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TitleAn antibody from single human V-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.
Journal, issue, pagesSci Immunol, Vol. 7, Issue 76, Page eadd5446, Year 2022
Publish dateOct 28, 2022
AuthorsSai Luo / Jun Zhang / Alex J B Kreutzberger / Amanda Eaton / Robert J Edwards / Changbin Jing / Hai-Qiang Dai / Gregory D Sempowski / Kenneth Cronin / Robert Parks / Adam Yongxin Ye / Katayoun Mansouri / Maggie Barr / Novalia Pishesha / Aimee Chapdelaine Williams / Lucas Vieira Francisco / Anand Saminathan / Hanqin Peng / Himanshu Batra / Lorenza Bellusci / Surender Khurana / S Munir Alam / David C Montefiori / Kevin O Saunders / Ming Tian / Hidde Ploegh / Tom Kirchhausen / Bing Chen / Barton F Haynes / Frederick W Alt /
PubMed AbstractSARS-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 ...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 V1-2 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 V1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived V1-2-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.
External linksSci Immunol / PubMed:35951767 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 15.0 Å
Structure data

26676

7upw

EMDB-26676, PDB-7upw:
Three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment
Method: EM (single particle) / Resolution: 2.7 Å

26677

7upx

EMDB-26677, PDB-7upx:
Three RBD-down state of SARS-CoV-2 D614G spike in complex with the SP1-77 neutralizing antibody Fab fragment (local refinement of the RBD and Fab variable domains)
Method: EM (single particle) / Resolution: 3.2 Å

26678

7upy

EMDB-26678, PDB-7upy:
An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-27043: Negative stain electron microscopy single particle reconstruction of monoclonal antibody SP1-77 Fab in complex with SARS-CoV2 2P spike
Method: EM (single particle) / Resolution: 15.0 Å

EMDB-27044: Negative stain electron microscopy single particle reconstruction of monoclonal antibody VHH7-7-53 Fab in complex with SARS-CoV2 2P spike
Method: EM (single particle) / Resolution: 14.2 Å

EMDB-27046: Negative stain electron microscopy single particle reconstruction of monoclonal antibody VHH7-5-82 Fab in complex with SARS-CoV2 2P spike
Method: EM (single particle) / Resolution: 13.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus
  • homo sapiens (human)
  • Severe acute respiratory syndrome coronavirus 2
  • mus musculus (house mouse)
KeywordsVIRAL PROTEIN

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