Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

• Published in: Science (American Association for the Advancement of Science) Vol. 371; no. 6531; pp. 823 - 829
• Main Authors: Rappazzo, C. Garrett, Tse, Longping V., Kaku, Chengzi I., Wrapp, Daniel, Sakharkar, Mrunal, Huang, Deli, Deveau, Laura M., Yockachonis, Thomas J., Herbert, Andrew S., Battles, Michael B., O’Brien, Cecilia M., Brown, Michael E., Geoghegan, James C., Belk, Jonathan, Peng, Linghang, Yang, Linlin, Hou, Yixuan, Scobey, Trevor D., Burton, Dennis R., Nemazee, David, Dye, John M., Voss, James E., Gunn, Bronwyn M., McLellan, Jason S., Baric, Ralph S., Gralinski, Lisa E., Walker, Laura M.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 19.02.2021; American Association for the Advancement of Science
• Subjects: Affinity; Angiotensin-Converting Enzyme 2 - metabolism; Animal models; Animals; Antibodies; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Viral - genetics; Antibodies, Viral - immunology; Antibodies, Viral - metabolism; Antibody Affinity; Betacoronavirus - immunology; Binding Sites; Binding Sites, Antibody; Broadly Neutralizing Antibodies - genetics; Broadly Neutralizing Antibodies - immunology; Broadly Neutralizing Antibodies - metabolism; Cell Surface Display Techniques; Coronaviridae; Coronaviruses; COVID-19; COVID-19 - prevention & control; COVID-19 - therapy; COVID-19 Serotherapy; Directed evolution; Directed Molecular Evolution; Domains; Epitopes; Epitopes - immunology; Human populations; Humans; Immunization, Passive; Immunoglobulin Fc Fragments - immunology; Immunology; Lungs; Mice; Mice, Inbred BALB C; Microbio; Monoclonal antibodies; Neutralization; Pandemics; Progeny; Protein Domains; Protein Engineering; Receptors; Receptors, Coronavirus - metabolism; Respiratory diseases; SARS-CoV-2 - immunology; Severe Acute Respiratory Syndrome - immunology; Severe Acute Respiratory Syndrome - prevention & control; Severe Acute Respiratory Syndrome - therapy; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome-related coronavirus - immunology; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Viral diseases; Viruses; Yeast
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abf4830

As we continue to battle the COVID-19 pandemic, we must confront the possibility of new pathogenic coronaviruses emerging in humans in the future. With this in mind, Rappazzo et al. isolated antibodies from a survivor of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV), used yeast display libraries to introduce diversity into these antibodies, and then screened for binding to SARS-CoV-2. One of the affinity-matured progeny strongly neutralized SARS-CoV-2, SARS-CoV, and two SARS-related viruses from bats. In addition, this antibody bound to the receptor-binding domains from a panel of sarbecoviruses, suggesting broader activity, and provided protection against SARS-CoV and SARS-CoV-2 in mouse models. Science , this issue p. 823 An affinity-optimized human monoclonal antibody displays broad in vivo efficacy in murine models of SARS and COVID-19. The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.