A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

By Yan Wu, Feiran Wang, Chenguang Shen, Weiyu Peng, Delin Li, Cheng Zhao, Z. Li, Shihua Li, Y. Bi, Yang Yang and 14 more. 2020

1,011 citations recorded by the source corpus.

An antibody defense against COVID-19 One of the responses of the immune system to invading viruses is the production of antibodies. Some of these are neutralizing, meaning that they prevent the virus from being infectious, and can thus be used to treat viral diseases. Wu et al. isolated four neutralizing antibodies from a convalescent coronavirus disease 2019 (COVID-19) patient. Two of the antibodies, B38 and H4, blocked the receptor binding domain (RBD) of the viral spike protein from binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). The structure of the RBD bound to B38 shows that the B38-binding site overlaps with the binding site for ACE2. Although H4 also blocks RBD binding to ACE2, it binds at a different site, and thus the two antibodies can bind simultaneously. This pair of antibodies could potentially be used together in clinical applications. Science, this issue p. 1274 A pair of neutralizing antibodies against COVID-19 bind to different epitopes to compete with cellular receptor binding. Neutralizing antibodies could potentially be used as antivirals against the coronavirus disease 2019 (COVID-19) pandemic. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. The antibodies B38 and H4 block binding between the spike glycoprotein receptor binding domain (RBD) of the virus and the cellular receptor angiotensin-converting enzyme 2 (ACE2). A competition assay indicated different epitopes on the RBD for these two antibodies, making them a potentially promising virus-targeting monoclonal antibody pair for avoiding immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.

Subfields: Infectious Diseases, Obstetrics and Gynecology

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In Infectious Diseases

1. D. Veesler
2. A. Walls
3. M. A. Tortorici
4. Jesse D. Bloom

Citations in the corpus

• Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “In Kymab Darwin mice, the nanoparticle vaccines had lower (better) ratios than S-2P–immunized mice, but higher than HCS (Figure 6E).”
• A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS (2020, positive): “, by passive transfer experiment) should be performed to further confirm whether the humoral response is sufficient to protect against CoV challenge, although our recent work by using human-origin monoclonal antibodies confirmed the passive protection (Shi et al., 2020; Wu et al., 2020).”
• Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice (2021, neutral): “Binding mode 1 antibodies, including B38 (60), recognize residues including K417 and Y489; some additionally contact N501 but do not interact with E484 or the WNb 2 contact regions 351 and 446 to 449.”
• Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, positive): “To better define the RBD’s evolutionary capacity for antibody escape, we examined mutational constraint in the epitopes of antibodies with available structures that bind the SARS-CoV-1 or SARS-CoV-2 RBD (Figures 7A, S7A,B) (Hwang et al., 2006; Pak et al., 2009; Pinto et al., 2020; Prabakaran et al.,”
• Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition (2020, neutral): “…studies showing that potent anti-RBD neutralizing antibodies often strongly compete with ACE2 binding (Brouwer et al., 2020; Cao et al., 2020; Huang et al., 2020; Ju et al., 2020; Liu et al., 2020; Rogers et al., 2020; Seydoux et al., 2020; Wec et al., 2020; Wu et al., 2020; Zost et al., 2020a) .”