A SARS-CoV-2 neutralizing antibody with extensive spike binding coverage

By Dr. Sanchari Sinha Dutta, Ph.D.May 17 2021

In a recently published research paper in the journal Nature Communications, a team of scientists from China has described the antiviral efficacy of a novel anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody isolated from recovered coronavirus disease 2019 (COVID-19) patients.

The structural and functional characterization of the antibody reveals that it covers most of the receptor-binding motif of the spike receptor-binding domain (RBD) and is highly potent in completely neutralizing SARS-CoV-2 in non-human primates.

Study: A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes. Image Credit: Nature Publishing

Background

The COVID-19 pandemic is the most significant pandemic of modern history, with over 162 million infected people and 3.37 million deaths globally as of May 17, 2021. Among various pharmaceutical control measures, therapeutic monoclonal antibodies and prophylactic vaccines have shown some ray of hope in controlling the pandemic disaster.

Although spike-targeting vaccines have shown good efficacy in preventing COVID-19 and reducing disease severity, the durability of induced immunity and actual vaccine efficacy in the vulnerable population remains uncertain.

For therapeutic purposes, monoclonal antibodies are primarily isolated and identified from convalescent COVID-19 individuals, humanized mice, and phage libraries. Two significant drawbacks in this field include antibody-dependent enhancement of infection and changing efficacy of antibodies against newly emerging viral variants with multiple spike mutations.

In the current study, the scientists have isolated a panel of anti-spike neutralizing antibodies from recovered COVID-19 patients. By screening these antibodies, they have identified and characterized one RBD-specific antibody with the highest efficacy.

Antibody identification and characterization

Using a single-cell B-cell receptor sequencing approach, the scientists isolated a panel of anti-spike neutralizing antibodies from two COVID-19 recovered patients. Of these antibodies, three efficiently interacted with the spike S1 subunit and blocked the interaction between S1 and human angiotensin-converting enzyme 2 (ACE2). Moreover, these antibodies effectively prevented SARS-CoV-2 from infecting target cells.

Based on the immunoGenetics database-based analysis, they selected a specific antibody, P4A1, for further analysis.

Structural analysis of antibody – RBD complex

Using X-ray crystallography, the scientists observed that hydrogen bond and hydrophobic interaction predominantly contribute to the interaction between the antigen-binding region of P4A1 and spike RBD. Specifically, they observed that the antibody directly binds to the receptor-binding motif of spike RBD. Thus, by creating steric hindrance, the antibody efficiently prevents the spike – ACE2 interaction.

Moreover, they observed that the antibody extensively covers the majority of RBD residues involved in spike – ACE2 interaction. This justifies the live virus neutralization potency of this antibody.

Antibody effectiveness against spike variants

To determine the range of antibody efficacy, they examined the binding of P4A1 to seventeen different RBD mutants and two S1 mutants. Using surface plasmon resonance and ELISA, they observed that the antibody binds to both wild-types RBD/S1 and mutated RBD/S1 with similar affinity. Moreover, the antibody exhibited similar efficacy in neutralizing pseudoviruses expressing wild-type spikes or their variants.  

To increase the antibody half-life and reduce the risk of antibody-dependent enhancement of infection, they further engineered the antibody to make an IgG4 antibody with unique structural and functional features. The engineered antibody showed enhanced binding affinity, longer half-life, and good safety profile in a panel of in vivo experiments.

Antibody efficacy in non-human primates

For in vivo characterization, the scientists first infected rhesus macaques with SARS-CoV-2 and subsequently administered the engineered antibody at day 1 post-infection. They observed a complete elimination of the virus 4 – 5 days after infection in animals treated with the antibody. Moreover, they could not detect viral RNA in the lung tissues of antibody-treated animals 6 – 7 days after infection. These observations indicate that the antibody is capable of efficiently inhibiting viral replication in host cells.    

Study significance

The study describes the identification and characterization of a novel anti-SARS-CoV-2 neutralizing antibody, which exhibits potent antiviral efficacy, prolonged half-life, and a broad range of viral neutralization. An acceptable safety profile together with antiviral potency makes the antibody a promising candidate to treat COVID-19 patients.