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| Title | Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human V1-2-rearranging mouse models. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 123, Issue 13, Page e2537053123, Year 2026 |
| Publish date | Mar 31, 2026 |
 Authors | Himanshu Batra / Sai Luo / Kevin O Saunders / Jaclyn S Higgins / Fanchong Jian / Jun Zhang / Md Golam Kibria / G M Jonaid / Qingchen J Zhou / Amanda Eaton / Kenneth Cronin / Michael L Mallory / Melissa Mattocks / Robert J Edwards / Robert Parks / Esther M Lee / Adam Yongxin Ye / Aimee Chapdelaine Williams / Geeyoun Jung / Katayoun Mansouri / S Munir Alam / David C Montefiori / Ming Tian / Ralph S Baric / Yunlong Cao / Barton F Haynes / Bing Chen / Frederick W Alt /   |
| PubMed Abstract | During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 ...During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human V1-2 and Vκ1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single V1-2 rearranges to human D3-3 and J6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human V- and Vκ-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens. |
 External links | Proc Natl Acad Sci U S A / PubMed:41871249 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.68 - 3.0 Å |
| Structure data | EMDB-73392, PDB-9ysg: EMDB-73457, PDB-9ytc: |
| Chemicals |  ChemComp-NAG: |
| Source |
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 Keywords | VIRAL PROTEIN/IMMUNE SYSTEM / antibody / fab / broadly neutralizing / vdj recombination / humanized mouse model / cdr3 diversity / SARS-COV-2 / ANTIVIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex |
mus musculus (house mouse)
severe acute respiratory syndrome coronavirus