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Scientific result | Biotechnology | Virus
Researchers from SIMoS and SPI (DMTS) demonstrate that molecular engineering of llama antibodies, capable of neutralizing SARS-CoV-1, allows to obtain optimized antibodies with very high affinities for SARS-CoV-2 and its variants, the culprits of the Covid-19 epidemic. This constitutes a step towards the design of novel neutralizing molecules, active against new emerging strains of pathogens.
In addition to vaccination of the population, which made it possible to contain the Covid-19 epidemic, passive immunization by infusion of monoclonal antibodies constitutes a very interesting complementary approach, in particular for the people most at risk. Several studies have shown that early administration of monoclonal antibodies targeting the viral protein Spike, and more specifically its receptor-binding domain (RBD), blocks the entry of the virus into human cells and prevents the progression to severe disease. Since 2020, multiple antibodies directed against the RBD domain of the Spike protein of Sars-CoV-2, the agent responsible for the Covid-19 pandemic, have been designed, but these antibodies have several limitations in use (narrow recognition spectrum, modest neutralization capacity, loss of recognition of emerging virus strains...). Alternative strategies to develop monoclonal antibodies with high neutralizing activity, capable of neutralizing circulating strains of SARS-CoV-2 with broad spectrum, are needed.
Among the antibodies neutralizing the SARS-CoV-1 virus, developed following the 2003 epidemic in Asian countries, very few have proven to be effective against the SARS-CoV-2 virus. The VHH72 antibody is a molecule derived from the immunization of a llama with the Spike protein of SARS-CoV-1 which is able to recognize the corresponding antigen of SARS-CoV-2 with however, a moderate binding affinity to the RBD of SARS-CoV-2. This nanobody was an extremely valuable starting point for the generation of new anti-SARS-CoV-2 antibodies due to its cross-reactivity to different viral strains. In the present study, scientists combined a systematic evaluation of the effect of mutations (Deep Mutational Scanning) on the activity of the VHH72 antibody with a high-throughput Yeast Surface Display. This resulted in novel highly neutralizing antibody-candidate variants with significantly improved affinity for SARS-CoV-2 and broad cross-reactivity for SARS-CoV-1 and SARS-CoV-2. The researchers thus identified all individual substitutions of VHH72 that increase its binding to the SARS-CoV-2 RBD, and then screened targeted combinatorial libraries to isolate modified antibodies with optimized properties. The resulting VHH molecules i) exhibit very high affinities (in the picomolar range) for SARS-CoV-2 antigens from various emerging variants and for SARS-CoV-1, ii) block the interaction between the RBD and its cellular receptor, and iii) neutralize the virus with high efficiency thanks to a common motif of three amino acids that gives them a very high recognition specificity.
An immediate prospect 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 combat the current pandemic. The power of the approach used here makes it possible to rapidly design, from existing antibodies, novel neutralizing molecules, active against new emerging strains of pathogens. Contact : Hervé Nozach, email@example.com See also the "Antibody Engineering and Immunogenicity" page of our website
A Laroche, ML Orsini-Delgado, B Chalopin, P Cuniasse, S Dubois, R Sierocki, F Gallais, S Debroas, L Bellanger, S Simon, B Maillère, H Nozach. Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift. MABS, 2022, vol14, n°1, e2076775 https://doi.org/10.1080/19420862.2022.2076775
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