Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can induce mild to life-threatening symptoms. Especially individuals over 60 years of age or with underlying comorbidities, including heart or lung disease and diabetes, or immunocompromised patients are at a higher risk. Fatal multiorgan damage in coronavirus disease 2019 (COVID-19) patients can be attributed to an interleukin-6 (IL-6)-dominated cytokine storm. Consequently, IL-6 receptor (IL-6R) monoclonal antibody treatment for severe COVID-19 cases has been approved for therapy. High concentrations of soluble IL-6R (sIL-6R) were found in COVID-19 intensive care unit patients, suggesting the involvement of IL-6 trans -signaling in disease pathology. Here, in analogy to bispecific antibodies (bsAbs), we developed the first bispecific IL-6 trans -signaling inhibitor, c19s130Fc, which blocks viral infection and IL-6 trans -signaling. c19s130Fc is a designer protein of the IL-6 trans -signaling inhibitor cs130 fused to a single-domain nanobody directed against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. c19s130Fc binds with high affinity to IL-6:sIL-6R complexes as well as the spike protein of SARS-CoV-2, as shown by surface plasmon resonance. Using cell-based assays, we demonstrate that c19s130Fc blocks IL-6 trans -signaling-induced proliferation and STAT3 phosphorylation in Ba/F3-gp130 cells as well as SARS-CoV-2 infection and STAT3 phosphorylation in Vero cells. Taken together, c19s130Fc represents a new class of bispecific inhibitors consisting of a soluble cytokine receptor fused to antiviral nanobodies and principally demonstrates the multifunctionalization of trans- signaling inhibitors. IMPORTANCE The availability of effective SARS-CoV-2 vaccines is a large step forward in managing the pandemic situation. In addition, therapeutic options, e.g., monoclonal antibodies to prevent viral cell entry and anti-inflammatory therapies, including glucocorticoid treatment, are currently developed or in clinical use to treat already infected patients. Here, we report a novel dual-specificity inhibitor to simultaneously target SARS-CoV-2 infection and virus-induced hyperinflammation. This was achieved by fusing an inhibitor of viral cell entry with a molecule blocking IL-6, a key mediator of SARS-CoV-2-induced hyperinflammation. Through this dual action, this molecule may have the potential to efficiently ameliorate symptoms of COVID-19 in infected individuals.
Keywords: IL-6; SARS-CoV-2; sgp130; trans-signaling.
【저자키워드】 SARS-CoV-2, IL-6, sgp130, trans-signaling., 【초록키워드】 COVID-19, coronavirus disease, viral infection, Cytokine storm, coronavirus, pandemic, therapy, intensive care, severe COVID-19, Antiviral, antibody, SARS-COV-2 infection, monoclonal antibody, Infection, Comorbidities, interleukin-6, Lung disease, diabetes, inhibitors, Symptoms, SARS-CoV-2 vaccine, Spike protein, Immunocompromised patient, Receptor binding domain, Protein, nanobody, RBD, hyperinflammation, Patient, Phosphorylation, Mild, age, inhibitor, patients, monoclonal antibody treatment, therapeutic options, Multiorgan, Signaling, Concentration, Glucocorticoid treatment, IL-6 receptor, proliferation, Clinical use, STAT3, acute respiratory syndrome, higher risk, infected patients, infected individuals, individual, high affinity, life-threatening, anti-inflammatory therapies, IL-6R, soluble IL-6R, Vero cells, treat, virus-induced hyperinflammation, symptoms of COVID-19, disease pathology, cytokine receptor, sIL-6R, viral cell, block, Prevent, effective, Cell, bind, shown, assays, addition, approved, the spike protein, induce, complexes, fused, fusing, the SARS-CoV-2, trans-signaling, 【제목키워드】 fusion, hybrid, block,