1. Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity.
- Author
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Jensen JL, Sankhala RS, Dussupt V, Bai H, Hajduczki A, Lal KG, Chang WC, Martinez EJ, Peterson CE, Golub ES, Rees PA, Mendez-Rivera L, Zemil M, Kavusak E, Mayer SV, Wieczorek L, Kannan S, Doranz BJ, Davidson E, Yang ES, Zhang Y, Chen M, Choe M, Wang L, Gromowski GD, Koup RA, Michael NL, Polonis VR, Rolland M, Modjarrad K, Krebs SJ, and Joyce MG
- Subjects
- Humans, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal metabolism, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing metabolism, SARS-CoV-2 chemistry, SARS-CoV-2 metabolism, Protein Domains, Crystallography, X-Ray, Protein Structure, Quaternary, Models, Molecular, Cell Line, Antibodies, Viral chemistry, Antibodies, Viral metabolism, COVID-19, Epitopes chemistry, Severe acute respiratory syndrome-related coronavirus chemistry
- Abstract
Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target. IMPORTANCE Characterization of MAbs against SARS-CoV-2, elicited through vaccination or natural infection, has provided vital immunotherapeutic options for curbing the COVID-19 pandemic and has supplied critical insights into SARS-CoV-2 escape, transmissibility, and mechanisms of viral inactivation. Neutralizing MAbs that target the RBD but do not block ACE2 binding are of particular interest because the epitopes are well conserved within sarbecoviruses and MAbs targeting this area demonstrate cross-reactivity. The class V RBD-targeted MAbs localize to an invariant site of vulnerability, provide a range of neutralization potency, and exhibit considerable breadth against divergent sarbecoviruses, with implications for vaccine and therapeutic development., Competing Interests: The authors declare a conflict of interest. Patent application number PCT/US 63/140,763, PCT WO 2022/159839 A1 was filed containing the mAbs described in this publication for authors S.J.K., K.M., V.D., and N.L.M. M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” The other authors declare no competing interests.
- Published
- 2023
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