Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan.
Front Immunol. 2020 Feb 14;11:124. doi: 10.3389/fimmu.2020.00124. eCollection 2020.
Alemtuzumab was designed to reduce the immunogenicity of the parent CD52-specific rat immunoglobulin. Although originally marketed for use in cancer (Mabcampath®), alemtuzumab is currently licensed and formulated for the treatment of relapsing multiple sclerosis (Lemtrada®). Perhaps due to its history as the first humanized antibody, the potential of immunogenicity of the molecule has been considered inconsequential, and anti-drug antibodies (ADA) responses were similarly reported as being clinically insignificant. Nonetheless, despite humanization and depletion of peripheral T and B cells, alemtuzumab probably generates the highest frequency of binding and neutralizing ADA of all humanized antibodies currently in clinical use, and they occur rapidly in a large majority of people with MS (pwMS) on alemtuzumab treatment. These ADA appear to be an inherent issue of the biology of the molecule-and more importantly, the target-such that avoidance of immunogenicity-related effects has been facilitated by the dosing schedule used in clinical practice. At the population level this enables the drug to work in most pwMS, but in some individuals, as we show here, antibody neutralization appears to be sufficiently severe to reduce efficacy and allow disease breakthrough. It is therefore imperative that efficacy of lymphocyte depletion and the anti-drug response is monitored in people requiring additional cycles of treatment, notably following disease breakthrough. This may help inform whether to re-treat or to switch to another disease-modifying treatment.
阿仑单抗旨在降低母体 CD52 特异性大鼠免疫球蛋白的免疫原性。虽然最初被用于癌症治疗（Mabcampath®），但阿仑单抗目前已获许可并配制成用于治疗复发性多发性硬化症（Lemtrada®）的药物。或许是由于它作为第一个人源化抗体的历史，该分子的免疫原性潜力被认为是无关紧要的，并且抗药物抗体（ADA）反应也被报道为临床意义不大。尽管进行了人源化和外周 T 和 B 细胞耗竭，阿仑单抗可能会产生目前所有在临床使用的人源化抗体中结合和中和 ADA 的频率最高，并且在接受阿仑单抗治疗的大多数多发性硬化症患者（pwMS）中迅速发生。这些 ADA 似乎是该分子的生物学特性的固有问题，更重要的是，是其靶标，因此通过在临床实践中使用的给药方案避免了与免疫原性相关的影响。在人群水平上，这使得该药物在大多数 pwMS 中发挥作用，但在某些个体中，如我们在这里所示，抗体中和似乎严重到足以降低疗效并允许疾病突破。因此，在需要额外治疗周期的人群中，特别是在疾病突破后，监测淋巴细胞耗竭和抗药物反应的疗效至关重要。这可能有助于确定是否需要重新治疗或切换到另一种疾病修正治疗。
