tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Runchu Zhao[SUP] #[/SUP][SUP] 4 5 [/SUP], Zhou Tong[SUP] #[/SUP][SUP] 4 6 [/SUP], Shuxin Guo[SUP] 7 [/SUP], Weiyu Peng[SUP] 8 [/SUP], Kefang Liu[SUP] 4 [/SUP], Shihua Li[SUP] 4 [/SUP], Lili Wu[SUP] 4 [/SUP], Jianyu Tong[SUP] 6 [/SUP], Yan Chai[SUP] 4 [/SUP], Pu Han[SUP] 4 [/SUP], Feiran Wang[SUP] 4 9 [/SUP], Peng Jia[SUP] 4 [/SUP], Zhaohui Li[SUP] 4 [/SUP], Xin Zhao[SUP] 4 [/SUP], Dedong Li[SUP] 4 [/SUP], Rong Zhang[SUP] 4 10 [/SUP], Xue Zhang[SUP] 11 [/SUP], Weiwei Zou[SUP] 11 [/SUP], Weiwei Li[SUP] 4 [/SUP], Qihui Wang[SUP] 3 4 [/SUP], George Fu Gao[SUP] 1 2 4 [/SUP], Yan Wu[SUP] 11 [/SUP], Lianpan Dai[SUP] 3 4 [/SUP], Feng Gao[SUP] 1 [/SUP]
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[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Runchu Zhao[SUP] #[/SUP][SUP] 4 5 [/SUP], Zhou Tong[SUP] #[/SUP][SUP] 4 6 [/SUP], Shuxin Guo[SUP] 7 [/SUP], Weiyu Peng[SUP] 8 [/SUP], Kefang Liu[SUP] 4 [/SUP], Shihua Li[SUP] 4 [/SUP], Lili Wu[SUP] 4 [/SUP], Jianyu Tong[SUP] 6 [/SUP], Yan Chai[SUP] 4 [/SUP], Pu Han[SUP] 4 [/SUP], Feiran Wang[SUP] 4 9 [/SUP], Peng Jia[SUP] 4 [/SUP], Zhaohui Li[SUP] 4 [/SUP], Xin Zhao[SUP] 4 [/SUP], Dedong Li[SUP] 4 [/SUP], Rong Zhang[SUP] 4 10 [/SUP], Xue Zhang[SUP] 11 [/SUP], Weiwei Zou[SUP] 11 [/SUP], Weiwei Li[SUP] 4 [/SUP], Qihui Wang[SUP] 3 4 [/SUP], George Fu Gao[SUP] 1 2 4 [/SUP], Yan Wu[SUP] 11 [/SUP], Lianpan Dai[SUP] 3 4 [/SUP], Feng Gao[SUP] 1 [/SUP]
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.