Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61472-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849238326059466752 |
|---|---|
| author | Qian Wang Yicheng Guo Ryan G. Casner Jian Yu Manoj S. Nair Jerren Ho Eswar R. Reddem Ian A. Mellis Madeline Wu Chih-Chen Tzang Hsiang Hong Yaoxing Huang Lawrence Shapiro Lihong Liu David D. Ho |
| author_facet | Qian Wang Yicheng Guo Ryan G. Casner Jian Yu Manoj S. Nair Jerren Ho Eswar R. Reddem Ian A. Mellis Madeline Wu Chih-Chen Tzang Hsiang Hong Yaoxing Huang Lawrence Shapiro Lihong Liu David D. Ho |
| author_sort | Qian Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b3ddc22585ff47a494d461a4edab6c1c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b3ddc22585ff47a494d461a4edab6c1c2025-08-20T04:01:41ZengNature PortfolioNature Communications2041-17232025-07-0116111410.1038/s41467-025-61472-zOptimizing a human monoclonal antibody for better neutralization of SARS-CoV-2Qian Wang0Yicheng Guo1Ryan G. Casner2Jian Yu3Manoj S. Nair4Jerren Ho5Eswar R. Reddem6Ian A. Mellis7Madeline Wu8Chih-Chen Tzang9Hsiang Hong10Yaoxing Huang11Lawrence Shapiro12Lihong Liu13David D. Ho14Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsZuckerman Mind Brain Behavior Institute, Columbia UniversityAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsZuckerman Mind Brain Behavior Institute, Columbia UniversityAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsAbstract 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.https://doi.org/10.1038/s41467-025-61472-z |
| spellingShingle | Qian Wang Yicheng Guo Ryan G. Casner Jian Yu Manoj S. Nair Jerren Ho Eswar R. Reddem Ian A. Mellis Madeline Wu Chih-Chen Tzang Hsiang Hong Yaoxing Huang Lawrence Shapiro Lihong Liu David D. Ho Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2 Nature Communications |
| title | Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2 |
| title_full | Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2 |
| title_fullStr | Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2 |
| title_full_unstemmed | Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2 |
| title_short | Optimizing a human monoclonal antibody for better neutralization of SARS-CoV-2 |
| title_sort | optimizing a human monoclonal antibody for better neutralization of sars cov 2 |
| url | https://doi.org/10.1038/s41467-025-61472-z |
| work_keys_str_mv | AT qianwang optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT yichengguo optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT ryangcasner optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT jianyu optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT manojsnair optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT jerrenho optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT eswarrreddem optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT ianamellis optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT madelinewu optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT chihchentzang optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT hsianghong optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT yaoxinghuang optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT lawrenceshapiro optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT lihongliu optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 AT daviddho optimizingahumanmonoclonalantibodyforbetterneutralizationofsarscov2 |