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Engineering SARS-CoV-2 specific 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 emergence of antibody resistance. Here we engineer two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single mole...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499943/ https://www.ncbi.nlm.nih.gov/pubmed/36138032 http://dx.doi.org/10.1038/s41467-022-33284-y |
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author | Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng Wu, Bin El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Tan, Eddie Yongjun Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Zou, Jing 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 Wu, Bin El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Tan, Eddie Yongjun Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Zou, Jing 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 emergence of antibody resistance. Here we engineer 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) shows increased antigen-binding and virus-neutralizing activities against multiple SARS-CoV-2 variants as well as increased breadth of neutralizing activity compared to the cocktail. X-ray crystallography and cryo-EM reveal distinct binding models for individual cocktail antibodies, and computational simulations suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and multiple 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-9499943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94999432022-09-24 Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng Wu, Bin El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Tan, Eddie Yongjun Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Zou, Jing Kalveram, Birte K. Menachery, Vineet D. Zhang, Ningyan Lescar, Julien Shi, Pei-Yong An, Zhiqiang Nat Commun Article One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer 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) shows increased antigen-binding and virus-neutralizing activities against multiple SARS-CoV-2 variants as well as increased breadth of neutralizing activity compared to the cocktail. X-ray crystallography and cryo-EM reveal distinct binding models for individual cocktail antibodies, and computational simulations suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and multiple 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. Nature Publishing Group UK 2022-09-22 /pmc/articles/PMC9499943/ /pubmed/36138032 http://dx.doi.org/10.1038/s41467-022-33284-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ku, Zhiqiang Xie, Xuping Lin, Jianqing Gao, Peng Wu, Bin El Sahili, Abbas Su, Hang Liu, Yang Ye, Xiaohua Tan, Eddie Yongjun Li, Xin Fan, Xuejun Goh, Boon Chong Xiong, Wei Boyd, Hannah Muruato, Antonio E. Deng, Hui Xia, Hongjie Zou, Jing Kalveram, Birte K. Menachery, Vineet D. Zhang, Ningyan Lescar, Julien Shi, Pei-Yong An, Zhiqiang Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title | Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_full | Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_fullStr | Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_full_unstemmed | Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_short | Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
title_sort | engineering sars-cov-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499943/ https://www.ncbi.nlm.nih.gov/pubmed/36138032 http://dx.doi.org/10.1038/s41467-022-33284-y |
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