| First Author | Xu J | Year | 2021 |
| Journal | Nature | Volume | 595 |
| Issue | 7866 | Pages | 278-282 |
| PubMed ID | 34098567 | Mgi Jnum | J:307753 |
| Mgi Id | MGI:6717248 | Doi | 10.1038/s41586-021-03676-z |
| Citation | Xu J, et al. (2021) Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants. Nature |
| abstractText | Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. While many vaccines have been deployed to date, the continual evolution of the viral receptor-binding domain (RBD) has challenged their efficacy. In particular, emerging variants B.1.1.7 (U.K.), B.1.351 (South Africa) and P.1 (Brazil) have compromised convalescent sera and immunotherapies that received emergency use authorization(1-3). One potential alternative to avert viral escape is the use of camelid VHHs or nanobodies, which can recognize epitopes often inaccessible to conventional antibodies(4). Here, we isolate anti-RBD nanobodies from llamas and "nanomice" we engineered to produce VHHs cloned from alpacas, dromedaries and camels. We identified two sets of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and fails to neutralize variants carrying E484K or N501Y substitutions. Notably however, group 2 nanobodies retain full neutralization activity against variants when expressed as homotrimers, rivaling the most potent antibodies produced to date against SARS-CoV-2. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2 binding domain, and recognition of conserved epitopes largely inaccessible to human antibodies. Therefore, while new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised. |
