tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Kai Xu[SUP] #[/SUP][SUP] 2 3 [/SUP], Seolkyoung Jung[SUP] 4 [/SUP], Andrea Conte[SUP] 4 [/SUP], Jenna Lieberman[SUP] 4 [/SUP], Frauke Muecksch[SUP] 5 [/SUP], Julio Cesar Cetrulo Lorenzi[SUP] 6 [/SUP], Solji Park[SUP] 4 [/SUP], Fabian Schmidt[SUP] 5 [/SUP], Zijun Wang[SUP] 6 [/SUP], Yaoxing Huang[SUP] 7 [/SUP], Yang Luo[SUP] 7 [/SUP], Manoj Nair[SUP] 7 [/SUP], Pengfei Wang[SUP] 7 [/SUP], Jonathan E Schulz[SUP] 8 [/SUP], Lino Tessarollo[SUP] 9 [/SUP], Tatsiana Bylund[SUP] 2 [/SUP], Gwo-Yu Chuang[SUP] 2 [/SUP], Adam S Olia[SUP] 2 [/SUP], Tyler Stephens[SUP] 10 [/SUP], I-Ting Teng[SUP] 2 [/SUP], Yaroslav Tsybovsky[SUP] 10 [/SUP], Tongqing Zhou[SUP] 2 [/SUP], Vincent Munster[SUP] 8 [/SUP], David D Ho[SUP] 7 [/SUP], Theodora Hatziioannou[SUP] 5 [/SUP], Paul D Bieniasz[SUP] 5 11 [/SUP], Michel C Nussenzweig[SUP] 12 13 [/SUP], Peter D Kwong[SUP] #[/SUP][SUP] 14 [/SUP], Rafael Casellas[SUP] #[/SUP][SUP] 15 16 17 [/SUP]
Affiliations
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[SUP]1-3[/SUP]. One potential alternative to avert viral escape is the use of camelid VHHs or nanobodies, which can recognize epitopes often inaccessible to conventional antibodies[SUP]4[/SUP]. 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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Kai Xu[SUP] #[/SUP][SUP] 2 3 [/SUP], Seolkyoung Jung[SUP] 4 [/SUP], Andrea Conte[SUP] 4 [/SUP], Jenna Lieberman[SUP] 4 [/SUP], Frauke Muecksch[SUP] 5 [/SUP], Julio Cesar Cetrulo Lorenzi[SUP] 6 [/SUP], Solji Park[SUP] 4 [/SUP], Fabian Schmidt[SUP] 5 [/SUP], Zijun Wang[SUP] 6 [/SUP], Yaoxing Huang[SUP] 7 [/SUP], Yang Luo[SUP] 7 [/SUP], Manoj Nair[SUP] 7 [/SUP], Pengfei Wang[SUP] 7 [/SUP], Jonathan E Schulz[SUP] 8 [/SUP], Lino Tessarollo[SUP] 9 [/SUP], Tatsiana Bylund[SUP] 2 [/SUP], Gwo-Yu Chuang[SUP] 2 [/SUP], Adam S Olia[SUP] 2 [/SUP], Tyler Stephens[SUP] 10 [/SUP], I-Ting Teng[SUP] 2 [/SUP], Yaroslav Tsybovsky[SUP] 10 [/SUP], Tongqing Zhou[SUP] 2 [/SUP], Vincent Munster[SUP] 8 [/SUP], David D Ho[SUP] 7 [/SUP], Theodora Hatziioannou[SUP] 5 [/SUP], Paul D Bieniasz[SUP] 5 11 [/SUP], Michel C Nussenzweig[SUP] 12 13 [/SUP], Peter D Kwong[SUP] #[/SUP][SUP] 14 [/SUP], Rafael Casellas[SUP] #[/SUP][SUP] 15 16 17 [/SUP]
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[SUP]1-3[/SUP]. One potential alternative to avert viral escape is the use of camelid VHHs or nanobodies, which can recognize epitopes often inaccessible to conventional antibodies[SUP]4[/SUP]. 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.