Development of monoclonal antibody therapeutics for ebolavirus infection

扎伊尔埃博拉病毒（EBOV）引起严重的出血热，死亡率高达90%。在没有获得许可的干预措施的情况下，最近在西非发生的令人震惊的流行病凸显了对感染控制措施的严重依赖。然而，EBOV研究的进展提供了强有力的证据，表明有效的疫苗或治疗方法应该唾手可得。第一代疫苗已进入临床试验，各种候选治疗方法正在评估中，包括小分子和基于sirna的抑制剂，以及单克隆抗体（mab）。单克隆抗体的被动治疗管理提供了一个延长的治疗窗口，并已被证明在非人类灵长类动物中非常有效。对于EBOV，目前的主要方法是使用一种名为“ZMapp”的三种抗体的混合物——它们最初都是从小鼠中分离出来的，嵌合到人类IgG1的主干上，并在烟草植物中大量生产。然而，仍然有令人信服的理由开发改进的基于单克隆抗体的治疗方法，并建立适合和准备好应对新出现和流行传染病病原体的平台方法。开发一种改进的基于单克隆抗体的治疗方法以用于未来的EBOV暴发，可能需要从人类疫苗接种者或幸存者以及小鼠和兔子中分离单克隆抗体；基于快速改进的结构、生物信息学和免疫学见解，合理而非“反复试验”地设计单抗鸡尾酒；对病毒逃逸突变体或可能构成未来流行病的埃博拉病毒变种（如苏丹埃博拉病毒和本迪布焦埃博拉病毒）具有明显效力；与ZMapp相比，改善了治疗效果；并且降低了产品的复杂性（少于三个成分），加上在高产的哺乳动物细胞表达系统中的生产。自2014年底以来，牛津大学的两个研究小组（Draper, Townsend）与UCB-Celltech进行了新的合作，以满足这一需求。该项目将建立在最近的高度互补的学术产业合作基础上，合理开发一种改进的下一代基于单克隆抗体的EBOV治疗药物，适合未来的临床发展。

Zaire ebolavirus (EBOV) causes severe haemorrhagic fever with up to 90% mortality. In the absence of licensed interventions, the recent and alarming epidemic in West Africa has highlighted the critical reliance on infection control measures. However, progress with EBOV research has provided strong evidence that effective vaccines or therapeutics should be within reach. First-generation vaccines have entered clinical testing, and a variety of candidate therapeutics are under evaluation including small molecule and siRNA-based inhibitors, as well as monoclonal antibodies (mAbs). Passive therapeutic administration of mAbs offers an extended treatment window and has proven highly efficacious in non-human primates. For EBOV, the current leading approach uses a mixture of three antibodies called 'ZMapp' - all originally isolated from mice, chimerised onto a backbone of human IgG1, and mass produced in tobacco plants. However, there remain compelling reasons to develop improved mAb-based therapeutics, and to establish platform approaches suitable and ready to address emerging and epidemic infectious disease agents. Development of an improved mAb-based therapeutic for future use against EBOV outbreaks will likely require isolation of mAbs from human vaccinees or survivors, as well as mice and rabbits; rational rather than 'trial and error' design of a mAb cocktail based on rapidly improving structural, bioinformatic and immunological insight; demonstrable potency against virus escape mutants or divergent ebolavirus species that may constitute future epidemics (such as Sudan and Bundibugyo ebolaviruses); improved therapeutic potency in comparison to ZMapp; and reduced product complexity (less than three components) coupled with production in high-producing mammalian cell-based expression systems.Since late 2014, two groups from the University of Oxford [Draper, Townsend] have entered into a new collaboration with UCB-Celltech to meet this need. This project will build on this recent and highly complementary academic industrial collaboration to rationally develop an improved next-generation mAb-based therapeutic for EBOV suitable for future clinical development.