Factors influencing the immunogenicity of therapeutic proteins
Factors influencing the immunogenicity of therapeutic proteins
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DOI：
10.1093/ndt/gfh1092
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发表时间：
2005-06-01
影响因子：
6.1
通讯作者：
Schellekens, H
中科院分区：
文献类型：
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作者：
Schellekens, H
一些疾病和失调可以用治疗性蛋白质治疗，但其中一些产品可能会引起免疫反应，特别是在长时间多次给药时。抗体是由经典的免疫反应或免疫耐受的破坏产生的；后者是人类同源产物的特征。许多因素影响蛋白质的免疫原性，包括结构特征（序列变异和糖基化）、储存条件（变性或氧化引起的聚集）、制剂中的污染物或杂质、剂量和治疗时间，以及给药途径、适当的配方和患者的遗传特征。针对特定蛋白质的抗体的临床表现可能包括失去效力、天然对应物的中和和一般免疫系统效应（包括过敏、过敏反应或血清病）。在使用重组人促红细胞生成素(epoetin- α，以Eprex （R)/Erypo (R)销售）的特定配方的患者中，抗体介导的纯红细胞再生不全（PRCA）的发生率激增；强生公司)在欧洲引起了广泛关注。1998年，人类血清白蛋白从epoetin- α中被去除，并被甘氨酸和聚山梨酸80所取代。虽然这种特殊产品的免疫原性可能通过产品的储存、处理和给药方式而增强，但应该注意的是，皮下给药途径本身并不赋予免疫原性。目前正在研究胶束（聚山梨酯80 + epoetin- α）形成在Eprex的PRCA激增中的可能作用。
Several diseases and disorders are treatable with therapeutic proteins, but some of these products may induce an immune response, especially when administered as multiple doses over prolonged periods. Antibodies are created by classical immune reactions or by the breakdown of immune tolerance; the latter is characteristic of human homologue products. Many factors influence the immunogenicity of proteins, including structural features (sequence variation and glycosylation), storage conditions (denaturation, or aggregation caused by oxidation), contaminants or impurities in the preparation, dose and length of treatment, as well as the route of administration, appropriate formulation and the genetic characteristics of patients. The clinical manifestations of antibodies directed against a given protein may include loss of efficacy, neutralization of the natural counterpart and general immune system effects (including allergy, anaphylaxis or serum sickness). An upsurge in the incidence of antibody-mediated pure red cell aplasia (PRCA) among patients taking one particular formulation of recombinant human erythropoietin (epoetin-alpha, marketed as Eprex (R)/Erypo (R); Johnson & Johnson) in Europe caused widespread concern. The PRCA upsurge coincided with removal of human serum albumin from epoetin-alpha in 1998 and its replacement with glycine and polysorbate 80. Although the immunogenic potential of this particular product may have been enhanced by the way the product was stored, handled and administered, it should be noted that the subcutaneous route of administration does not confer immunogenicity per se. The possible role of micelle (polysorbate 80 plus epoetin-alpha) formation in the PRCA upsurge with Eprex is currently being investigated.