@article { doi:10.1126/sciimmunol.add5446,
	title = {An Antibody from Single Human VH-rearranging Mouse Neutralizes All SARS-CoV-2 Variants Through BA.5 by Inhibiting Membrane Fusion},
	journal = {Science Immunology},
	year = {2022},
	pages = {eadd5446},
	abstract = {SARS-CoV-2 Omicron sub-variants have generated a world-wide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron sub-variants and prepare for potential new variants, 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 complementarity-region-3 (CDR3) sequences generated by non-templated junctional modifications during V(D)J recombination. Immunizing the human VH1-2/Vκ1-33-rearranging 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 human 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 non-traditonal mechanism of action suggest this antibody might have therapeutic potential. Likewise, the SP1-77 binding epitope may further inform on vacccine strategies. Finally, the general class of humanized mouse models we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens. A humanized antibody from a recently-developed mouse model potently neutralizes SARS-CoV-2 variants by inhibiting membrane fusion.},
	doi = {10.1126/sciimmunol.add5446},
	url = {https://www.science.org/doi/abs/10.1126/sciimmunol.add5446},
	author = {Sai Luo and Zhang, Jun and Alex J.B. Kreutzberger and Amanda Eaton and Robert J. Edwards and Changbin Jing and Hai-Qiang Dai and Gregory D. Sempowski and Kenneth Cronin and Robert Parks and Ye, Adam Yongxin and Katayoun Mansouri and Maggie Barr and Pishesha, Novalia and Aimee Chapdelaine Williams and Lucas Vieira Francisco and Anand Saminathan and Peng, Hanqin and Himanshu Batra and Lorenza Bellusci and Surender Khurana and S. Munir Alam and David C. Montefiori and Kevin O. Saunders and Tian, Ming and Ploegh, Hidde and Tom Kirchhausen and Chen, Bing and Barton F. Haynes and Frederick W. Alt}
}
