Potent SARS-CoV-2 neutralizing antibodies selected from a human antibody library constructed decades ago

Qiang, Min; Ma, Peixiang; Li, Yu; Liu, Hejun; Harding, Adam; Min, Chenyu; Liu, Lili; Yuan, Meng; Ji, Qun; Tao, Pingdong; Shi, Xiaojie; Li, Zhean; Wang, Fulian; Zhang, Yu; Wu, Nicholas C.; Lee, Chang-Chun D.; Zhu, Xueyong; Gilbert-Jaramillo, Javier; Saxena, Abhishek; Huang, Xingxu; Wang, Hou; James, William; Dwek, Raymond A.; Wilson, Ian A.; Yang, Guang; Lerner, Richard A.

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The SARS-CoV-2 pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, we used a combinatorial human antibody library constructed 20 years before the COVID-19 pandemic to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these antibodies contain over 13-22 SHMs, many of which are involved in specific interactions in crystal structures with SARS-CoV-2 spike RBD. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of human immune responses to SARS-CoV-2.