2. Academic Validation
  3. A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection

A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection

  • Cell Rep Med. 2023 Dec 19;4(12):101305. doi: 10.1016/j.xcrm.2023.101305.
Lucas J Adams 1,  Laura A VanBlargan 2,  Zhuoming Liu 3,  Pavlo Gilchuk 4,  Haiyan Zhao 1,  Rita E Chen 5,  Saravanan Raju 1,  Zhenlu Chong 2,  Bradley M Whitener 2,  Swathi Shrihari 2,  Prashant N Jethva 6,  Michael L Gross 6,  James E Crowe Jr 4,  Sean P J Whelan 3,  Michael S Diamond 7,  Daved H Fremont 8
Affiliations

Affiliations

  • 1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Department of Molecular Microbiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
  • 4 Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 5 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 6 Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
  • 7 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
  • 8 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
PMID: 38039973 DOI: 10.1016/j.xcrm.2023.101305
Abstract

Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or Other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 Infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape.

Keywords

B cell epitope mapping; SARS-CoV-2; cryo-EM; neutralizing antibodies; variants of concern.

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