Development of Broadly Neutralising Antibodies Against SARS-CoV-2

β冠状病毒，SARS-CoV-2，在现代造成了前所未有的影响，全球近3000万病例，超过90万人死亡，经济损失不可估量。自然，疫苗开发以及作为治疗剂的单克隆抗体的生产是一个巨大的焦点。虽然原则上，SARS-CoV-2由于其低突变率而成为此类工具的理想靶标，但全球范围内非常高的感染数量意味着抗原漂移的可能性相当大。令人担忧的是，在短短2-3个月内，免疫显性表位发生了突变。这意味着，将不断需要新的疫苗和单克隆抗体，这是一个真实的风险。在这里，我们建议专注于有效产生广泛中和抗体的能力，以开发新的工具来对抗绝大多数病毒株。广泛中和抗体提供了一个巨大的优势，因为它们可以到达通常封闭但高度保守的表位，这些表位不太容易突变。此外，通过鉴定这些表位，可以鉴定下一代长效疫苗的靶标。最佳表征的广泛中和抗体的中和活性完全在超长CDR-H3内。在这里，我们建议进行迭代筛选，诱变和选择的幼稚超长重链基因库，通过哺乳动物细胞展示表达。将选择并表征针对SARS 2-CoV-2刺突蛋白的最高亲和力CDR-H3。值得注意的是，超长的CDR-H3区可以转移到人抗体支架上，而效力损失最小，我们建议产生人源化的、广泛中和的抗体作为新型的长期治疗工具。

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.