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An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.

Publication ,  Journal Article
Luo, S; Zhang, J; Kreutzberger, AJB; Eaton, A; Edwards, RJ; Jing, C; Dai, H-Q; Sempowski, GD; Cronin, K; Parks, R; Ye, AY; Mansouri, K ...
Published in: Sci Immunol
October 28, 2022

SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several VH1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived VH1-2-based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy-based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.

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Published In

Sci Immunol

DOI

EISSN

2470-9468

Publication Date

October 28, 2022

Volume

7

Issue

76

Start / End Page

eadd5446

Location

United States

Related Subject Headings

  • Spike Glycoprotein, Coronavirus
  • SARS-CoV-2
  • Receptors, Antigen, B-Cell
  • Mice
  • Membrane Fusion
  • Humans
  • Epitopes
  • COVID-19
  • Antibodies, Viral
  • Antibodies, Neutralizing
 

Citation

APA
Chicago
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MLA
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Luo, S., Zhang, J., Kreutzberger, A. J. B., Eaton, A., Edwards, R. J., Jing, C., … Alt, F. W. (2022). An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion. Sci Immunol, 7(76), eadd5446. https://doi.org/10.1126/sciimmunol.add5446
Luo, Sai, Jun Zhang, Alex J. B. Kreutzberger, Amanda Eaton, Robert J. Edwards, Changbin Jing, Hai-Qiang Dai, et al. “An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.Sci Immunol 7, no. 76 (October 28, 2022): eadd5446. https://doi.org/10.1126/sciimmunol.add5446.
Luo S, Zhang J, Kreutzberger AJB, Eaton A, Edwards RJ, Jing C, et al. An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion. Sci Immunol. 2022 Oct 28;7(76):eadd5446.
Luo, Sai, et al. “An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.Sci Immunol, vol. 7, no. 76, Oct. 2022, p. eadd5446. Pubmed, doi:10.1126/sciimmunol.add5446.
Luo S, Zhang J, Kreutzberger AJB, Eaton A, Edwards RJ, Jing C, Dai H-Q, Sempowski GD, Cronin K, Parks R, Ye AY, Mansouri K, Barr M, Pishesha N, Williams AC, Vieira Francisco L, Saminathan A, Peng H, Batra H, Bellusci L, Khurana S, Alam SM, Montefiori DC, Saunders KO, Tian M, Ploegh H, Kirchhausen T, Chen B, Haynes BF, Alt FW. An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion. Sci Immunol. 2022 Oct 28;7(76):eadd5446.

Published In

Sci Immunol

DOI

EISSN

2470-9468

Publication Date

October 28, 2022

Volume

7

Issue

76

Start / End Page

eadd5446

Location

United States

Related Subject Headings

  • Spike Glycoprotein, Coronavirus
  • SARS-CoV-2
  • Receptors, Antigen, B-Cell
  • Mice
  • Membrane Fusion
  • Humans
  • Epitopes
  • COVID-19
  • Antibodies, Viral
  • Antibodies, Neutralizing