Camel nanobodies broadly neutralize SARS-CoV-2 variants.
Ontology highlight
ABSTRACT: One-sentence summary
Dromedary camel ( Camelus dromedarius ) V H H phage libraries were built for isolation of the nanobodies that broadly neutralize SARS-CoV-2 variants.
SUBMITTER: Hong J
PROVIDER: S-EPMC8575140 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The COVID-19 pandemic continues to be a severe threat to human health, especially due to current and emerging SARS-CoV-2 variants with potential to escape humoral immunity developed after vaccination or infection. The development of broadly neutralizing antibodies that engage evolutionarily conserved epitopes on coronavirus spike proteins represents a promising strategy to improve therapy and prophylaxis against SARS-CoV-2 and variants thereof. Herein, a facile multivalent engineering approach is employed to achieve large synergistic improvements in the neutralizing activity of a SARS-CoV-2 cross-reactive nanobody (VHH-72) initially generated against SARS-CoV. This synergy is epitope specific and is not observed for a second high-affinity nanobody against a non-conserved epitope in the receptor-binding domain. Importantly, a hexavalent VHH-72 nanobody retains binding to spike proteins from multiple highly transmissible SARS-CoV-2 variants (B.1.1.7 and B.1.351) and potently neutralizes them. Multivalent VHH-72 nanobodies also display drug-like biophysical properties, including high stability, high solubility, and low levels of non-specific binding. The unique neutralizing and biophysical properties of VHH-72 multivalent nanobodies make them attractive as therapeutics against SARS-CoV-2 variants.
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Project description:Since the start of the coronavirus disease-2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than 2 million deaths worldwide. Many vaccines have been deployed to date; however, the continual evolution of the viral receptor binding domain (RBD) has recently challenged their efficacy. In particular, SARS-CoV-2 variants originating in South Africa (B.1.351) and the U.K. (B.1.1.7) have reduced plasma neutralization activity and crippled antibody cocktails that received emergency use authorization1-3. Whereas vaccines can be updated periodically to account for emerging variants, complementary strategies are urgently needed to overcome viral escape. One potential alternative are camelid VHHs (also known as nanobodies), which can access conserved epitopes often hidden to conventional antibodies4-6. We here isolate anti-RBD nanobodies from llamas and mice engineered to produce VHHs from alpacas, dromedaries and camels. Through neutralization assays and cryo-electron microscopy we identify two “nanomouse” VHHs that circumvent RBD antigenic drift by recognizing a domain conserved in coronaviruses, away from the ACE2 binding motif. Conversely, llama nanobodies recognize the RBD-ACE2 interphase and as monomers they are ineffective against E484K or N501Y substitutions. Notably, as homotrimers those same VHHs neutralize RBD variants with ultrahigh (pM) affinity, rivaling the most potent antibodies produced to date against SARS-CoV-2. We conclude that multivalent nanobodies can avert SARS-CoV-2 escape mutants and thus they represent promising tools to prevent COVID-19 mortality when vaccines are compromised.
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