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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
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.
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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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