9BJ4

Structure of the SARS-CoV-2 S 6P trimer complex with the human neutralizing antibody Fab fragment, C952

Summary for 9BJ4

• Entry DOI: 10.2210/pdb9bj4/pdb
• EMDB information: 44629
• Descriptor: Spike glycoprotein, C952 Heavy Chain, C952 Light Chain, ... (4 entities in total)
• Functional Keywords: antiviral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 9
• Total formula weight: 583870.45

Authors

Rubio, A.A.,Abernathy, M.E.,Barnes, C.O. (deposition date: 2024-04-24, release date: 2025-03-05, Last modification date: 2025-03-19)

Primary citation

Rubio, A.A.,Baharani, V.A.,Dadonaite, B.,Parada, M.,Abernathy, M.E.,Wang, Z.,Lee, Y.E.,Eso, M.R.,Phung, J.,Ramos, I.,Chen, T.,El Nesr, G.,Bloom, J.D.,Bieniasz, P.D.,Nussenzweig, M.C.,Barnes, C.O.
Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern.
Sci Transl Med, 17:eadq5720-eadq5720, 2025

PubMed Abstract: The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.

PubMed: 40043139
DOI: 10.1126/scitranslmed.adq5720

Experimental method

ELECTRON MICROSCOPY (3.4 Å)