Project description:Vaccinated, non-vaccinated, and immunosuppressed individuals will continue to be infected with SARS-CoV-2. Therefore, there is a priority to develop treatments that reduce the severity of COVID-19 in patients who require hospital admission. Interleukin-6 (IL-6) is a proinflammatory cytokine. In 2011, a humanized monoclonal antibody to the IL-6 receptor (IL-6R), tocilizumab, was approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, and Castleman's disease. In 2017, tocilizumab was approved to treat chimeric antigen receptor (CAR) T-cell therapy-induced cytokine release syndrome (CRS). In 2021, the results of the REMAP-CAP clinical trial (NCT02735707) and the COVID-19 Therapy (RECOVERY) clinical trial (NCT04381936) supported FDA Emergency Use Authorization (EUA) for tocilizumab to treat hospitalized patients with moderate and severe COVID-19. Monoclonal antibodies are currently in clinical development or undergoing clinical trials to treat COVID-19. Further clinical trials will provide safety and efficacy data on targeting IL-6 and IL-6R and provide rationales for more personalized combination treatments to control the systemic effects of SARS-CoV-2 infection in hospitalized patients with moderate and severe COVID-19. This Editorial aims to present the background to the recent authorization of tocilizumab, a humanized therapeutic monoclonal antibody to the IL-6 receptor (IL-6R), for hospitalized patients with moderate and severe COVID-19 and future combination therapies.
Project description:The 3p21.31 locus, which locus contains a chemokine receptor (CKR) cluster, is the most robust genomic region associated with COVID-19 severity. We tested expression quantitative trait loci (eQTL) targeting the 3p21.31 CKR cluster linked to COVID-19 hospitalization in Europeans from the COVID-19 HGI meta-analysis. Among these, CCRL2, a key regulator of neutrophil trafficking, was targeted by neutrophil-restricted eQTLs. We confirmed these eQTLs in an Italian COVID-19 cohort. Haplotype analysis revealed a link between an increased CCRL2 expression and COVID-19 severity and hospitalization. By the exposure of neutrophils to a TLR8 ligand, reflecting a viral infection, we revealed specific chromatin domains within the 3p21.31 locus exclusive to neutrophils. In addition, the identified variants mapped within these regions altered the binding motif of neutrophils expressed transcription factors. These results support that CCRL2 eQTL variants contribute to the risk of severe COVID-19 by selectively affecting neutrophil’s function
Project description:Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r(2)=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13-140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35-71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 x 10(-62). The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 x 10(-4)). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.
Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine with known multiple functions in immune regulation, inflammation, and oncogenesis. Binding of IL-6 to the IL-6 receptor (IL-6R) induces homodimerization and recruitment of glycoprotein 130 (gp130), which leads to activation of downstream signaling. Emerging evidence suggests that high levels of IL-6 are correlated with poor prognosis in breast cancer patients. IL-6 appears to play a critical role in the growth and metastasis of breast cancer cells, renewal of breast cancer stem cells (BCSCs), and drug resistance of BCSCs, making anti-IL-6/IL-6R/gp130 therapies promising options for the treatment and prevention of breast cancers. However, preclinical and clinical studies of the applications of anti-IL-6/IL-6R/gp130 therapy in breast cancers are limited. In this review, we summarize the structures, preclinical and clinical studies, mechanisms of action of chemical and biological blockers that directly bind to IL-6, IL-6R, or gp130, and the potential clinical applications of these pharmacological agents as breast cancer therapies.
Project description:Acting on the cytokine cascade is key to preventing disease progression and death in hospitalised patients with COVID-19. Among anti-cytokine therapies, interleukin (IL)-6 inhibitors have been the most used and studied since the beginning of the pandemic. Going through previous observational studies, subsequent randomised controlled trials, and meta-analyses, we focused on the baseline characteristics of the patients recruited, identifying the most favourable features in the light of positive or negative study outcomes; taking into account the biological significance and predictivity of IL-6 and other biomarkers according to specific thresholds, we ultimately attempted to delineate precise windows for therapeutic intervention. By stimulating scavenger macrophages and T-cell responsivity, IL-6 seems protective against viral replication during asymptomatic infection; still protective on early tissue damage by modulating the release of granzymes and lymphokines in mild-moderate disease; importantly pathogenic in severe disease by inducing the proinflammatory activation of immune and endothelial cells (through trans-signalling and trans-presentation); and again protective in critical disease by exerting homeostatic roles for tissue repair (through cis-signalling), while IL-1 still drives hyperinflammation. IL-6 inhibitors, particularly anti-IL-6R monoclonal antibodies (e.g., tocilizumab, sarilumab), are effective in severe disease, characterised by baseline IL-6 concentrations ranging from 35 to 90 ng/mL (reached in the circulation within 6 days of hospital admission), a ratio of partial pressure arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2) between 100 and 200 mmHg, requirement of high-flow oxygen or non-invasive ventilation, C-reactive protein levels between 120 and 160 mg/L, ferritin levels between 800 and 1600 ng/mL, D-dimer levels between 750 and 3000 ng/mL, and lactate dehydrogenase levels between 350 and 500 U/L. Granulocyte-macrophage colony-stimulating factor inhibitors might have similar windows of opportunity but different age preferences compared to IL-6 inhibitors (over or under 70 years old, respectively). Janus kinase inhibitors (e.g., baricitinib) may also be effective in moderate disease, whereas IL-1 inhibitors (e.g., anakinra) may also be effective in critical disease. Correct use of biologics based on therapeutic windows is essential for successful outcomes and could inform future new trials with more appropriate recruiting criteria.
Project description:COVID-19 has infected 244 million people globally and evolved several variants with higher infectivity. Drug repurposing could be an efficient and timely means of drug discovery for the pandemic. To date, more than two hundred repurposed SARS-CoV-2 inhibitors have been reported but with moderate efficacy or acute toxicity. Thus, there is a great need to find new effective candidates against SARS-CoV-2, especially the new variants, with good safety profiles. We analyzed 17 hundred published host RNA-seq samples of SARS/MERS/SARS-CoV-2 infection derived from pre-clinical models or patients, together with the reported coronavirus inhibitors to summarize a robust coronavirus-induced host gene expression change signature, which captured biological processes involved in host cell machinery hijacking and immune evasion. Then we searched for drugs potently reversing the infection signature and discovered IMD-0354 as a promising candidate with nanomolar IC50 against SARS-CoV-2 and 6 variants, showing a wide therapeutic window of more than 100-fold. The RNA-seq of IMD-0354 treated cells infected with SARS-CoV-2 reaved that this drug could stimulate type I interferon antiviral response, inhibit viral entry and down-regulate hijacked proteins. This work demonstrated the power of biological big data and the efficiency of a system-based drug discovery approach, which can be used in future pandemic.
Project description:Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation.