Etesevimab in combination with JS026 neutralizing SARS-CoV-2 and its variants

ABSTRACT

The neutralizing antibody is a potential therapeutic for the ongoing COVID-19 pandemic. As an antiviral agent, numerous mAbs recognize the epitopes that overlap with ACE2-binding sites in the SARS-CoV-2-RBD. Some studies have shown that residual changes on the spike protein can significantly decrease the efficiency of neutralizing antibodies. To address this issue, a therapeutic cocktail could be an effective countermeasure. In the present study, we isolated a fully human neutralizing antibody, JS026, from a convalescent patient. The comparative analysis revealed that JS026 binding to SARS-CoV-2-RBD mainly located between epitopes for class 2 and class 3 mAbs as opposed to that of class 1 (etesevimab) antibodies. A cocktail of etesevimab and JS026 increased neutralizing efficacy against both wild-type SARS-CoV-2 and the recent emergence of Alpha, Beta, Gamma, and Delta variants. JS026 and the cocktail reduced virus titers in the infected lungs of hACE2 transgenic mice and relieved pathological changes. These findings would benefit antibody-based therapeutic countermeasures in the treatment of COVID-19.

KEYWORDS:

• SARS-CoV-2
• etesevimab
• JS026
• antibody cocktail
• variants of concern

Acknowledgments

We are grateful to Y. Bi and the staff of the Biosafety Level 3 (BSL-3) equipped laboratories at Institute of Microbiology, Chinese Academy of Sciences for providing SARS-CoV-2 virus and assistance during animal experiments. We also thank colleagues from Vazyme Biotech Co. Ltd. for antibodies isolation. L.L., H.L., J.Z., D.L., J.W., Y.H., and H.F. are employees of Shanghai Junshi Biosciences Co. Ltd. The remaining authors declare no competing interests. Conceptualization: H.F. and J.Y. Methodology: L.L. and R.S., Investigation: F.W., L.L., X.D., H.L., J.Z., D.L., J.W., and Y.H. Crystal diffraction and determination: Y.D., J.L., and B.L. Data analysis, writing, and editing: L.L., R.S., F. H., and J.Y.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Further information and requests for resources should be directed to and will be fulfilled by the corresponding authors.

Code availability statement

The accession number for the atomic coordinates and diffraction data reported in this study is PDB 7F7E.

Additional information

Funding

This project was funded by the Strategic Priority Research Program of CAS [grant number XDB29040201], the National Natural Science Foundation of China [grant number 81830050], and China Postdoctoral Science Foundation [grant number 2021M703450].