CD49d expression as a promising biomarker to monitor natalizumab efficacy
CD49d expression as a promising biomarker to monitor natalizumab efficacy
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DOI：
10.1016/j.jns.2011.10.005
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发表时间：
2012-03-15
影响因子：
4.4
通讯作者：
Le Mauff, Brigitte
中科院分区：
文献类型：
--
作者：
Defer, Gilles;Mariotte, Delphine;Le Mauff, Brigitte
那他珠单抗（Tysabri（TM））是一种抗白细胞VLA-4（CD 49 d）抗原的α 4-整联蛋白的单克隆抗体，在多发性硬化症（MS）中非常有效。治疗失败最常见的原因是中和抗体（NAb）的产生。根据卫生当局的建议，如果出现复发或反复输注反应，则建议进行Nabs检测。然而，NAb可能在临床无症状患者中发展。在这项研究中，我们研究了CD 49 d表达是否可以作为那他珠单抗生物利用度和治疗反应的生物标志物。在49名那他珠单抗治疗的复发缓解型MS的队列中，随访超过2年，在每次输注前测定外周血单核细胞（PBMC）上的CD 49 d表达，并与NAb和血清那他珠单抗水平进行比较。并在整个治疗期间维持在低水平。相比之下，在8例患者（16%）中，CD 49 d表达早期恢复至与NAB发展相关的治疗前水平。虽然3例病例发生超敏反应，但仅根据CD 49 d水平未降低确定了另外3例病例，未发生输注反应或临床恶化。这3例患者的NAb水平非常高，血清中未检测到那他珠单抗。另外2例患者CD 49 d表达早期但短暂恢复。这些患者具有低水平的短暂Nab，并且在几次那他珠单抗输注后恢复到显著的CD 49 d抑制。我们建议监测CD 49 d表达可作为那他珠单抗疗效的替代生物标志物。如果CD 49 d表达维持在治疗前水平，则应检测患者是否存在持续NAb，并考虑中断治疗。(C)2011 Elsevier B. V.保留所有权利。
Natalizumab (Tysabri (TM)), a monoclonal antibody against the alpha 4-integrin of VLA-4 (CD49d) antigen of leukocytes, is highly effective in multiple sclerosis (MS). The most common reason for treatment failure is the development of neutralizing antibodies (NAbs). According to health authorities Nabs testing is recommended in case of relapse or repeated infusion reactions. However NAbs may develop in clinically asymptomatic patients. In this study we investigated if CD49d expression could serve as a biomarker of natalizumab bioavailability and treatment response. In a cohort of 49 natalizumab treated relapsing-remitting MS, followed over 2 years, CD49d expression was determined on peripheral blood mononuclear cells (PBMCs) before each infusion and compared to NAbs and serum natalizumab levels.In a majority of patients (41/49) the CD49d expression in PBMCs was strongly inhibited (>50%) after the first infusion and maintained at low levels throughout the treatment period. In contrast, in eight patients (16%) there was an early recovery of CD49d expression to pre-treatment levels related to NABs development. While three cases experienced hypersensitivity reactions, three others were identified solely on the basis of an undiminished level of CD49d, with neither infusion reaction nor clinical worsening. These 3 patients had very high levels of NAbs and no detectable serum natalizumab. Two additional patients had early but transient recovery of CD49d expression. These patients had low levels of transient Nabs and returned to significant CD49d inhibition after few natalizumab infusions. We suggest that monitoring of CD49d expression can be used as a surrogate biomarker of natalizumab efficiency. If the CD49d expression is sustained at pre-treatment levels, patients should be tested for persistent NAbs and considered for treatment interruption. (C) 2011 Elsevier B.V. All rights reserved.