Mary Wilson
Well-known member
11 Aug 2022
First Release
DOI: 10.1126/sciimmunol.add5446
SAI LUO, JUN ZHANG, ALEX J.B. KREUTZBERGER, AMANDA EATON, ROBERT J. EDWARDS, CHANGBIN JING, 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 3, DAVID C. MONTEFIORI, KEVIN O. SAUNDERS, MING TIAN, HIDDE PLOEGH, TOM KIRCHHAUSEN, BING CHEN, BARTON F. HAYNES, AND FREDERICK W. ALT
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 V[SUB]H[/SUB]1-2 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 V[SUB]H[/SUB]1-2/Vκ1-33-rearranging mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several V[SUB]H[/SUB]1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior human patient-derived V[SUB]H[/SUB]1-2-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.
https://www.science.org/doi/10.1126/sciimmunol.add5446#.YvfezBNP7Nk.twitter
First Release
DOI: 10.1126/sciimmunol.add5446
SAI LUO, JUN ZHANG, ALEX J.B. KREUTZBERGER, AMANDA EATON, ROBERT J. EDWARDS, CHANGBIN JING, 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 3, DAVID C. MONTEFIORI, KEVIN O. SAUNDERS, MING TIAN, HIDDE PLOEGH, TOM KIRCHHAUSEN, BING CHEN, BARTON F. HAYNES, AND FREDERICK W. ALT
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 V[SUB]H[/SUB]1-2 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 V[SUB]H[/SUB]1-2/Vκ1-33-rearranging mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several V[SUB]H[/SUB]1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior human patient-derived V[SUB]H[/SUB]1-2-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.
https://www.science.org/doi/10.1126/sciimmunol.add5446#.YvfezBNP7Nk.twitter