7UPY

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

7UPY の概要

• エントリーDOI: 10.2210/pdb7upy/pdb
• EMDBエントリー: 26678
• 分子名称: Spike glycoprotein, SP1-77 Fab heavy chain, SP1-77 Fab light chain, ... (7 entities in total)
• 機能のキーワード: viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus; 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 675795.01

構造登録者

Zhang, J.,Luo, S.,Kreutzberger, A.,Kirchhausen, T.,Chen, B.,Haynes, B.,Alt, F. (登録日: 2022-04-18, 公開日: 2022-08-10, 最終更新日: 2024-11-20)

主引用文献

Luo, S.,Zhang, J.,Kreutzberger, A.J.B.,Eaton, A.,Edwards, R.J.,Jing, C.,Dai, H.Q.,Sempowski, G.D.,Cronin, K.,Parks, R.,Ye, A.Y.,Mansouri, K.,Barr, M.,Pishesha, N.,Williams, A.C.,Vieira Francisco, L.,Saminathan, A.,Peng, H.,Batra, H.,Bellusci, L.,Khurana, S.,Alam, S.M.,Montefiori, D.C.,Saunders, K.O.,Tian, M.,Ploegh, H.,Kirchhausen, T.,Chen, B.,Haynes, B.F.,Alt, F.W.
An antibody from single human V H -rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.
Sci Immunol, 7:eadd5446-eadd5446, 2022

PubMed Abstract: 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.

PubMed: 35951767
DOI: 10.1126/sciimmunol.add5446

実験手法

ELECTRON MICROSCOPY (3.1 Å)