Development of Broadly Neutralising Antibodies Against SARS-CoV-2

The beta coronavirus, SARS-CoV-2, has caused a pandemic of unprecedented impact in modern times with nearly 30 million cases worldwide, over 900,000 deaths and immeasurable economic cost. Naturally, there is a huge focus on vaccine development as well as production of monoclonal antibodies as therapeutic agents. Whilst in principle, SARS-CoV-2 is an ideal target for such tools due to its low mutation rate, the very high number of infections worldwide mean the potential for antigenic drift is considerable. Worryingly, mutations arose in the immunodominant epitope within just 2-3 months. This means that there is a real risk new vaccines and monoclonal antibodies will be constantly required. Here, we propose to focus on the ability to efficiently generate broadly neutralising antibodies to develop novel tools to combat the vast majority of virus strains. Broadly neutralising antibodies offer a huge advantage in that they reach normally occluded but highly conserved epitopes that are less prone to mutation. Furthermore, by identifying these epitopes, the targets for next generation, long-lasting, vaccines may be identified.

The neutralising activity of the best characterised broadly neutralising antibodies lies entirely within an ultra-long CDR-H3. Here, we propose to perform iterative screening, mutagenesis and selection of a library of naïve ultra-long heavy chain genes, expressed via mammalian cell display. The highest affinity CDR-H3s against the SARS2-CoV-2 spike protein will be selected and characterised. Notably, ultra-long CDR-H3 regions can be transferred to human antibody scaffolds with minimal loss of potency and we propose to generate humanised, broadly neutralising antibodies as novel, long-term therapeutic tools.