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

• Published in: Acta pharmacologica Sinica Vol. 44; no. 7; pp. 1455 - 1463
• Main Authors: Ma, Hang, Zong, Hui-fang, Liu, Jun-jun, Yue, Ya-li, Ke, Yong, Liao, Yun-ji, Tang, Hao-neng, Wang, Lei, Wang, Shu-sheng, Yuan, Yun-sheng, Wu, Ming-yuan, Bian, Yan-lin, Zhang, Bao-hong, Yin, Hai-yang, Jiang, Hua, Sun, Tao, Han, Lei, Xie, Yue-qing, Zhu, Jian-wei
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01-07-2023; Nature Publishing Group
• Subjects: ACE2; Angiotensin-converting enzyme 2; Antibodies; Biomedical and Life Sciences; Biomedicine; Bispecific antibodies; Coronaviruses; Immunology; Internal Medicine; Medical Microbiology; Monoclonal antibodies; Mutation; Next-generation sequencing; Pharmacology/Toxicology; Replication; Severe acute respiratory syndrome coronavirus 2; Stomatitis; Vaccine; Viruses; variant; SARS-CoV-2; antibody; neutralization; vesicular stomatitis virus
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-022-01043-w

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.