Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab

Magnus, Clara Luzia; Hiergeist, Andreas; Schuster, Philipp; Rohrhofer, Anette; Medenbach, Jan; Gessner, André; Peterhoff, David; Schmidt, Bárbara

doi:10.3389/fimmu.2022.966236

Cited by 15 publications

(14 citation statements)

References 58 publications

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“…R346G has been selected in vitro by cilgavimab+tixagevimab [35] . R346S occurred in vitro after 12 weeks of propagating SARS-CoV-2 in the presence of sotrovimab, and before the other epitope mutation (P337L) which leads to sotrovimab resistance [36]. R346I has been selected in vitro under the selective pressure from cilgavimab [37,38].…”

Section: S:r346xmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

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The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and reevaluate the potential for polyclonal therapies (such as COVID19 convalescent plasma) in immunocompromised patients.

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Section: S:r346xmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

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show abstract

“…Furthermore, and to test our method, we examined some experimentally evaluated mutations in residues P337, R346, G339, and S371 that are located in the S309 epitope and once more our computational method was compatible with the experimental results (Table 2). This reduced susceptibility of Sotrovimab with P337, R346 and other mutations has been experimentally recognized [13,23,25]. Considering the clinical observations of the e ciency of Sotrovimab in neutralization of SARS-CoV, SARS-CoV-2 variants and Omicron sub variants, a 50% reduction of the binding a nity as compared to the reference model might be taken as cut off for considering if a monoclonal antibody will neutralize a new variant using the method described in this paper.…”

Section: Discussionmentioning

confidence: 93%

“…mutations showed to be resistance to inhibition by S309 leading to an antibody escape. These key residues include R346 and P337, G339, N440 and S371 [23,25]. Therefore, we apply our method to computationally test the effect of some mutations on these residues.…”

Section: Models and Complexes Constructionmentioning

confidence: 99%

In silico evaluation of anti SARS-CoV-2 antibodies neutralization power: A blueprint with monoclonal antibody Sotrovimab

Ashoor

Marzouq

Fathallah

2023

Preprint

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Immune escape caused by genetic variations of SARS-CoV-2 S protein immunogenic epitopes affects the efficiency of monoclonal antibody-based therapy of COVID-19. Therefore, predicting the effects of these variations on immune escape is important to adapt rapidly anti SARS-CoV-2 Mab therapy. We herein describe a computational method to evaluate the neutralizing power a monoclonal antibody specific of a given SARS-CoV-2 variant and to compare it to its potential neutralizing power of others and emergent variants. The method’s calls for building in silico complex between the spike protein of a SARS-CoV-2 variant and a neutralizing antibody, analyzing the molecular interactions pattern and calculating the binding energy. This data is assigned a neutralizing value of 100% to which can be compared the neutralization value of any SARS-CoV-2 variant determined after molecular replacement in the complex of the RBD sequence with the RBD of this variant. Application of this method to the class 3 neutralizing antibody Sotrovimab and 24 variants and subvariants showed that the affinity binding and neutralizing power, decreased gradually with new variants. This method is of interest to adapt the use of therapeutic antibodies to the treatment of emerging variants. It could be applied to antibody-based treatment of other viral infections.

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“…The monoclonal antibody C98C7 that binds these residues has previously been reported to broadly neutralize VOCs including Omicron BA.1 [ 49 ]. RBD class 3 and 4 monoclonal antibodies C309 and CR3022 that bind epitopes immediately upstream of the receptor binding motif have similarly been shown to broadly neutralize VOCs including Omicron BA.1, BA.1.1, and BA.2 [ 50 , 51 , 52 , 53 ]. We found only a weak binding to this region, with a maximum RFU of 854 in all three rabbits.…”

Section: Discussionmentioning

confidence: 99%

A Candidate DNA Vaccine Encoding the Native SARS-CoV-2 Spike Protein Induces Anti-Subdomain 1 Antibodies

Frische,

Gunalan,

Krogfelt

et al. 2023

Vaccines

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The ideal vaccine against viral infections should elicit antibody responses that protect against divergent strains. Designing broadly protective vaccines against SARS-CoV-2 and other divergent viruses requires insight into the specific targets of cross-protective antibodies on the viral surface protein(s). However, unlike therapeutic monoclonal antibodies, the B-cell epitopes of vaccine-induced polyclonal antibody responses remain poorly defined. Here we show that, through the combination of neutralizing antibody functional responses with B-cell epitope mapping, it is possible to identify unique antibody targets associated with neutralization breadth. The polyclonal antibody profiles of SARS-CoV-2 index-strain-vaccinated rabbits that demonstrated a low, intermediate, or high neutralization efficiency of different SARS-CoV-2 variants of concern (VOCs) were distinctly different. Animals with an intermediate and high cross-neutralization of VOCs targeted fewer antigenic sites on the spike protein and targeted one particular epitope, subdomain 1 (SD1), situated outside the receptor binding domain (RBD). Our results indicate that a targeted functional antibody response and an additional focus on non-RBD epitopes could be effective for broad protection against different SARS-CoV-2 variants. We anticipate that the approach taken in this study can be applied to other viral vaccines for identifying future epitopes that confer cross-neutralizing antibody responses, and that our findings will inform a rational vaccine design for SARS-CoV-2.

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Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab

Cited by 15 publications

References 58 publications

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

In silico evaluation of anti SARS-CoV-2 antibodies neutralization power: A blueprint with monoclonal antibody Sotrovimab

A Candidate DNA Vaccine Encoding the Native SARS-CoV-2 Spike Protein Induces Anti-Subdomain 1 Antibodies

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