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Molecular engineering of antibodies: from SARS-CoV-1 to SARS-CoV-2 and its variants

​Researchers from the CEA-Joliot have shown that molecular engineering of llama antibodies directed against SARS-CoV-1 can be used to obtain optimized antibodies with very high affinities for SARS-CoV-2 and its variants. This is a step towards designing neutralizing molecules for new emerging pathogen strains!

Published on 13 October 2022

As a complement to vaccination, passive immunization by monoclonal antibody infusion is an interesting approach for treating the most vulnerable patients against COVID-19. Several studies show that early administration of monoclonal antibodies targeting the viral protein Spike, and more precisely its receptor-binding domain (RBD), blocks the entry of the virus into human cells and prevents progression to severe forms of the disease.

Since 2020, various antibodies directed against the RBD domain of the SARS-CoV-2 Spike protein have been developed. However, their use is limited by a narrow recognition spectrum, modest neutralization capacity, loss of recognition of emerging virus strains, etc.

In this context, what role can the molecular engineering of antibodies play?

The scientists naturally turned to antibodies that neutralize the SARS-CoV-1 virus, developed during the 2003 epidemic, but very few have proven effective against the SARS-CoV-2 virus. One of them, the antibody VHH72, was derived from the immunization of a llama with the SARS-CoV-1 Spike protein. It recognizes the corresponding SARS-CoV-2 antigen, with moderate binding affinity to the SARS-CoV-2 RBD.

Researchers at the Joliot Institute have chosen this antibody as a starting point to generate new anti-SARS-CoV-2 antibodies. They systematically evaluated the effect of mutations (Deep Mutational Scanning) on the activity of the VHH72 antibody, using the Yeast Surface Display high-throughput screen. Then they screened targeted combinatorial libraries to isolate modified antibodies with optimized properties.

They obtained variants of novel, highly neutralizing antibody candidates with a significantly enhanced affinity for SARS-CoV-2 and broad cross-reactivity for SARS-CoV-1 and SARS-CoV-2. The resulting VHH molecules have very high affinities for SARS-CoV-2 antigens from various emerging variants and for SARS-CoV-1. They block the interaction between the RBD and its cellular receptor and neutralize the virus with high efficiency thanks to a common motif of three amino acids that endows them with a very high recognition specificity.

One immediate perspective of this work could be to adapt VHH72, or one of the many antibodies affected by omicron mutations, to these new antigens and thus generate neutralizing antibodies of interest to fight the current pandemic.

The power of this approach makes it possible to rapidly design, from existing antibodies, novel neutralizing molecules that are active against new emerging strains of pathogens.

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