Development of monoclonal antibody therapeutics for ebolavirus infection

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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.