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 K. Kalveram, Vineet D. Menachery, Ningyan Zhang, Julien Lescar (), Pei-Yong Shi () and Zhiqiang An ()
Additional contact information
Zhiqiang Ku: University of Texas Health Science Center at Houston
Xuping Xie: University of Texas Medical Branch
Jianqing Lin: Nanyang Technological University
Peng Gao: University of Texas Health Science Center at Houston
Bin Wu: Nanyang Technological University
Abbas El Sahili: Nanyang Technological University
Hang Su: University of Texas Health Science Center at Houston
Yang Liu: University of Texas Medical Branch
Xiaohua Ye: University of Texas Health Science Center at Houston
Eddie Yongjun Tan: Nanyang Technological University
Xin Li: University of Texas Health Science Center at Houston
Xuejun Fan: University of Texas Health Science Center at Houston
Boon Chong Goh: Nanyang Technological University
Wei Xiong: University of Texas Health Science Center at Houston
Hannah Boyd: University of Texas Health Science Center at Houston
Antonio E. Muruato: University of Texas Medical Branch
Hui Deng: University of Texas Health Science Center at Houston
Hongjie Xia: University of Texas Medical Branch
Jing Zou: University of Texas Medical Branch
Birte K. Kalveram: University of Texas Medical Branch
Vineet D. Menachery: University of Texas Medical Branch
Ningyan Zhang: University of Texas Health Science Center at Houston
Julien Lescar: Nanyang Technological University
Pei-Yong Shi: University of Texas Medical Branch
Zhiqiang An: University of Texas Health Science Center at Houston

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33284-y

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