Long-term passaging of pseudo-typed SARS-CoV-2 reveals the breadth of monoclonal and bispecific antibody cocktails  

作　　者：Hang Ma Hui-fang Zong Jun-jun Liu Ya-li Yue Yong Ke Yun-ji Liao Hao-neng Tang Lei Wang Shu-sheng Wang Yun-sheng Yuan Ming-yuan Wu Yan-lin Bian Bao-hong Zhang Hai-yang Yin Hua Jiang Tao Sun Lei Han Yue-qing Xie Jian-wei Zhu 

机构地区：[1]Engineering Research Center of Cell and Therapeutic Antibody,Ministry of Education,Shanghai 200240,China [2]School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240,China [3]School of Pharmaceutical Sciences,Southwest University,Chongqing 400715,China [4]Jecho Institute,Co.,Ltd.,Shanghai 200240,China [5]Jecho Laboratories,Inc.,Frederick,MD 21704,USA [6]School of Agriculture and Biology,Shanghai Jiao Tong University,Shanghai 200240,China [7]Shanghai Municipal Veterinary Key Laboratory,Shanghai 200240,China

出　　处：《Acta Pharmacologica Sinica》2023年第7期1455-1463,共9页中国药理学报（英文版）

基　　金：he National Natural Science Foundation of China(81773621,82073751 to JWZ);the National Science and Technology Major Project"Key New Drug Creation and Manufacturing Program"of China(No.2019ZX09732001-019 to JWZ);the Key R&D Supporting Program(Special support for developing medicine for infectious diseases)from the Administration of Chinese and Singapore Tianjin Eco-city to Jecho Biopharmaceuticals Ltd.Co;Zhejiang University special COVID-19 grant 2020XGZX099 and Shanghai Jiao Tong University"Crossing Medical and Engineering"grant20x190020003 to JWZ.

摘　　要：The continuous emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants poses challenges to the effectiveness of neutralizing antibodies.Rational design of antibody cocktails is a realizable approach addressing viral immune evasion.However,evaluating the breadth of antibody cocktails is essential for understanding the development potential.Here,based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2(VSV-SARS-CoV-2),we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails.Results from over two-month passaging of the virus showed that 9E12+10D4+2G1 and 7B9-9D11+2G1 from these cocktails were highly resistant to random mutation,and there was no breakthrough after 30 rounds of passaging.As a control,antibody REGN10933 was broken through in the third passage.Next generation sequencing was performed and several critical mutations related to viral evasion were identified.These mutations caused a decrease in neutralization efficiency,but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains.The 9E12+10D4+2G1 and 7B9-9D11+2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron,as well as SARS-CoV-1.Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

关 键 词：SARS-CoV-2 antibody vesicular stomatitis virus VARIANT NEUTRALIZATION 

分 类 号：R589.2[医药卫生—内分泌]