Giovannoni Gavin
Department of Neuroinflammation, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
J Neurol. 2004 Sep;251 Suppl 5:v30-v35. doi: 10.1007/s00415-004-1505-x.
A proportion of people with multiple sclerosis (MS) treated with interferon (IFN) a develop neutralising anti-IFN beta antibodies (NABs). The immunogenicity of the available commercial compounds relates to the genetic structure of the IFN beta molecule, its mode of production, glycosylation status, aggregate formation, commercial formulation, potency, dose, frequency and, possibly, route of administration. At present, it is not possible to predict who will develop NABs usually appear within the first 2 years of starting therapy. In patients treated with IFN beta in whom NABs persist for a significant period of time, their presence is associated with a reduction in both the biological effects and clinical efficacy. Approximately one third of NAB-positive patients with a titre > 20 NU/mL will revert to NAB-negative status with long-term follow-up. The persistence of NABs appears to be linked to the type of IFN beta treatment as well as the titre of antibodies. The overall efficacy of IFN beta and, hence, of any biological disease-modifying treatment (DMT) would be substantially improved if the development of NABs could be prevented or reversed. Although the overall efficacy of IFN beta in MS is relatively modest, the efficacy in individuals who remain NAB-negative is considerably better than in those who become persistently NAB-positive. One could argue that when comparing the 'true' clinical efficacy of different IFN beta products, the comparisons should be limited to the cohorts that remain NAB-negative. As a corollary, the therapeutic efficacy of IFN beta could be maximised if patients who tolerate higher-dose preparations could be prevented from developing persistent NABs. Strategies employed to prevent or reverse the development of NABs with other biological compounds (e. g. insulin, factor VIII, IFN beta, recombinant human erythropoietin) include improvements in the manufacturing process, immunosuppression, induction of tolerance and deimmunisation, and these should be considered in relation to biological DMT therapy as part of future clinical studies.
一部分接受干扰素（IFN）β治疗的多发性硬化症（MS）患者会产生中和性抗IFNβ抗体（NABs）。现有商用化合物的免疫原性与IFNβ分子的基因结构、生产方式、糖基化状态、聚集体形成、商业配方、效价、剂量、给药频率以及可能的给药途径有关。目前，尚无法预测谁会产生NABs，NABs通常在开始治疗的头2年内出现。在接受IFNβ治疗且NABs持续较长时间的患者中，其存在与生物学效应和临床疗效的降低有关。大约三分之一NAB阳性且滴度>20 NU/mL的患者在长期随访后会恢复为NAB阴性状态。NABs的持续存在似乎与IFNβ治疗的类型以及抗体滴度有关。如果能够预防或逆转NABs的产生，IFNβ以及任何生物疾病修饰治疗（DMT）的总体疗效将得到显著提高。尽管IFNβ在MS中的总体疗效相对一般，但在仍为NAB阴性的个体中的疗效明显优于持续NAB阳性的个体。有人可能会说，在比较不同IFNβ产品的“真正”临床疗效时，比较应仅限于仍为NAB阴性的队列。作为推论，如果能够防止耐受高剂量制剂的患者产生持续性NABs，IFNβ的治疗效果将最大化。用于预防或逆转其他生物化合物（如胰岛素、凝血因子VIII、IFNβ、重组人促红细胞生成素）产生NABs的策略包括改进生产工艺、免疫抑制、诱导耐受性和去免疫，在未来的临床研究中，应将这些策略作为生物DMT治疗的一部分加以考虑。
