Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody

Abstract

The SARS-CoV-2 BA.1 and BA.2 (Omicron) variants contain more than 30 mutations within the spike protein and evade therapeutic monoclonal antibodies (mAbs). Here, we report a receptor-binding domain (RBD) targeting human antibody (002-S21F2) that effectively neutralizes live viral isolates of SARS-CoV-2 variants of concern (VOCs) including Alpha, Beta, Gamma, Delta, and Omicron (BA.1 and BA.2) with IC50 ranging from 0.02 – 0.05 μg/ml. This near germline antibody 002-S21F2 has unique genetic features that are distinct from any reported SARS-CoV-2 mAbs. Structural studies of the full-length IgG in complex with spike trimers (Omicron and WA.1) reveal that 002-S21F2 recognizes an epitope on the outer face of RBD (class-3 surface), outside the ACE2 binding motif and its unique molecular features enable it to overcome mutations found in the Omicron variants. The discovery and comprehensive structural analysis of 002-S21F2 provide valuable insight for broad and potent neutralization of SARS-CoV-2 Omicron variants BA.1 and BA.2.

SARS-CoV-2 neutralizing antibody bebtelovimab – a systematic scoping review and meta-analysis

“…The remaining 5 studies were clinical research ( 18 , 53 – 56 ), comprising randomized controlled trial ( 53 ) and retrospective cohort studies ( 18 , 54 – 56 ). 17 studies were conducted in the United States ( 28 , 30 , 34 , 35 , 38 , 42 , 45 , 49 , 50 , 56 ), 8 in China ( 19 , 23 – 26 , 31 , 48 ), 7 in Europe ( 20 – 22 , 29 , 36 , 37 , 41 ), 4 in Japan ( 39 , 40 , 46 , 47 ), 2 in India ( 32 , 51 ), and 1 across three countries, namely United States, Argentina, and Puerto Rico ( 53 ). A summary of the main characteristics of each individual study is outlined in Tables 1 , 2 .…”

Broadly Neutralizing Antibodies to SARS-CoV-2 Provide Novel Insights Into the Neutralization of Variants and Other Human Coronaviruses

“…Therefore, for the treatment of Omicron infected patients, US-FDA has provided emergency use authorization (EUA) to a class III or RBD-5 targeting bnAb Bebtelovimab (or LyCoV1404) in Feb 2022 that maintains its potency and neutralizes all SARS-CoV-2 VOCs ( Westendorf et al., 2022 ). Currently, majority of the RBD class III mAbs (Bebtelovimab, 002-S21F2 and Sotrovimab) binding the outer RBD region have shown highest effectiveness against Omicron variants ( Kumar et al., 2022 ; Zhou T. et al., 2022 ). Interestingly, though Omicron mutations are present in the epitope regions of Bebtelovimab and 002-S21F2 SARS-CoV-2 bnAbs, no loss in potency have been reported ( Kumar et al., 2022 ; Westendorf et al., 2022 ).…”

“…Currently, majority of the RBD class III mAbs (Bebtelovimab, 002-S21F2 and Sotrovimab) binding the outer RBD region have shown highest effectiveness against Omicron variants ( Kumar et al., 2022 ; Zhou T. et al., 2022 ). Interestingly, though Omicron mutations are present in the epitope regions of Bebtelovimab and 002-S21F2 SARS-CoV-2 bnAbs, no loss in potency have been reported ( Kumar et al., 2022 ; Westendorf et al., 2022 ). This has been explained in their structural studies showing that Omicron mutations in their targeted regions are either favoring the binding by making favorable interaction or not a part of epitope residues targeted by Bebtelovimab and 002-S21F2 bnAbs ( Kumar et al., 2022 ; Zhou T. et al., 2022 ).…”

“…Interestingly, though Omicron mutations are present in the epitope regions of Bebtelovimab and 002-S21F2 SARS-CoV-2 bnAbs, no loss in potency have been reported ( Kumar et al., 2022 ; Westendorf et al., 2022 ). This has been explained in their structural studies showing that Omicron mutations in their targeted regions are either favoring the binding by making favorable interaction or not a part of epitope residues targeted by Bebtelovimab and 002-S21F2 bnAbs ( Kumar et al., 2022 ; Zhou T. et al., 2022 ). This suggests that understanding the structural basis of bnAbs mediated neutralization mechanism of immune evading viruses can provide blueprints to guide structural-based therapeutics and vaccine design by employing affinity maturation through directed evolution, CDRH3 swapping and Reverse Vaccinology 2.0 approaches, respectively ( Burton, 2017 ; Kadam et al., 2017 ; Traboulsi et al., 2021 ; Zhao et al., 2021 ; Zupancic et al., 2021 ).…”

“…Targeted NAb epitopes of RBD specific class I to class IV and therapeutic NAbs (marked in asterisks) along with ACE2 contacts, RBD mutations and Omicron mutations are highlighted. Information of contact residues for each mAb shown here was obtained from previously reported studies ( Greaney et al., 2022 ; Kumar et al., 2022 ; Zhou T. et al., 2022 ). (D) Mutations identified among the key SARS-CoV-2 variants from Alpha to Omicron documented in CoVariants database ( Elbe and Buckland-Merrett, 2017 ) is represented as a Shannon entropy plot.…”