Development of neutralizing antibodies against SARS-CoV-2

Abstract

The COVID-19 pandemic that has spread over the last two years is still ongoing, despite the fact that various strategies have been developed to prevent infection or alleviate clinical manifestations. Most of the efforts have been invested in the development of vaccines, capable of inducing an immune response against the viral protein Spike, and neutralizing antibodies against Spike. However, considering the mutant nature of SARS-CoV-2 which mainly affects the Spike region, the effectiveness of the tools available to date is not demonstrated for current and future variants of the virus.

The goal of our research project is to find more durable and broad-spectrum treatments that are effective against the numerous variants of the virus and that can also counteract future coronavirus pandemics. In particular, we are involved in the development of antibodies, in the form of single chain fragment variable (scFv), against the Nucleocapsid protein (N) and the Nsp9 protein of SARS-CoV-2, rather than on the Spike protein whose rapid and high mutability results in a reduction in the effectiveness of the treatments available. Both chosen proteins are of extreme biological and therapeutic relevance. Nsp9 is a highly conserved ssRNA-binding dimeric protein among Betacoronaviruses and is involved in virus replication and transcription. Protein N, also dimeric, packages the positive strand of viral RNA and plays an important role in improving the transcription efficiency of subgenomic viral RNA.

Impact:

Since the onset of the COVID-19 pandemic, most efforts have been invested in developing vaccines capable of inducing an immune response against the viral protein Spike, and neutralizing antibodies against Spike. However, one of the questions that researchers immediately tried to answer concerns the extreme variability of the SARS-CoV-2 virus, mainly due to the highly mutability nature of the Spike protein, which makes the therapeutic tools developed so far less and less effective. Therefore, it remains essential to investigate other stages of viral infection and replication. We aim to develop new molecules against proteins other than Spike, while implementing a platform and workflow for rapid and decisive intervention in the event of future coronavirus pandemics. The data produced so far on Nsp9 and the Nucleocapsid protein N provide the prerequisite for selecting and developing new neutralizing antibodies against these two proteins, thus preventing viral replication and/or attenuating the aggressiveness of the virus.

Pipeline