluis A, Platts-Mills T, Ragheb J A, Reipert B M, Schellekens H, Seitz R, Stas P, Subramanyam M, Thorpe R, Trouvin J-H, Weise M, Windisch J, Schneider C K
Paul-Ehrlich-Institut, Federal Agency for Vaccines and Biomedicines, Division EU Cooperation/Microbiology, Langen, Germany.
Biologicals. 2011 Mar;39(2):100-9. doi: 10.1016/j.biologicals.2011.01.006. Epub 2011 Feb 24.
Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.
治疗性蛋白质为多种疾病提供了创新且有效的治疗方法。然而，其中一些产品会引发不良免疫原性，这可能导致临床后果，如疗效降低或丧失、药代动力学（PK）改变、一般免疫和超敏反应，以及天然对应物（如生理激素）的中和。免疫原性评估的监管指南需要考虑产品、适应症和患者群体的巨大多样性，以及不断发展的制造技术。此类指南需要足够具体，同时允许进行互动讨论，并根据具体情况对每个产品进行效益风险权衡调整，例如，对于危及生命疾病的独特治疗，可接受的治疗风险可能与不太严重疾病的情况有很大差异。这一主题是2010年6月10日至11日在德国朗根的保罗·埃利希研究所举行的国际会议“将治疗性蛋白质的免疫原性评估提升到新高度”的焦点。会议的目标是强调该领域如何从仅仅描述风险因素转向风险评估和缓解系统，以及理解不良免疫原性对药品整体效益/风险考量的影响。来自全球业界、学术界和监管机构的150多名专家从不同角度讨论了不良免疫原性现象。会议聚焦于与三个领域相关的问题：（1）目前正在讨论的新欧洲指南；（2）免疫原性评估的检测策略；（3）可能导致免疫原性发病机制发展的产品相关因素的科学进展，特别是在蛋白质聚集和翻译后修饰领域。本报告概述了会议期间讨论的问题、见解和达成的结论。
