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%。在没有许可的干预措施的情况下，西非最近令人震惊的流行病突出表明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是可以实现的。第一代疫苗已进入临床测试，各种候选疗法正在评估中，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性给药提供了延长的治疗窗口，并已证明在非人灵长类动物中高度有效。对于EBOV，目前领先的方法使用了三种抗体的混合物，称为“ZMapp”-所有抗体最初都是从小鼠中分离出来的，嵌合到人类IgG 1的骨架上，并在烟草植物中大规模生产。然而，仍然有令人信服的理由来开发改进的基于mAb的治疗方法，并建立适合并准备好应对新兴和流行性传染病病原体的平台方法。开发用于未来对抗EBOV爆发的改进的基于mAb的治疗剂可能需要从人疫苗接种者或幸存者以及小鼠和兔中分离mAb;基于快速改进的结构、生物信息学和免疫学见解的mAb混合物的合理而非“试错”设计;对可能构成未来流行病的病毒逃逸突变体或不同埃博拉病毒种属具有可证实的效力（如苏丹和本迪布焦埃博拉病毒）;与ZMapp相比，改善的治疗效力;降低产品复杂性（少于三种组分）结合在基于高产哺乳动物细胞的表达系统中的生产。自2014年底以来，来自牛津大学[德雷珀，汤森]的两个小组已经与UCB-Celltech进行了新的合作，以满足这种需要。该项目将建立在最近的高度互补的学术产业合作基础上，合理开发适合未来临床开发的改进的下一代EBOV单克隆抗体治疗药物。

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.