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Editorial: Tocilizumab, a Humanized Therapeutic IL-6 Receptor (IL-6R) Monoclonal Antibody, and Future Combination Therapies for Severe COVID-19.

ABSTRACT: 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.

SUBMITTER: Parums DV

PROVIDER: S-EPMC8299871 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT‑3, IL‑6 receptor (R) and IL‑6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT‑3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE‑1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU‑145 (metastatic, castration‑resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT‑3, phosphorylated STAT‑3 (In‑Cell Western), IL‑6R, vimentin and epithelial (E‑) cadherin (Western Blot). The effect of inhibition of STAT‑3 (expressed constitutively in DU‑145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E‑cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL‑6, C‑X‑C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E‑cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU‑145 cells; addition of IL‑6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL‑6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT‑3 inhibitor, with Tcz, an antibody against IL‑6R, to target tumor cells.

Project description:BackgroundIn the absence of highly effective antiviral therapies against SARS-CoV-2, it is crucial to counter the known pathophysiological causes of severe COVID-19. Evaluating the efficacy existing drugs may expedite the development of such therapeutics. Severe COVID-19 is largely the result of a dysregulated immune response characterized by lymphocytopenia, neutrophilia and critical hypercytokinemia, or "cytokine storm," which is largely mediated by the cytokine interleukin-6 (IL-6). The IL-6 inhibitor tocilizumab (TCZ) could potentially suppress the effects of the pro-inflammatory cytokine and thereby lower mortality from the disease. This systematic analysis aimed to investigate and synthesize existing evidence for the efficacy of TCZ in reducing COVID-19 mortality.MethodologyPubMed and SearchWorks searches were performed to locate clinical studies with primary data on TCZ treatment for severe COVID-19. Sixteen case-control studies comparing mortality between TCZ and standard of care (SOC) were identified for quantitative synthesis. The systematic analysis was pre-approved through PROSPERO (CRD42020193479).ResultsCombined mortality for the TCZ-treated and SOC groups were 26.0% and 43.4% respectively. In all but one of the studies, the odds ratio of mortality from COVID-19 pointed towards lower fatality with TCZ vs the SOC. A combined random effects odds ratio calculation yielded an odds ratio of 0.453 (95% CI [0.376-0.547], p < 0.001). Additionally, 18 uncontrolled trials were identified for qualitative analysis producing a raw combined mortality rate of 16.0%.ConclusionsImportant caveats to this research include the lack of prospective randomized control trials and the absence of data from the large COVATA study from the published literature. However, results from this systematic analysis of published research provide positive evidence for the potential efficacy of TCZ to treat severe COVID-19, validating the ethical basis and merit of ongoing randomized controlled clinical trials.

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Editorial: Tocilizumab, a Humanized Therapeutic IL-6 Receptor (IL-6R) Monoclonal Antibody, and Future Combination Therapies for Severe COVID-19.

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