Developing neutralizing antibodies to 2019-nCoV
Coronavirus entry starts with the S protein binding to a target receptor on the cell surface, where after fusion is mediated at the cell membrane, delivering the viral nucleocapsid inside the cell for subsequent replication 14. The S protein is famous for causing syncytial formation between infected cells and other receptor-bearing cells around them, emphasizing that the S protein does not function in just the virion state alone.
A neutralizing antibody targeting the S protein on the surface of 2019-nCoV is likely the first therapy contemplated by biomedical researchers in academia and industry, providing passive immunity to disease 15. The recently published genome sequence of 2019-nCoV (GenBank: MN908947.3) allows researchers to perform gene synthesis in the lab and consider expressing the S protein as an immunogen. Traditional methods of screening mice or rabbits for neutralizing antibodies may be too slow for this outbreak, but faster methods such as using phage or yeast display libraries that express antibody fragments could be used quickly to identify lead candidates for viral neutralization 16, 17. The challenge is that any antibody candidate would need to be rigorously tested in cell culture and animal models to confirm that it can neutralize 2019-nCoV and prevent infection. Furthermore, several isolates would need to be tested that are circulating in the population to try to assess if sufficient breadth of coverage is obtained with the neutralizing antibody. Information from other coronaviruses species like SARS would be helpful as to where to target the best epitope in order to produce neutralizing antibodies (the receptor-binding domain in the S protein is a key target) 18, but again this is a slow and challenging process, which may not yield significant gains for several months. Moreover, ultimately a cocktail of antibodies may be required to ensure full protection for patients, which would add additional complexity for formulation and manufacturing. Like some of the therapeutic options discussed below, the ability to express any lead candidates in lower organisms for protein expression (bacteria, yeast, insect cells) would facilitate faster production of therapy for patients 19.
An alternative strategy of generating neutralizing antibodies against 2019-nCoV S protein would be to immunize large animals (sheep, goat, cow) with the 2019-nCoV S protein, and then purifying polyclonal antibodies from the animals 20. This strategy may serve an expedited service in the setting of an outbreak and has many advantages such as simplifying production and manufacturing, but has limited guarantees that each animal would produce neutralizing antisera, or what the antibody titer would be in each animal 21. Moreover, there is also the human immune response against foreign immunoglobulins to other species, which would potentially complicate any treatment scenarios 22. In a truly desperate scenario, this strategy may be viable for a short-term, but would not easily scale in the 2019-nCoV outbreak, which is already rapidly multiplying.