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

Jianliang Xu (), Kai Xu, Seolkyoung Jung, Andrea Conte, Jenna Lieberman, Frauke Muecksch, Julio Cesar Cetrulo Lorenzi, Solji Park, Fabian Schmidt, Zijun Wang, Yaoxing Huang, Yang Luo, Manoj S. Nair, Pengfei Wang, Jonathan E. Schulz, Lino Tessarollo, Tatsiana Bylund, Gwo-Yu Chuang, Adam S. Olia, Tyler Stephens, I-Ting Teng, Yaroslav Tsybovsky, Tongqing Zhou, Vincent Munster, David D. Ho, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig (), Peter D. Kwong () and Rafael Casellas ()
Additional contact information
Jianliang Xu: NIAMS, NIH
Kai Xu: NIAID, NIH
Seolkyoung Jung: NIAMS, NIH
Andrea Conte: NIAMS, NIH
Jenna Lieberman: NIAMS, NIH
Frauke Muecksch: The Rockefeller University
Julio Cesar Cetrulo Lorenzi: The Rockefeller University
Solji Park: NIAMS, NIH
Fabian Schmidt: The Rockefeller University
Zijun Wang: The Rockefeller University
Yaoxing Huang: Columbia University Vagelos College of Physicians and Surgeons
Yang Luo: Columbia University Vagelos College of Physicians and Surgeons
Manoj S. Nair: Columbia University Vagelos College of Physicians and Surgeons
Pengfei Wang: Columbia University Vagelos College of Physicians and Surgeons
Jonathan E. Schulz: Division of Intramural Research, NIAID, NIH, Rocky Mountain Laboratories
Lino Tessarollo: CCR, NCI, NIH
Tatsiana Bylund: NIAID, NIH
Gwo-Yu Chuang: NIAID, NIH
Adam S. Olia: NIAID, NIH
Tyler Stephens: Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute
I-Ting Teng: NIAID, NIH
Yaroslav Tsybovsky: Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute
Tongqing Zhou: NIAID, NIH
Vincent Munster: Division of Intramural Research, NIAID, NIH, Rocky Mountain Laboratories
David D. Ho: Columbia University Vagelos College of Physicians and Surgeons
Theodora Hatziioannou: The Rockefeller University
Paul D. Bieniasz: The Rockefeller University
Michel C. Nussenzweig: The Rockefeller University
Peter D. Kwong: NIAID, NIH
Rafael Casellas: NIAMS, NIH

Nature, 2021, vol. 595, issue 7866, 278-282

Abstract: Abstract Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization1–3. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies4. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups 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 does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and—to our knowledge—rival the most potent antibodies against SARS-CoV-2 that have been produced to date. 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 that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.

Date: 2021
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DOI: 10.1038/s41586-021-03676-z

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