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Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages

The SARS-CoV-2 variant, Omicron (B.1.1.529), rapidly swept the world since its emergence. Compared with previous variants, Omicron has a high number of mutations, especially those in its spike glycoprotein that drastically dampen or abolish the efficacy of currently available vaccines and therapeuti...

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Autores principales: Ren, Ping, Hu, Yingxia, Peng, Lei, Yang, Luojia, Suzuki, Kazushi, Fang, Zhenhao, Bai, Meizhu, Zhou, Liqun, Feng, Yanzhi, Zou, Yongji, Xiong, Yong, Chen, Sidi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9387138/
https://www.ncbi.nlm.nih.gov/pubmed/35982661
http://dx.doi.org/10.1101/2022.08.09.503414
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author Ren, Ping
Hu, Yingxia
Peng, Lei
Yang, Luojia
Suzuki, Kazushi
Fang, Zhenhao
Bai, Meizhu
Zhou, Liqun
Feng, Yanzhi
Zou, Yongji
Xiong, Yong
Chen, Sidi
author_facet Ren, Ping
Hu, Yingxia
Peng, Lei
Yang, Luojia
Suzuki, Kazushi
Fang, Zhenhao
Bai, Meizhu
Zhou, Liqun
Feng, Yanzhi
Zou, Yongji
Xiong, Yong
Chen, Sidi
author_sort Ren, Ping
collection PubMed
description The SARS-CoV-2 variant, Omicron (B.1.1.529), rapidly swept the world since its emergence. Compared with previous variants, Omicron has a high number of mutations, especially those in its spike glycoprotein that drastically dampen or abolish the efficacy of currently available vaccines and therapeutic antibodies. Several major sublineages of Omicron evolved, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4/5, and BA.2.75, which rapidly changing the global and regional landscape of the pandemic. Although vaccines are available, therapeutic antibodies remain critical for infected and especially hospitalized patients. To address this, we have designed and generated a panel of human/humanized therapeutic bispecific antibodies against Omicron and its sub-lineage variants, with activity spectrum against other lineages. Among these, the top clone CoV2–0213 has broadly potent activities against multiple SARS-CoV-2 ancestral and Omicron lineages, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4/5, and BA.2.75. We have solved the cryo-EM structure of the lead bi-specific antibody CoV-0213 and its major Fab arm MB.02. Three-dimensional structural analysis shows distinct epitope of antibody - spike receptor binding domain (RBD) interactions and reveals that both Fab fragments of CoV2–0213 can simultaneously target one single spike RBD or two adjacent ones in the same spike trimer, further corroborating its mechanism of action. CoV2–0213 represents a unique and potent broad-spectrum SARS-CoV-2 neutralizing bispecific antibody (nbsAb) against the currently circulating major Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.3, and BA.4/5). CoV2–0213 is primarily human and ready for translational testing as a countermeasure against the ever-evolving pathogen.
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spelling pubmed-93871382022-08-19 Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages Ren, Ping Hu, Yingxia Peng, Lei Yang, Luojia Suzuki, Kazushi Fang, Zhenhao Bai, Meizhu Zhou, Liqun Feng, Yanzhi Zou, Yongji Xiong, Yong Chen, Sidi bioRxiv Article The SARS-CoV-2 variant, Omicron (B.1.1.529), rapidly swept the world since its emergence. Compared with previous variants, Omicron has a high number of mutations, especially those in its spike glycoprotein that drastically dampen or abolish the efficacy of currently available vaccines and therapeutic antibodies. Several major sublineages of Omicron evolved, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4/5, and BA.2.75, which rapidly changing the global and regional landscape of the pandemic. Although vaccines are available, therapeutic antibodies remain critical for infected and especially hospitalized patients. To address this, we have designed and generated a panel of human/humanized therapeutic bispecific antibodies against Omicron and its sub-lineage variants, with activity spectrum against other lineages. Among these, the top clone CoV2–0213 has broadly potent activities against multiple SARS-CoV-2 ancestral and Omicron lineages, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4/5, and BA.2.75. We have solved the cryo-EM structure of the lead bi-specific antibody CoV-0213 and its major Fab arm MB.02. Three-dimensional structural analysis shows distinct epitope of antibody - spike receptor binding domain (RBD) interactions and reveals that both Fab fragments of CoV2–0213 can simultaneously target one single spike RBD or two adjacent ones in the same spike trimer, further corroborating its mechanism of action. CoV2–0213 represents a unique and potent broad-spectrum SARS-CoV-2 neutralizing bispecific antibody (nbsAb) against the currently circulating major Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.3, and BA.4/5). CoV2–0213 is primarily human and ready for translational testing as a countermeasure against the ever-evolving pathogen. Cold Spring Harbor Laboratory 2023-03-15 /pmc/articles/PMC9387138/ /pubmed/35982661 http://dx.doi.org/10.1101/2022.08.09.503414 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Ren, Ping
Hu, Yingxia
Peng, Lei
Yang, Luojia
Suzuki, Kazushi
Fang, Zhenhao
Bai, Meizhu
Zhou, Liqun
Feng, Yanzhi
Zou, Yongji
Xiong, Yong
Chen, Sidi
Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
title Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
title_full Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
title_fullStr Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
title_full_unstemmed Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
title_short Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
title_sort function and cryo-em structures of broadly potent bispecific antibodies against multiple sars-cov-2 omicron sublineages
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9387138/
https://www.ncbi.nlm.nih.gov/pubmed/35982661
http://dx.doi.org/10.1101/2022.08.09.503414
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