From the Blizard Institute (G.S., M.J., G.P., L.A., G.R.L., V.V., K.S., G.G., S.G., D.B., A.S.K.), Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Division of Psychological Medicine and Clinical Neurosciences (J.M.M., S.L., N.P.R., E.C.T.), Cardiff University School of Medicine, United Kingdom; Department of Biological Sciences (L.A.), National University of Medical Sciences, Rawalpindi, Pakistan; Centre for Oral Immunobiology and Regenerative Medicine (G.R.L., A.S.K.), Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Clinical Board:Medicine (Neuroscience) (V.V., K.S., G.G., S.G.), The Royal London Hospital, Barts Health NHS Trust; and Welsh Neuroscience Research Tissue Bank (S.L., N.P.R.), Cardiff University, United Kingdom.
Neurol Neuroimmunol Neuroinflamm. 2020 Jun 4;7(4). doi: 10.1212/NXI.0000000000000767. Print 2020 Jul.
To test the hypothesis that antidrug antibodies (ADAs) against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance.
Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding ADAs. Alemtuzumab immunoglobulin G Alexa Fluor 488 conjugate was used in a competitive binding cell-based assay to detect neutralizing ADAs. The assays were used to retrospectively screen, blinded, banked serum samples from people with MS (n = 32) who had received 3 or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month postinfusion.
The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. ADA responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred before the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Preinfusion, ADA levels predicted limited, postinfusion lymphocyte depletion.
Although ADAs to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of lymphocyte depletion and the antidrug response may be of practical value in patients requiring additional cycles of alemtuzumab. ADA detection may help to inform on retreatment or switching to another treatment.
验证这样一个假设，即在一些个体中，经过多次治疗后，针对阿仑单抗的抗药物抗体（ADAs）可能变得相关，这可能解释了偶尔的治疗抵抗。
构建了带有双串联纳米荧光素酶报告子接头的重组阿仑单抗单链可变片段抗体，并用于检测结合 ADA。阿仑单抗免疫球蛋白 G Alexa Fluor 488 缀合物用于竞争性结合细胞测定法，以检测中和 ADA。该测定法用于回顾性筛选、盲法、储存多发性硬化症（MS）患者（n=32）的血清样本，这些患者接受了 3 次或更多次阿仑单抗治疗周期。在输注前后约 1 个月测量淋巴细胞耗竭。
显示淋巴细胞有限耗竭的个体数量随着治疗周期的增加而增加。耗竭不足也是未来疾病活动的不良预后特征。在 32/32（90.6%）个体中检测到 ADA 反应。在 6/7 个个体（整个样本的 18.8%）中，在发生有限耗竭之前就出现了中和抗体。输注前，ADA 水平预测了有限的、输注后淋巴细胞耗竭。
尽管阿仑单抗的 ADA 已被描述为无临床意义，但阿仑单抗特异性抗体似乎对某些个体具有临床相关性，尽管因果关系仍有待确定。在需要额外的阿仑单抗治疗周期的患者中，监测淋巴细胞耗竭和抗药反应可能具有实际价值。ADA 检测可能有助于告知是否需要重新治疗或切换到另一种治疗方法。
