A novel biparatopic antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy

Miao, Xiaoniu; Luo, Yi; Huang, Xi; Lee, Suki M. Y.; Yuan, Zhijun; Tang, Yongzhou; Chen, Liandi; Wang, Chao; Jiang, Wenchao; Gao, Wei; Song, Xuedong; Yan, Yao; Pang, Tuling; Zou, Yuefeng; Fu, Weihui; Wan, Liping; Gilbert-Jaramillo, Javier; Knight, Michael; Tan, Tiong Kit; Rijal, Pramila; Townsend, Alain; Sun, Joanne; Liu, Xiaolin; James, William; Tsun, Andy; Xu, Yingda

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provides a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain (NTD) of the viral S glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain (RBD) of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic virus infection in a standard assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.