Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern

作者：Hyeseon Cho, Kristina Kay Gonzales-Wartz, Deli Huang, Meng Yuan, Mary Peterson, Janie Liang, Nathan Beutler, Jonathan L. Torres, Yu Cong, Elena Postnikova, Sandhya Bangaru, Chloe Adrienna Talana, Wei Shi, Eun Sung Yang, Yi Zhang, Kwanyee Leung, Lingshu Wang, Linghang Peng, Jeff Skinner, Shanping Li, Nicholas C. Wu, Hejun Liu, Cherrelle Dacon, Thomas P. Moyer, Melanie Cohen, Ming Zhao, F. Eun‐Hyung Lee, Rona Singer Weinberg, Iyadh Douagi, Robin Gross, Connie S. Schmaljohn, Amarendra Pegu, John R. Mascola, Michael R. Holbrook, David Nemazee, Thomas F. Rogers, Andrew B. Ward, Ian A. Wilson, Peter D. Crompton, Joshua Tan · 发表于：Science Translational Medicine · 年份：2021 · DOI：10.1126/scitranslmed.abj5413 · 被引用次数：138 · 研究领域：SARS-CoV-2 and COVID-19 Research、Bacteriophages and microbial interactions、Monoclonal and Polyclonal Antibodies Research

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Del...