Department of Pharmaceutical Sciences and Department of Innovation Studies, Utrecht University, Utrecht, The Netherlands.
J Immunotoxicol. 2006 Sep 1;3(3):123-30. doi: 10.1080/15476910600845567.
The peak of erythropoietin-associated pure red cell aplasia (PRCA) incidents occurred over 4 years ago, but the debate on what triggered the autoimmune disorder continues today. The association with the recombinant human erythropoietin (epoetin, rhEPO) alpha-branded Eprex (Johnson and Johnson), makes PRCA of interest to medical and scientific communities, as well as the biotechnology industry, as it opens a broader question of the potential immunogenicity of biopharmaceuticals in general. An overview of the background and a perspective on current thought in erythropoietin-associated PRCA may assist in avoiding a repeat of similar immunogenic cases with other biopharmaceuticals and their emerging follow-on products. At the same time, it is also important to clarify what are the relevant questions to ask in order to ensure appropriate testing in the regulation of biopharmaceuticals. The upsurge of PRCA is associated with a formulation change introduced in 1998 when human serum albumin (HSA) as protein stabilizer was exchanged with polysorbate 80. Several explanations have been offered to explain how this change led to Eprex-associated PRCA. Leachates from uncoated rubber stoppers acting as adjuvant are blamed by the manufacturer of Eprex, but the experimental data substantiating this claim are poor and the leachates theory has no biological rationale and is also inconsistent with epidemiological and clinical data. A more likely explanation that is consistent with all data is a higher tendency for aggregate formation during handling and storage due to the exchange of HSA by polysorbate 80 as stabilizer.
促红细胞生成素相关纯红细胞再生障碍性贫血 (PRCA) 事件的高峰期发生在 4 年多以前，但关于是什么引发这种自身免疫性疾病的争论仍在继续。与重组人促红细胞生成素 (epoetin，rhEPO) 品牌 Eprex（强生公司）的关联，使 PRCA 引起了医学和科学界以及生物技术行业的关注，因为它提出了一个更广泛的问题，即生物制药一般的潜在免疫原性。对促红细胞生成素相关 PRCA 的背景和当前观点的概述，可能有助于避免其他生物制药及其新兴后续产品再次出现类似的免疫性病例。与此同时，澄清哪些是相关问题以确保对生物制药进行适当的检测也很重要。PRCA 的激增与 1998 年推出的一种配方变化有关，当时作为蛋白质稳定剂的人血清白蛋白 (HSA) 被聚山梨酯 80 取代。已经提出了几种解释来说明这种变化如何导致 Eprex 相关的 PRCA。Eprex 的制造商指责未涂覆橡胶瓶塞的浸出物作为佐剂，但支持这一说法的实验数据很差，浸出物理论没有生物学依据，也与流行病学和临床数据不一致。一个更有可能的解释是，由于稳定剂 HSA 被聚山梨酯 80 取代，在处理和储存过程中形成聚集物的趋势更高。
