Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2
Open accessPublished version of a preprint
Abstract
SARS-CoV-2 has largely evolved to resist antibody pressure, with each successive viral variant becoming more and more resistant to serum antibodies in the population. This evolution renders all previously authorized anti-spike therapeutic monoclonal antibodies inactive, and it threatens the remaining pipelines against COVID-19. We report herein the isolation of a human monoclonal antibody with a broad but incomplete SARS-CoV-2 neutralization profile, but structural analyses and mutational scanning lead to the engineering of variants that result in greater antibody flexibility while binding to the viral spike. Three such optimized monoclonal antibodies neutralize all SARS-CoV-2 strains tested with much improved potency and breadth, including against subvariants XEC and LP.8.1. The findings of this study not only present antibody candidates for clinical development against COVID-19, but also introduce an engineering approach to improve antibody activity via increasing conformational flexibility.
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- Authors
- Wang, Q., Guo, Y., Casner, R. G., Yu, J., Nair, M. S., Ho, J., Reddem, E. R., Mellis, I. A., Wu, M., Tzang, C.-C., Hong, H., Huang, Y., Shapiro, L., Liu, L., & Ho, D. D.
- Affiliations
- Aaron Diamond AIDS Research Center (US)
- Mortimer B. Zuckerman Mind Brain Behavior Institute (US)
- Corresponding author
- Shapiro, Lawrence
- Liu, Lihong
- Ho, David D.
- ORCID
- Venue
- Nature Communications
- Published
- 2025-07-04
- Volume
- 16
- Issue
- 1
- Pages
- 6195-6195
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12227675
- OpenAlex
- W4412020829
- Cited by
- 15
- References
- 9
- Citations by year
- 2026: 8 · 2025: 7
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Bill and Melinda Gates Foundation (INV019355)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- SARS-CoV-2, human monoclonal antibodies, antibody engineering, neutralizing antibodies, spike protein, Omicron subvariants, COVID-19 treatment, mutation scanning
- MeSH terms
- COVID-19, SARS-CoV-2, Animals, Antibodies, Monoclonal, Antibodies, Viral, Humans, Mutation, Neutralization Tests, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus
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