Diebold Martin, Derfuss Tobias
Neurological Policlinic and Clinic, University Hospital and University of Basel, Basel, Switzerland.
Neurological Policlinic and Clinic, University Hospital and University of Basel, Petersgraben 4, Basel, 4031, Switzerland.
Ther Adv Neurol Disord. 2019 Mar 7;12:1756286419833574. doi: 10.1177/1756286419833574. eCollection 2019.
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS). Despite improvements of immunomodulatory therapies in relapsing-remitting MS, the pathomechanisms of progressive disease are poorly understood and therapeutically addressed to date. A pathophysiological role for proteins encoded by human endogenous retroviruses (HERVs) has been proposed. GNbAC1 is a monoclonal antibody directed against the envelope protein of a HERV with postulated involvement in MS.
This review addresses the treatment concept of GNbAC1, the design, preclinical and clinical development of the antibody, as published by November 2018. All four in-human trials (of which two addressed MS) are discussed.
The treatment concept of GNbAC1 is appealing but remains controversial due to conflicting results regarding the hypothesized underlying pathomechanism. Anticipated immunomodulatory effects were not observed in clinical or pharmacodynamic analyses of the currently available data. However, a magnetic resonance imaging sign compatible with the remyelinating potential of GNbAC1 encouraged further development of this antibody in progressive MS. No relevant issues with tolerability or safety have been described to date.
多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性脱髓鞘疾病。尽管免疫调节疗法在复发缓解型MS中有所改善，但进展性疾病的发病机制至今仍知之甚少且缺乏有效的治疗方法。有人提出人类内源性逆转录病毒（HERV）编码的蛋白质具有病理生理作用。GNbAC1是一种单克隆抗体，针对一种假定与MS有关的HERV包膜蛋白。
本综述阐述了截至2018年11月已发表的GNbAC1的治疗理念、该抗体的设计、临床前和临床开发情况。讨论了所有四项人体试验（其中两项针对MS）。
GNbAC1的治疗理念很有吸引力，但由于关于假定的潜在发病机制的结果相互矛盾，仍存在争议。在对现有数据的临床或药效学分析中未观察到预期的免疫调节作用。然而，一种与GNbAC1的髓鞘再生潜力相符的磁共振成像迹象鼓励在进展性MS中进一步开发这种抗体。迄今为止，尚未描述有关耐受性或安全性的相关问题。
