Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2
Currently, monoclonal antibodies (MAbs) targeting the SARS-CoV-2 receptor binding domain (RBD) of spike (S) protein are classified into seven classes based on their binding epitopes. However, most of these antibodies are seriously impaired by SARS-CoV-2 Omicron and its subvariants, especially the recent BQ.1.1, XBB and its derivatives. Identification of broadly neutralizing MAbs against currently circulating variants is imperative. In this study, we identified a "breathing" cryptic epitope in the S protein, named as RBD-8. Two human MAbs, BIOLS56 and IMCAS74, were isolated recognizing this epitope with broad neutralization abilities against tested sarbecoviruses, including SARS-CoV, pangolin-origin coronaviruses, and all the SARS-CoV-2 variants tested (Omicron BA.4/BA.5, BQ.1.1, and XBB subvariants). Searching through the literature, some more RBD-8 MAbs were defined. More importantly, BIOLS56 rescues the immune-evaded antibody, RBD-5 MAb IMCAS-L4.65, by making a bispecific MAb, to neutralize BQ.1 and BQ.1.1, thereby producing an MAb to cover all the currently circulating Omicron subvariants. Structural analysis reveals that the neutralization effect of RBD-8 antibodies depends on the extent of epitope exposure, which is affected by the angle of antibody binding and the number of up-RBDs induced by angiotensin-converting enzyme 2 binding. This cryptic epitope which recognizes non- receptor binding motif (non-RBM) provides guidance for the development of universal therapeutic antibodies and vaccines against COVID-19.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 120(2023), 52 vom: 26. Dez., Seite e2314193120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rao, Xia [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.12.2023 Date Revised 31.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2314193120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Rao, Xia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2 |
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| 500 | |a Date Revised 31.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Currently, monoclonal antibodies (MAbs) targeting the SARS-CoV-2 receptor binding domain (RBD) of spike (S) protein are classified into seven classes based on their binding epitopes. However, most of these antibodies are seriously impaired by SARS-CoV-2 Omicron and its subvariants, especially the recent BQ.1.1, XBB and its derivatives. Identification of broadly neutralizing MAbs against currently circulating variants is imperative. In this study, we identified a "breathing" cryptic epitope in the S protein, named as RBD-8. Two human MAbs, BIOLS56 and IMCAS74, were isolated recognizing this epitope with broad neutralization abilities against tested sarbecoviruses, including SARS-CoV, pangolin-origin coronaviruses, and all the SARS-CoV-2 variants tested (Omicron BA.4/BA.5, BQ.1.1, and XBB subvariants). Searching through the literature, some more RBD-8 MAbs were defined. More importantly, BIOLS56 rescues the immune-evaded antibody, RBD-5 MAb IMCAS-L4.65, by making a bispecific MAb, to neutralize BQ.1 and BQ.1.1, thereby producing an MAb to cover all the currently circulating Omicron subvariants. Structural analysis reveals that the neutralization effect of RBD-8 antibodies depends on the extent of epitope exposure, which is affected by the angle of antibody binding and the number of up-RBDs induced by angiotensin-converting enzyme 2 binding. This cryptic epitope which recognizes non- receptor binding motif (non-RBM) provides guidance for the development of universal therapeutic antibodies and vaccines against COVID-19 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Omicron BA.4/BA.5/BQ.1.1/XBB subvariants | |
| 650 | 4 | |a RBD-8 | |
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| 650 | 4 | |a cryptic epitope | |
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| 700 | 1 | |a Zhao, Runchu |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Zhou |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Shuxin |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Weiyu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Kefang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shihua |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Lili |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Jianyu |e verfasserin |4 aut | |
| 700 | 1 | |a Chai, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Pu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Feiran |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhaohui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Dedong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xue |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Weiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Weiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qihui |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, George Fu |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Lianpan |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Feng |e verfasserin |4 aut | |
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