Insertion Unique to SARS-CoV-2 Exhibits Superantigenic Characteristics

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a myriad of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers, strongly resembling toxic shock syndrome. This escalation of the cytotoxic adaptive immune response is triggered upon the binding of pathogenic superantigens to MHCII molecules and T cell receptors, and points to important implications for the development of new therapeutic techniques.

Description

Using structure-based computational models, researchers have demonstrated that the SARS-CoV-2 spike harbors a sequence motif unique to SARS-CoV-2 and not present in other SARS coronaviruses, which is highly similar in both sequence and structure to bacterial superantigens. Further examination suggested that the SARS-CoV-2 spike may act as a superantigen that drives the development of MIS-C as well as the cytokine storm in adult COVID-19 patients. Potential development strategies include preparing a decoy peptide that can bind to the site in the viral structure and prevent it from binding to T cell receptors or preparing a monoclonal antibody specific to the viral superantigenic binding site and thus block the interaction with the T cell receptor.

Applications

· Development of monoclonal antibodies that would target this new site on the spike
· Potential use of these monoclonal antibodies in antibody cocktails containing known antibodies that target the receptor-binding-domain of the spike, thus minimizing the evasion of variants to antibody treatments

Advantages

· Identification of a new target site on the viral spike protein potentially responsible for excessive autoimmune response
· Possibility of taking advantage of monoclonal antibodies developed for bacterial superantigens, and in particular those for Staphylococcal enterotoxin B containing a similar superantigenic site, for neutralizing the viral superantigenic site
· Overlap between superantigenic site and cleavage site by human proteases essential to prompting viral entry, which implies that monoclonal antibodies targeting that site would have the dual advantage of potentially blocking proteolytic cleavage and thereby reduce, if not prevent, viral entry

Invention Readiness

Design; candidate antibodies identified

IP Status

https://patents.google.com/patent/US11746144B2

Related Publication(s)

Porritt, R. A., Paschold, L., Rivas, M. N., Cheng, M. H., Yonker, L. M., Chandnani, H., Lopez, M., Simnica, D., Schultheiß, C., Santiskulvong, C., Van Eyk, J., McCormick, J. K., Fasano, A., Bahar, I., Binder, M., & Arditi, M. (2021). HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children. Journal of Clinical Investigation, 131(10). https://doi.org/10.1172/jci146614

Noval Rivas, M., Porritt, R. A., Cheng, M. H., Bahar, I., & Arditi, M. (2021). COVID-19–associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome—the superantigen hypothesis. Journal of Allergy and Clinical Immunology, 147(1), 57–59. https://doi.org/10.1016/j.jaci.2020.10.008

Ivet Bahar, et al. (2020). A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry in vitro. bioRxiv 2020.11.24.395079; doi: https://doi.org/10.1101/2020.11.24.395079

Bahar I, Binder M, Arditi M, et al. (2020) Identification of a Unique TCR Repertoire, Consistent with a Superantigen Selection Process in Children with Multi-system Inflammatory Syndrome. BioRxiv doi: https://doi.org/10.1101/2020.11.09.372169