A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2.
Julia EttichJulia WernerHendrik T WeitzEva MuellerRoland SchwarzerPhilipp A LangJürgen SchellerJens M MollPublished in: Journal of virology (2021)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- intensive care unit
- heart failure
- type diabetes
- induced apoptosis
- cardiovascular disease
- stem cells
- high glucose
- single cell
- oxidative stress
- monoclonal antibody
- cell therapy
- patient reported outcomes
- binding protein
- prognostic factors
- ejection fraction
- protein protein
- physical activity
- small molecule
- risk assessment
- drug induced
- skeletal muscle
- replacement therapy
- chronic kidney disease
- amino acid
- extracorporeal membrane oxygenation
- early onset
- weight loss
- depressive symptoms
- endoplasmic reticulum stress
- respiratory failure
- insulin resistance
- adipose tissue