Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth

Zhiqiang Ku; Xuping Xie; Jianqing Lin; Peng Gao; Bin Wu; Abbas El Sahili; Hang Su; Yang Liu; Xiaohua Ye; Eddie Yongjun Tan; Xin Li; Xuejun Fan; Boon Chong Goh; Wei Xiong; Hannah Boyd; Antonio E. Muruato; Hui Deng; Hongjie Xia; Jing Zou; Birte Kalveram; Vineet D. Menachery; Ningyan Zhang; Julien Lescar; Pei-Yong Shi; Zhiqiang An

doi:10.1038/s41467-022-33284-y

Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth

Zhiqiang Ku, Xuping Xie, Jianqing Lin, Peng Gao, Bin Wu, Abbas El Sahili, Hang Su, Yang Liu, Xiaohua Ye, Eddie Yongjun Tan, Xin Li, Xuejun Fan, Boon Chong Goh, Wei Xiong, Hannah Boyd, Antonio E. Muruato, Hui Deng, Hongjie Xia, Jing Zou, Birte KalveramVineet D. Menachery, Ningyan Zhang, Julien Lescar, Pei-Yong Shi, Zhiqiang An

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

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.

Original language	English (US)
Article number	5552
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33284-y
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Ku, Z., Xie, X., Lin, J., Gao, P., Wu, B., El Sahili, A., Su, H., Liu, Y., Ye, X., Tan, E. Y., Li, X., Fan, X., Goh, B. C., Xiong, W., Boyd, H., Muruato, A. E., Deng, H., Xia, H., Zou, J., ... An, Z. (2022). Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth. Nature communications, 13(1), Article 5552. https://doi.org/10.1038/s41467-022-33284-y

Ku, Z, Xie, X, Lin, J, Gao, P, Wu, B, El Sahili, A, Su, H, Liu, Y, Ye, X, Tan, EY, Li, X, Fan, X, Goh, BC, Xiong, W, Boyd, H, Muruato, AE, Deng, H, Xia, H, Zou, J, Kalveram, B, Menachery, VD, Zhang, N, Lescar, J, Shi, P-Y & An, Z 2022, 'Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth', Nature communications, vol. 13, no. 1, 5552. https://doi.org/10.1038/s41467-022-33284-y

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abstract = "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.",

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AU - El Sahili, Abbas

AU - Su, Hang

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AU - Ye, Xiaohua

AU - Tan, Eddie Yongjun

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AU - Fan, Xuejun

AU - Goh, Boon Chong

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AU - Boyd, Hannah

AU - Muruato, Antonio E.

AU - Deng, Hui

AU - Xia, Hongjie

AU - Zou, Jing

AU - Kalveram, Birte

AU - Menachery, Vineet D.

AU - Zhang, Ningyan

AU - Lescar, Julien

AU - Shi, Pei-Yong

AU - An, Zhiqiang

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N2 - 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.

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Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth

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