In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains

Chen, Rita E.; Winkler, Emma S.; Case, James Brett; Aziati, Ishmael D.; Bricker, Traci L.; Joshi, Astha; Darling, Tamarand L.; Bai, Ying; Errico, John M.; Shrihari, Swathi; VanBlargan, Laura A.; Xie, Xuping; Gilchuk, Pavlo; Zost, Seth J.; Droit, Lindsay; Liu, Zhuoming; Stumpf, Spencer; Wang, David; Handley, Scott A.; Stine, W. Blaine; Shi, Pei Yong; Davis-Gardner, Meredith E.; Suthar, Mehul S.; Garcia-Knight, Miguel; Andino, Raul; Chiu, Charles Y.; Ellebedy, Ali H.; Fremont, Daved H.; Whelan, Sean P. J.; Crowe, James E.; Purcell, Lisa A.; Corti, Davide; Boon, Adrianus C. M.; Diamond, Michael S.

doi:10.1038/s41586-021-03720-y

Cited by 241 publications

(217 citation statements)

References 46 publications

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“…Additional mutations within the receptor-binding site (K417N and E484K) changed the amino acid sequence of the epitope and may contribute to the escape from antibody binding. Thus, a higher vaccine-induced antibody titer or neutralizing antibodies of higher affinity are needed to compete for the RBD N501Y –ACE2 interaction ( Chen et al, 2021 ; Focosi and Maggi, 2021 ). This will make the current vaccine less effective against SARS-CoV-2 variants that contain the N501Y mutation.…”

Section: Discussionmentioning

confidence: 99%

N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

Tian

Tong

Sun

et al. 2021

eLife

298

220

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SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD–ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD–ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.

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Section: Discussionmentioning

confidence: 99%

N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

Tian

Tong

Sun

et al. 2021

eLife

298

220

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“…Lethal CNS invasion, combined with the absence of severe pulmonary hallmarks associated with lethal COVID-19, therefore calls for attentive caution when utilizing the K18-hACE2 mouse model to investigate certain aspects of SARS-CoV-2 pulmonary pathogenesis. Furthermore, due to the acute and fulminant neuroinvasion of this model, the protective ability of anti-viral therapies and T-cell based vaccines against lethal challenge in this model might indeed be underestimated, which is reflected in several studies that have utilized terminal timepoints proceeding neuroinvasion as their efficacy endpoints (58–60). Regardless, the K18-hACE2 mouse model represents a promising model for understanding the mechanisms governing SARS-CoV-2 neuroinvasion, ACE2-independent virus entry, and evaluating potent and fast-acting prophylactic countermeasures.…”

Section: Discussionmentioning

confidence: 99%

Fatal neuroinvasion and SARS-CoV-2 tropism in K18-hACE2 mice is partially independent on hACE2 expression

Carossino

Montanaro

O'Connell

et al. 2021

Preprint

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Animal models recapitulating the distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. However, the cause(s) and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate inflammation in the lungs, lethality was invariably associated with viral neuroinvasion and neuronal damage (including spinal motor neurons). Neuroinvasion occurred following virus transport through the olfactory neuroepithelium in a manner that was only partially dependent on hACE2. Interestingly, SARS-CoV-2 tropism was overall neither widespread among nor restricted to only ACE2-expressing cells. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis.SUMMARYCOVID-19 is a respiratory disease caused by SARS-CoV-2, a betacoronavirus. Here, we show that in a widely used transgenic mouse model of COVID-19, lethality is invariably associated with viral neuroinvasion and the ensuing neuronal disease, while lung inflammation remains moderate.

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“…Even though these nanobodies make contacts with sites of circulating variants K417, L452 and E484, our results showed that these positions can be quite tolerant to mutations (Supporting Information, Figure S4). Interestingly, mutations L452R and T478K of B.617.2 lineage that can induce escape to neutralizing antibodies targeting the NTD and RBD 63, 64 resulted in relatively moderate binding energy losses for the biparatopic nanobody (Figure 5C,D). This is consistent with the observed effectiveness of the nanobodies against these antigenic variants.…”

Section: Resultsmentioning

confidence: 99%

“…61, 62 Highly transmissible SARS-CoV-2 variants with the increased affinity for ACE2 were discovered in lineage B.1.617 that encodes for mutations L452R, T478K, E484Q, D614G and P681R as well as B.1.618 lineage with mutations Δ145-146, E484K and D614G. 63, 64 The B.617.2 variant with L452R and T478K can induce a significant escape to neutralizing antibodies targeting the NTD and RBD, and polyclonal antibodies elicited by previous SARS-CoV-2 infection or vaccination. Nanobody and antibody mixtures targeting non-overlapping epitopes on the RBD have shown promise in preventing occurrence of resistance mutations.…”

Section: Introductionmentioning

confidence: 99%

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

Verkhivker

Agajanian

et al. 2021

Preprint

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Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

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In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains

Cited by 241 publications

References 46 publications

N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

Fatal neuroinvasion and SARS-CoV-2 tropism in K18-hACE2 mice is partially independent on hACE2 expression

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

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