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Proc Natl Acad Sci U S A
. 2023 Dec 26;120(52):e2314193120.
doi: 10.1073/pnas.2314193120. Epub 2023 Dec 18. Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2
Xia Rao # 1 2 3 , Runchu Zhao # 4 5 , Zhou Tong # 4 6 , Shuxin Guo 7 , Weiyu Peng 8 , Kefang Liu 4 , Shihua Li 4 , Lili Wu 4 , Jianyu Tong 6 , Yan Chai 4 , Pu Han 4 , Feiran Wang 4 9 , Peng Jia 4 , Zhaohui Li 4 , Xin Zhao 4 , Dedong Li 4 , Rong Zhang 4 10 , Xue Zhang 11 , Weiwei Zou 11 , Weiwei Li 4 , Qihui Wang 3 4 , George Fu Gao 1 2 4 , Yan Wu 11 , Lianpan Dai 3 4 , Feng Gao 1
Affiliations
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.
Keywords: Omicron BA.4/BA.5/BQ.1.1/XBB subvariants; RBD-8; SARS-CoV-2; cryptic epitope; neutralizing antibody.
. 2023 Dec 26;120(52):e2314193120.
doi: 10.1073/pnas.2314193120. Epub 2023 Dec 18. Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2
Xia Rao # 1 2 3 , Runchu Zhao # 4 5 , Zhou Tong # 4 6 , Shuxin Guo 7 , Weiyu Peng 8 , Kefang Liu 4 , Shihua Li 4 , Lili Wu 4 , Jianyu Tong 6 , Yan Chai 4 , Pu Han 4 , Feiran Wang 4 9 , Peng Jia 4 , Zhaohui Li 4 , Xin Zhao 4 , Dedong Li 4 , Rong Zhang 4 10 , Xue Zhang 11 , Weiwei Zou 11 , Weiwei Li 4 , Qihui Wang 3 4 , George Fu Gao 1 2 4 , Yan Wu 11 , Lianpan Dai 3 4 , Feng Gao 1
Affiliations
- PMID: 38109549
- DOI: 10.1073/pnas.2314193120
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.
Keywords: Omicron BA.4/BA.5/BQ.1.1/XBB subvariants; RBD-8; SARS-CoV-2; cryptic epitope; neutralizing antibody.