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Study identifies broad-spectrum antibodies that neutralize feared SARS-CoV-2 variants

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In a recent article published in a magazine scientific immunologyscientists describe the identification and therapeutic evaluation of antibodies that broadly neutralize major variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including alpha, beta, delta, and omicron variants. Did.

study: Antibodies that neutralize SARS-CoV-1 and SARS-CoV-2 by binding to conserved spike epitopes outside the receptor binding motifs. Image Credit: ThSucho/Shutterstock

Background

Several potential vaccines, therapeutic antibodies, and antiviral drugs are being developed in response to the deadly coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2. These have helped reduce the trajectory of the pandemic as a whole. However, the continuous emergence of new viral variants with enhanced infectivity and immunity emphasizes the need to develop broad-spectrum therapeutic and preventive interventions that can neutralize different viral variants. .

Most monoclonal therapeutic antibodies developed during the early stages of the pandemic work by preventing interactions between SARS-CoV-2. spike protein Human angiotensin-converting enzyme 2 (ACE2) is a key step for virus entry into host cells. These antibodies primarily target epitopes in the receptor binding motif (RBM) of the spike receptor binding domain (RBD).

The recently emerged SARS-CoV-2 omicron variants contain more than 15 mutations in the spike RBD, making the variants highly resistant to monoclonal and vaccine-induced antibodies. Developing broadly neutralizing antibodies against immune escape variants like omicron is essential to better manage the pandemic.

In the current study, scientists describe the identification and therapeutic evaluation of monoclonal antibodies with broad neutralizing effects against SARS-CoV-2 variants.

Identification of anti-SARS-CoV-2 monoclonal antibodies

Generation of spike-targeting antibodies was performed by immunizing mice with the spike ectodomain or RBD of the original SARS-CoV-2 Wuhan strain, followed by boosting. LIBRA (Linking B Cell Receptors to Antigen Specificity by Sequencing) sequencing technology was used to identify antigen-specific memory B cells and single-cell sequenced B cell receptors.

DNA encoding the identified B-cell receptor variable regions was inserted into a human immunoglobulin G1 (IgG1) antibody scaffold to create a chimeric antibody. This generated 27 RBD-targeted antibodies and 7 non-RBD-targeted antibodies.

The virus neutralization assay in this study identified seven antibodies with high neutralization efficiency against the Wuhan strain of SARS-CoV-2. Among these antibodies, one (SW186) showed optimal neutralization efficiency against a wide range of SARS-CoV-2 variants including alpha, beta, delta, gamma, lambda, and mu.

The identified SW186 antibody showed high neutralization efficacy against wild-type SARS-CoV-2 and its mutants at nanomolar concentrations. However, this antibody showed significantly reduced neutralization efficiency against omicron and its subvariants.

In particular, the SW186 antibody showed high neutralization efficiency against severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), the betacoronavirus responsible for the 2002-2004 SARS epidemic. I was. This finding indicates that the SW186 antibody targets a highly conserved epitope between SARS-CoV-1 and SARS-CoV-2.

Structural analysis of antigen-antibody complexes

Cryo-electron microscopy analysis of antibody-antigen complexes revealed that the epitope targeting the SW186 antibody was located outside the RBM of the spiked RBD. The epitope contained several conserved amino acids. Further analysis revealed that the SW186 antibody does not bind to the RBD-ACE2 interface.

The epitope of the SW186 antibody contained a glycosylation site (N343) important for viral entry into host cells. This residue is highly conserved among humans. coronavirus.

Further analysis reveals that the heavy chain complementarity determining region 3 (HCDR3) of the SW186 antibody is partially inserted into the RBD minor groove and that the interaction is largely contributed by the polypeptide backbone rather than the side chains of the RBD minor groove. became. This finding suggests that the RBD mutation may not significantly affect the binding of her SW186 antibody.

Therapeutic effect of SW186

The therapeutic efficacy of antibodies was tested by first infecting mice with alpha, beta, or delta variants of SARS-CoV-2, followed by treatment with SW186 antibody. The results revealed that SW186 antibody-treated mice had significantly lower viral loads in the lungs than untreated mice. Furthermore, antibody treatment protected mice from weight loss, lung injury, and lung infiltration of inflammatory mediators.

To test the efficacy of the SW186 antibody in humans, we generated a panel of humanized antibodies and tested their neutralization efficiency against alpha, beta, and delta variants. This finding revealed that most of these humanized antibodies neutralize the tested variants with similar efficacy as the murine SW186 antibody.

Significance of research

This study identifies a broad-spectrum monoclonal antibody (SW186) that efficiently neutralizes SARS-CoV-2 variants of concern and SARS-CoV-1. Scientists believe that the conserved RBD epitope targeted by the SW186 antibody may be considered in future studies to develop new therapeutic antibodies.

Sources

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2/ https://www.news-medical.net/news/20220805/Study-identifies-broad-spectrum-antibody-that-neutralizes-SARS-CoV-2-variants-of-concern.aspx

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