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Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth
One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bs...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820655/ https://www.ncbi.nlm.nih.gov/pubmed/35132410 http://dx.doi.org/10.1101/2022.02.01.478504 |
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author | Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Jing, Zou Kalveram, Birte K. Menachery, Vineet D. Zhang, Ningyan Lescar, Julien Shi, Pei-Yong An, Zhiqiang |
author_facet | Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Jing, Zou Kalveram, Birte K. Menachery, Vineet D. Zhang, Ningyan Lescar, Julien Shi, Pei-Yong An, Zhiqiang |
author_sort | Ku, Zhiqiang |
collection | PubMed |
description | One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)(2) design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth. |
format | Online Article Text |
id | pubmed-8820655 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-88206552022-02-08 Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Jing, Zou Kalveram, Birte K. Menachery, Vineet D. Zhang, Ningyan Lescar, Julien Shi, Pei-Yong An, Zhiqiang bioRxiv Article One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)(2) design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth. Cold Spring Harbor Laboratory 2022-02-01 /pmc/articles/PMC8820655/ /pubmed/35132410 http://dx.doi.org/10.1101/2022.02.01.478504 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 Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Jing, Zou Kalveram, Birte K. Menachery, Vineet D. Zhang, Ningyan Lescar, Julien Shi, Pei-Yong An, Zhiqiang Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title | Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_full | Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_fullStr | Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_full_unstemmed | Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_short | Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_sort | engineering sars-cov-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820655/ https://www.ncbi.nlm.nih.gov/pubmed/35132410 http://dx.doi.org/10.1101/2022.02.01.478504 |
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