National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
P01 AI144462
米国
Bill & Melinda Gates Foundation
OPP1170236
米国
引用
ジャーナル: J Clin Invest / 年: 2024 タイトル: Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV. 著者: Naveenchandra Suryadevara / Nurgun Kose / Sandhya Bangaru / Elad Binshtein / Jennifer Munt / David R Martinez / Alexandra Schäfer / Luke Myers / Trevor D Scobey / Robert H Carnahan / Andrew ...著者: Naveenchandra Suryadevara / Nurgun Kose / Sandhya Bangaru / Elad Binshtein / Jennifer Munt / David R Martinez / Alexandra Schäfer / Luke Myers / Trevor D Scobey / Robert H Carnahan / Andrew B Ward / Ralph S Baric / James E Crowe / 要旨: The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the ...The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute, in part, to protective immunity. Pansarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a high level of sequence divergence; therefore, cross-reactive NTD-specific antibodies are unexpected, and there is no structure of a SARS-CoV NTD-specific antibody in complex with NTD. Here, we report a monoclonal antibody COV1-65, encoded by the IGHV1-69 gene, that recognizes the NTD of SARS-CoV S protein. A prophylaxis study showed the mAb COV1-65 prevented disease when administered before SARS-CoV challenge of BALB/c mice, an effect that requires intact fragment crystallizable region (Fc) effector functions for optimal protection in vivo. The footprint on the S protein of COV1-65 is near to functional components of the S2 fusion machinery, and the selection of COV1-65 escape mutant viruses identified critical residues Y886H and Q974H, which likely affect the epitope through allosteric effects. Structural features of the mAb COV1-65-SARS-CoV antigen interaction suggest critical antigenic determinants that should be considered in the rational design of sarbecovirus vaccine candidates.