SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Barnes, Christopher O.; Jette, C.A.; Abernathy, Morgan E.; Dam, Kim-Marie A; Esswein, Shannon R.; Gristick, Harry B.; Malyutin, Andrey; Sharaf, Naima G.; Huey-Tubman, Kathryn E.; Lee, Yu E.; Robbiani, Davide F.; Nussenzweig, Michel C.; West, Anthony P.; Björkman, Pamela J.

doi:10.1038/s41586-020-2852-1

Cited by 1,521 publications

(2,314 citation statements)

References 78 publications

(100 reference statements)

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“…Overall, these structural analyses indicate that RBD rotational flexibility and acquisition of quaternary interactions can play an important role in CR3022 interaction with the S protein. CR3022 adds to the growing list of neutralization antibodies that can utilize quaternary interactions for binding to the S protein [12,36].…”

Section: Plos Pathogensmentioning

confidence: 99%

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Yuan

Bangaru

et al. 2020

PLoS Pathog

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Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that is able to cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential cross-neutralizing epitopes on SARS-like viruses.

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Section: Plos Pathogensmentioning

confidence: 99%

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Yuan

Bangaru

et al. 2020

PLoS Pathog

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“…The S RBDs can be in "down" or "up" conformations 14,15 , and ACE2 and IGHV3-53/3-66 neutralizing antibodies can only bind the RBD when it is "up" 8,16 . Although described IGHV3-53/3-66 neutralizing antibodies have short CDR H3 loops, some IGHV3-53 antibodies with longer CDR H3 loops can make contacts with neighboring RBDs to close the trimer 17 .…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2

Pan

et al. 2020

Preprint

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The SARS-CoV-2 viral spike (S) protein mediates attachment and entry into host cells and is a major target of vaccine and drug design. Potent SARS-CoV-2 neutralizing antibodies derived from closely related antibody heavy chain genes (IGHV3-53 or 3-66) have been isolated from multiple COVID-19 convalescent individuals. These usually contain minimal somatic mutations and bind the S receptor-binding domain (RBD) to interfere with attachment to the cellular receptor angiotensin-converting enzyme 2 (ACE2). We used antigen-specific single B cell sorting to isolate S-reactive monoclonal antibodies from the blood of a COVID-19 convalescent individual. The seven most potent neutralizing antibodies were somatic variants of the same IGHV3-53-derived antibody and bind the RBD with varying affinity. We report X-ray crystal structures of four Fab variants bound to the RBD and use the structures to explain the basis for changes in RBD affinity. We show that a germline revertant antibody binds tightly to the SARS-CoV-2 RBD and neutralizes virus, and that gains in affinity for the RBD do not necessarily correlate with increased neutralization potency, suggesting that somatic mutation is not required to exert robust antiviral effect. Our studies clarify the molecular basis for a heavily germline-biased human antibody response to SARS-CoV-2.

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“…To determine whether the antibodies expressed by memory B cells at the late time point also showed altered breadth, we compared them to earlier clonal relatives in binding assays using control and mutant RBDs: The mutations E484K and Q493R 15 were selected for resistance to class 2 antibodies such as C144 and C121 that bind directly to the ACE2 interaction ridge in the RBD 1,[16][17][18] while R346S, N439K, and N440K were selected for resistance to class 3 antibodies such as C135 that do not directly interfere with ACE2 binding 1,[15][16][17][18] (Fig.3c). In addition, V367F, A475V, S477N, and V483A represent circulating variants that confer complete or partial resistance to class 1 and 2 antibodies 15,16,19 (Fig. 3c).…”

mentioning

confidence: 99%

Evolution of Antibody Immunity to SARS-CoV-2

Gaebler

Wang

Lorenzi

et al. 2020

Preprint

Self Cite

178

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SARS-CoV-2 has infected 47 million individuals and is responsible for over 1.2 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 3 months after COVID-19 onset, using immunofluorescence, electron tomography or polymerase chain reaction, revealed persistence of SARS-CoV-2 in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Cited by 1,521 publications

References 78 publications

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2

Evolution of Antibody Immunity to SARS-CoV-2

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