Nature . Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants

[tetano]

Nature


. 2021 Jun 7.
doi: 10.1038/s41586-021-03676-z. Online ahead of print.
Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants


Jianliang Xu ^{# 1} , Kai Xu ^{# 2 3} , Seolkyoung Jung ⁴ , Andrea Conte ⁴ , Jenna Lieberman ⁴ , Frauke Muecksch ⁵ , Julio Cesar Cetrulo Lorenzi ⁶ , Solji Park ⁴ , Fabian Schmidt ⁵ , Zijun Wang ⁶ , Yaoxing Huang ⁷ , Yang Luo ⁷ , Manoj Nair ⁷ , Pengfei Wang ⁷ , Jonathan E Schulz ⁸ , Lino Tessarollo ⁹ , Tatsiana Bylund ² , Gwo-Yu Chuang ² , Adam S Olia ² , Tyler Stephens ¹⁰ , I-Ting Teng ² , Yaroslav Tsybovsky ¹⁰ , Tongqing Zhou ² , Vincent Munster ⁸ , David D Ho ⁷ , Theodora Hatziioannou ⁵ , Paul D Bieniasz ^{5 11} , Michel C Nussenzweig ^{12 13} , Peter D Kwong ^{# 14} , Rafael Casellas ^{# 15 16 17}



Affiliations

• PMID: 34098567
• DOI: 10.1038/s41586-021-03676-z

Abstract

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 antibodies⁴. 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.