Li Yi-Yang Yvonne, Perez H Daniel, Zollner Thomas M
Expert Opin Ther Targets. 2006 Aug;10(4):489-99. doi: 10.1517/14728222.10.4.489.
Natalizumab (Tysabri), Biogen Idec/Elan) is a humanised neutralising antibody directed against alpha4 integrin expressed by leukocytes. Although it is an effective therapy for multiple sclerosis (MS), the serious adverse effect of progressive multifocal leukoencephalopathy (PML) resulted in its voluntary withdrawal from the market by Biogen Idec/Elan in February 2005. This has raised debates on whether PML was caused by blocking leukocyte trafficking-mediated immune suppression or by other effects through targeting alpha4 integrin per se. The authors propose that natalizumab-associated PML is a target-specific side effect predominantly due to the combination of: i) blocking leukocyte trafficking to peripheral organs resulting in reduced immune surveillance; ii) mobilisation of PML-causative JC virus-carrying bone marrow precursor cells and splenic marginal zone B cells; and iii) migration of these cells to sites of inflammation such as the brain. Therefore, combination of these effects is, so far, specific for the target alpha4 integrin and should not occur in general when interfering with other targets involved in leukocyte trafficking.
那他珠单抗（泰萨比，百健艾迪/伊兰公司）是一种人源化中和抗体，靶向白细胞表达的α4整合素。尽管它是治疗多发性硬化症（MS）的有效药物，但进行性多灶性白质脑病（PML）这一严重不良反应导致百健艾迪/伊兰公司于2005年2月自愿将其撤出市场。这引发了关于PML是由阻断白细胞运输介导的免疫抑制引起，还是通过靶向α4整合素本身的其他效应引起的争论。作者提出，那他珠单抗相关的PML是一种靶点特异性副作用，主要是由于以下因素共同作用：i）阻断白细胞向外周器官的运输，导致免疫监视减弱；ii）动员携带导致PML的JC病毒的骨髓前体细胞和脾边缘区B细胞；iii）这些细胞迁移到炎症部位，如大脑。因此，到目前为止，这些效应的组合对靶点α4整合素具有特异性，在干扰白细胞运输中涉及的其他靶点时一般不会发生。
