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TitleOptimizing a human monoclonal antibody for better neutralization of SARS-CoV-2.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 6195, Year 2025
Publish dateJul 4, 2025
AuthorsQian 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 /
PubMed AbstractSARS-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 ...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.
External linksNat Commun / PubMed:40615407 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.1 Å
Structure data

EMDB-45543, PDB-9cfe:
Cryo-EM Local Refinement of Antibody 19-77 in complex with prefusion SARS-CoV-2 Spike glycoprotein RBD
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-45544, PDB-9cff:
Cryo-EM Refinement of Antibody 19-77 in complex with SARS-CoV-2 HK.3 RBD
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-45545, PDB-9cfg:
Cryo-EM Refinement of Antibody 19-77 R71V in complex with SARS-CoV-2 HK.3 RBD
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-45546, PDB-9cfh:
Cryo-EM Refinement of Antibody 19-77 R71V in complex with SARS-CoV-2 JD.1.1 RBD
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-45548: Cryo-EM Refinement of Antibody 19-77 in complex with SARS-CoV-2 prefusion spike
Method: EM (single particle) / Resolution: 2.5 Å

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Neutralizing Antibody / Viral Fusion Protein / SARS-CoV-2 / VIRAL PROTEIN-IMMUNE SYSTEM complex / VIRAL PROTEIN

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