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Neutralizing Ability of a Single Domain VNAR Antibody: In Vitro Neutralization of SARS-CoV-2 Variants of Concern.

ABSTRACT: Severe Acute Respiratory Syndrome Coronavirus 2 is the causal pathogen of coronavirus disease 2019 (COVID-19). The emergence of new variants with different mutational patterns has limited the therapeutic options available and complicated the development of effective neutralizing antibodies targeting the spike (S) protein. Variable New Antigen Receptors (VNARs) constitute a neutralizing antibody technology that has been introduced into the list of possible therapeutic options against SARS-CoV-2. The unique qualities of VNARs, such as high affinities for target molecules, capacity for paratope reformatting, and relatively high stability, make them attractive molecules to counteract the emerging SARS-CoV-2 variants. In this study, we characterized a VNAR antibody (SP240) that was isolated from a synthetic phage library of VNAR domains. In the phage display, a plasma with high antibody titers against SARS-CoV-2 was used to selectively displace the VNAR antibodies bound to the antigen SARS-CoV-2 receptor binding domain (RBD). In silico data suggested that the SP240 binding epitopes are located within the ACE2 binding interface. The neutralizing ability of SP240 was tested against live Delta and Omicron SARS-CoV-2 variants and was found to clear the infection of both variants in the lung cell line A549-ACE2-TMPRSS2. This study highlights the potential of VNARs to act as neutralizing antibodies against emerging SARS-CoV-2 variants.

SUBMITTER: Valdovino-Navarro BJ

PROVIDER: S-EPMC9603574 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Neutralizing Ability of a Single Domain VNAR Antibody: In Vitro Neutralization of SARS-CoV-2 Variants of Concern.

Valdovino-Navarro Blanca J BJ Dueñas Salvador S Flores-Acosta G Isaí GI Gasperin-Bulbarela Jahaziel J Bernaldez-Sarabia Johanna J Cabanillas-Bernal Olivia O Cervantes-Luevano Karla E KE Licea-Navarro Alexei F AF

International journal of molecular sciences 20221014 20

Severe Acute Respiratory Syndrome Coronavirus 2 is the causal pathogen of coronavirus disease 2019 (COVID-19). The emergence of new variants with different mutational patterns has limited the therapeutic options available and complicated the development of effective neutralizing antibodies targeting the spike (S) protein. Variable New Antigen Receptors (VNARs) constitute a neutralizing antibody technology that has been introduced into the list of possible therapeutic options against SARS-CoV-2. ...[more]

PMID: 36293124

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Project description:IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), had a major impact on both the global health and economy. Numerous virus-neutralizing antibodies were developed against the S1 subunit of SARS-CoV-2 spike (S) protein to block viral binding to host cells and were authorized for control of the COVID-19 pandemic. However, frequent mutations in the S1 subunit of SARS-CoV-2 enabled the emergence of immune evasive variants. To address these challenges, broadly neutralizing antibodies targeting the relatively conserved S2 subunit and its epitopes have been investigated as antibody therapeutics and universal vaccines.MethodsWe initiated this study by immunizing BALB/c mice with β-propiolactone-inactivated SARS-CoV-2 (IAV) to generate B-cell hybridomas. These hybridomas were subsequently screened using HEK293T cells expressing the S2-ECD domain. Hybridomas that produced anti-S2 antibodies were selected, and we conducted a comprehensive evaluation of the potential of these anti-S2 antibodies as antiviral agents and versatile tools for research and diagnostics.ResultsIn this study, we present a novel S2-specific antibody, 4A5, isolated from BALB/c mice immunized with inactivated SARS-CoV-2. 4A5 exhibited specific affinity to SARS-CoV-2 S2 subunits compared with those of other β-CoVs. 4A5 bound to epitope segment F1109-V1133 between the heptad-repeat1 (HR1) and the stem-helix (SH) region. The 4A5 epitope is highly conserved in SARS-CoV-2 variants, with a significant conformational feature in both pre- and postfusion S proteins. Notably, 4A5 exhibited broad neutralizing activity against variants and triggered Fc-enhanced antibody-dependent cellular phagocytosis.DiscussionThese findings offer a promising avenue for novel antibody therapeutics and insights for next-generation vaccine design. The identification of 4A5, with its unique binding properties and broad neutralizing capacity, offers a potential solution to the challenge posed by SARS-CoV-2 variants and highlights the importance of targeting the conserved S2 subunit in combating the COVID-19.

Dataset Information

Neutralizing Ability of a Single Domain VNAR Antibody: In Vitro Neutralization of SARS-CoV-2 Variants of Concern.

Publications

Neutralizing Ability of a Single Domain VNAR Antibody: In Vitro Neutralization of SARS-CoV-2 Variants of Concern.

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