Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia

• Published in: Cell Vol. 184; no. 12; pp. 3192 - 3204.e16
• Main Authors: Asarnow, Daniel, Wang, Bei, Lee, Wen-Hsin, Hu, Yuanyu, Huang, Ching-Wen, Faust, Bryan, Ng, Patricia Miang Lon, Ngoh, Eve Zi Xian, Bohn, Markus, Bulkley, David, Pizzorno, Andrés, Ary, Beatrice, Tan, Hwee Ching, Lee, Chia Yin, Minhat, Rabiatul Adawiyah, Terrier, Olivier, Soh, Mun Kuen, Teo, Frannie Jiuyi, Yeap, Yvonne Yee Chin, Seah, Shirley Gek Kheng, Chan, Conrad En Zuo, Connelly, Emily, Young, Nicholas J., Maurer-Stroh, Sebastian, Renia, Laurent, Hanson, Brendon John, Rosa-Calatrava, Manuel, Manglik, Aashish, Cheng, Yifan, Craik, Charles S., Wang, Cheng-I
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2021; MDPI
• Subjects: Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - immunology; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antigen-Antibody Complex - chemistry; Antigen-Antibody Complex - metabolism; Binding Sites; CHO Cells; coronavirus; COVID-19; COVID-19 - pathology; COVID-19 - virology; Cricetinae; Cricetulus; Cryoelectron Microscopy; Giant Cells - cytology; Giant Cells - metabolism; Humans; Immunology; Life Sciences; Membrane Fusion; Microbiology and Parasitology; Peptide Library; phage display; Protein Binding; Protein Domains; Protein Structure, Quaternary; receptor binding domain (RBD); recombinant monoclonal antibody; SARS-CoV; SARS-CoV-2; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; syncytia; Virology; COVID-19; SARS-CoV-2; recombinant monoclonal antibody; Spike protein; syncytia; phage display; SARS-CoV; coronavirus; receptor binding domain (RBD)
• ISSN: 0092-8674; 2073-4409; 1097-4172; 2073-4409
• DOI: 10.1016/j.cell.2021.04.033

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity. [Display omitted] •The affinity of neutralizing antibodies does not always predict antiviral potency•Receptor-blocking antibodies can inhibit or enhance syncytium formation•Cryo-EM reveals one antibody inhibits syncytia by trapping the pre-fusion Spike•Another antibody acts as an allosteric effector that promotes syncytium formation A series of antibodies against SARS-CoV-2 that potently block binding to the host receptor ACE2 are found to enhance or inhibit virus Spike-mediated membrane fusion and formation of syncytia, a sign of tissue damage in individuals with COVID-19.