SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies
By C. Barnes, C. A. Jette, M. Abernathy, K. A. Dam, S. Esswein, H. Gristick, A. Malyutin, N. G. Sharaf, Kathryn E Huey-Tubman, Y. E. Lee and 4 more. 2020
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The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein1–5 show promise therapeutically and are being evaluated clinically6–8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to ‘up’ RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and ‘down’ RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs9. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2. Eight structures of human neutralizing antibodies that target the SARS-CoV-2 spike receptor-binding domain are reported and classified into four categories, suggesting combinations for clinical use.
Subfields: Infectious Diseases
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Citations in the corpus
- Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum (2022, positive): “S is the major target for neutralizing antibodies, and studies by a number of groups have isolated panels of monoclonal antibodies from infected or vaccinated volunteers (Barnes et al., 2020; Dejnirattisai et al., 2021a; Yuan et al., 2020a).”
- Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa (2020, neutral): “NAbs to the RBD can be broadly divided into four main classes 38 .”
- Title: Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice (2020, neutral): “trimer preparation used for immunizations (24).”
- mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant (2021, neutral): “Importantly, our spike did not contain R346K, which has been observed at relatively low frequency (<10%) within the Omicron lineage, but which is known to mediate escape from class 3 neutralizing monoclonal antibodies such as AZD1061/cilgavimab (Barnes et al., 2020; Dong et al., 2021; Greaney et al.”
- Early computational detection of potential high-risk SARS-CoV-2 variants (2021, methodology): “The 227 antibodies and corresponding 719 epitopes used were well distributed across different receptor-binding domain (RBD)-targeting antibody classes [17] and epitope classes [25] (Tables S2 and S3).”
- Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition (2020, positive): “In addition, anti-RBD antibodies often dominate the neutralizing activity of the polyclonal antibody response elicited by natural infection (Barnes et al., 2020a; Steffen et al., 2020; Weisblum et al., 2020) .”
- Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice (2021, neutral): “Individual responses that partly overlap the WNb binding site include P2B-2F6 (VH4-38, PDB: 7BWJ), 1 to 57 (VH3-72, PDB: 7LS9), C104 (VH4-34, PDB: 7K8U), and C110 (VH5-51, PDB: 7K8V), which overlap around residue Y449 and the 490 to 494 region (14, 58, 64).”