Author: Pymm, Phillip; Adair, Amy; Chan, Li-Jin; Cooney, James P.; Mordant, Francesca L.; Allison, Cody C.; Lopez, Ester; Haycroft, Ebene R.; O’Neill, Matthew T.; Tan, Li Lynn; Dietrich, Melanie H.; Drew, Damien; Doerflinger, Marcel; Dengler, Michael A.; Scott, Nichollas E.; Wheatley, Adam K.; Gherardin, Nicholas A.; Venugopal, Hariprasad; Cromer, Deborah; Davenport, Miles P.; Pickering, Raelene; Godfrey, Dale I.; Purcell, Damian F. J.; Kent, Stephen J.; Chung, Amy W.; Subbarao, Kanta; Pellegrini, Marc; Glukhova, Alisa; Tham, Wai-Hong
Title: Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice Cord-id: sc3glss7 Document date: 2021_5_11
ID: sc3glss7
Snippet: Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites a
Document: Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 10(4)-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.
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