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Structural mechanism of SARS-CoV-2 neutralization by two murine antibodies targeting the RBD.
<div class='caption-title'>Anti-SARS-CoV-2 mAbs 2B04 and 2H04 bind to the RBD of the trimeric spike (S) protein</div>
<div class='caption-title'>2B04 and 2H04 target distinct epitopes on the RBD</div>
Errico JM, Zhao H, Chen RE, Liu Z, Case JB, Ma M, Schmitz AJ, Rau MJ, Fitzpatrick JAJ, Shi PY, Diamond MS, Whelan SPJ, Ellebedy AH, Fremont DH
OpenAccess logo Cell Rep 37 109881 (2021)
Related entries: 7k9i, 7k9j, 7k9k

Cited: 16 times
EuropePMC logo PMID: 34655519

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has necessitated the rapid development of antibody-based therapies and vaccines as countermeasures. Here, we use cryoelectron microscopy (cryo-EM) to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies (mAbs) in complex with the spike protein, revealing similarities between epitopes targeted by human and murine B cells. The more neutralizing mAb, 2B04, binds the receptor-binding motif (RBM) of the receptor-binding domain (RBD) and competes with angiotensin-converting enzyme 2 (ACE2). By contrast, 2H04 binds adjacent to the RBM and does not compete for ACE2 binding. Naturally occurring sequence variants of SARS-CoV-2 and corresponding neutralization escape variants selected in vitro map to our structurally defined epitopes, suggesting that SARS-CoV-2 might evade therapeutic antibodies with a limited set of mutations, underscoring the importance of combination mAb therapeutics. Finally, we show that 2B04 neutralizes SARS-CoV-2 infection by preventing ACE2 engagement, whereas 2H04 reduces host cell attachment without directly disrupting ACE2-RBM interactions, providing distinct inhibitory mechanisms used by RBD-specific mAbs.

Articles - 7k9h mentioned but not cited (4)

  1. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Liu Z, VanBlargan LA, Bloyet LM, Rothlauf PW, Chen RE, Stumpf S, Zhao H, Errico JM, Theel ES, Liebeskind MJ, Alford B, Buchser WJ, Ellebedy AH, Fremont DH, Diamond MS, Whelan SPJ. Cell Host Microbe 29 477-488.e4 (2021)
  2. Structural mechanism of SARS-CoV-2 neutralization by two murine antibodies targeting the RBD. Errico JM, Zhao H, Chen RE, Liu Z, Case JB, Ma M, Schmitz AJ, Rau MJ, Fitzpatrick JAJ, Shi PY, Diamond MS, Whelan SPJ, Ellebedy AH, Fremont DH. Cell Rep 37 109881 (2021)
  3. Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against SARS-CoV-2 Omicron variants. Chi X, Xia L, Zhang G, Chi X, Huang B, Zhang Y, Chen Z, Han J, Wu L, Li Z, Sun H, Huang P, Yu C, Chen W, Zhou Q. Cell Discov 9 37 (2023)
  4. research-article Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces. Lubin JH, Markosian C, Balamurugan D, Pasqualini R, Arap W, Burley SK, Khare SD. bioRxiv 2021.12.12.472313 (2021)


Reviews citing this publication (5)

  1. SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion. Quaglia F, Salladini E, Carraro M, Minervini G, Tosatto SCE, Le Mercier P. FEBS J 289 4240-4250 (2022)
  2. Evolution of SARS-CoV-2 Variants: Implications on Immune Escape, Vaccination, Therapeutic and Diagnostic Strategies. Zabidi NZ, Liew HL, Farouk IA, Puniyamurti A, Yip AJW, Wijesinghe VN, Low ZY, Tang JW, Chow VTK, Lal SK. Viruses 15 944 (2023)
  3. Importance, Applications and Features of Assays Measuring SARS-CoV-2 Neutralizing Antibodies. Gattinger P, Ohradanova-Repic A, Valenta R. Int J Mol Sci 24 5352 (2023)
  4. Antibody-mediated immunity to SARS-CoV-2 spike. Errico JM, Adams LJ, Fremont DH. Adv Immunol 154 1-69 (2022)
  5. A structural view of the SARS-CoV-2 virus and its assembly. Hardenbrook NJ, Zhang P. Curr Opin Virol 52 123-134 (2022)

Articles citing this publication (7)

  1. Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice. Hunt AC, Case JB, Park YJ, Cao L, Wu K, Walls AC, Liu Z, Bowen JE, Yeh HW, Saini S, Helms L, Zhao YT, Hsiang TY, Starr TN, Goreshnik I, Kozodoy L, Carter L, Ravichandran R, Green LB, Matochko WL, Thomson CA, Vögeli B, Krüger A, VanBlargan LA, Chen RE, Ying B, Bailey AL, Kafai NM, Boyken SE, Ljubetič A, Edman N, Ueda G, Chow CM, Johnson M, Addetia A, Navarro MJ, Panpradist N, Gale M, Freedman BS, Bloom JD, Ruohola-Baker H, Whelan SPJ, Stewart L, Diamond MS, Veesler D, Jewett MC, Baker D. Sci Transl Med 14 eabn1252 (2022)
  2. An antibody that neutralizes SARS-CoV-1 and SARS-CoV-2 by binding to a conserved spike epitope outside the receptor binding motif. Fang Y, Sun P, Xie X, Du M, Du F, Ye J, Kalveram BK, Plante JA, Plante KS, Li B, Bai XC, Shi PY, Chen ZJ. Sci Immunol 7 eabp9962 (2022)
  3. A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection. Adams LJ, VanBlargan LA, Liu Z, Gilchuk P, Zhao H, Chen RE, Raju S, Chong Z, Whitener BM, Shrihari S, Jethva PN, Gross ML, Crowe JE, Whelan SPJ, Diamond MS, Fremont DH. Cell Rep Med 4 101305 (2023)
  4. Addition of arginine hydrochloride and proline to the culture medium enhances recombinant protein expression in Brevibacillus choshinensis: The case of RBD of SARS-CoV-2 spike protein and its antibody. Matsunaga R, Tsumoto K. Protein Expr Purif 194 106075 (2022)
  5. Cryptic-site-specific antibodies to the SARS-CoV-2 receptor binding domain can retain functional binding affinity to spike variants. Li K, Huntwork RHC, Horn GQ, Abraha M, Hastie KM, Li H, Rayaprolu V, Olmedillas E, Feeney E, Cronin K, Schendel SL, Heise M, Bedinger D, Mattocks MD, Baric RS, Alam SM, Ollmann Saphire E, Tomaras GD, Dennison SM. J Virol 97 e0107023 (2023)
  6. Emergence of SARS-CoV-2 serotype(s): Is it a matter of time? Silva Júnior JVJ, Durães-Carvalho R, de Souza JR, Ramos Janini LM, Weiblen R, Flores EF. Virology 585 78-81 (2023)
  7. Production of neutralizing antibody fragment variants in the cytoplasm of E. coli for rapid screening: SARS-CoV-2 a case study. Tungekar AA, Recacha R, Ruddock LW. Sci Rep 13 4408 (2023)


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