Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice

Pymm, P; Adair, A; Chan, LJ; Cooney, JP; Mordant, FL; Allison, CC; Lopez, E; Haycroft, ER; O&#39;Neill, MT; Tan, LL; Dietrich, MH; Drew, D; Doerflinger, M; Dengler, MA; Scott, NE; Wheatley, AK; Gherardin, NA; Venugopal, H; Cromer, D; Davenport, MP; Pickering, R; Godfrey, DI; Purcell, DFJ; Kent, SJ; Chung, AW; Subbarao, K; Pellegrini, M; Glukhova, A; Tham, WH

Author(s): Pymm, P; Adair, A; Chan, LJ; Cooney, JP; Mordant, FL; Allison, CC; Lopez, E; Haycroft, ER; O'Neill, MT; Tan, LL; Dietrich, MH; Drew, D; Doerflinger, M; Dengler, MA; Scott, NE; Wheatley, AK; Gherardin, NA; Venugopal, H; Cromer, D; Davenport, MP; Pickering, R; Godfrey, DI; Purcell, DFJ; Kent, SJ; Chung, AW; Subbarao, K; Pellegrini, M; Glukhova, A; Tham, WH;
Details: Publication Year 2021-05-11,Volume 118,Issue #19,Page e2101918118
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Abstract: 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.
Publisher: NAS
Keywords: SARS-CoV-2; antiviral therapeutics; cryo-EM; crystallography; nanobodies; patent covering the nanobodies described in this manuscript.
Research Division(s): Infectious Diseases And Immune Defence
PubMed ID: 33893175
Publisher's Version: https://doi.org/10.1073/pnas.2101918118
Open Access at Publisher's Site: https://doi.org/10.1073/pnas.2101918118
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Pymm P et al PNAS_2021.pdf - (2.02MB, application/pdf)

Creation Date: 2021-05-11 02:09:53

Last Modified: 2021-05-11 03:58:54