Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab

Agresti, Nicholas; Lalezari, Jacob; Amodeo, Phillip P.; Mody, Kabir; Mosher, Steven; Seethamraju, Harish; Kelly, Scott A.; Pourhassan, Nader; Sudduth, C D; Bovinet, Christopher; Elsharkawi, A; Patterson, Bruce K.; Stephen, Reejis; Sacha, Jonah B.; Wu, Helen L.; Gross, Seth A.; Dhody, Kush

doi:10.1016/j.jtauto.2021.100083

Cited by 41 publications

(28 citation statements)

References 39 publications

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“…It has been shown that inhibition of CCL5/CCR5 axis by monoclonal antibody, leronlimab, can relieve the symptoms of patients who are critically ill. 85 Also, it has been observed that, following the anti-CCR5 treatment, the level of inflammatory molecules such as CCL5, IL-6, TNF

were reduced. 86 Furthermore, 17 years ago, patients with SARS also had shown elevated CCL5 level. 87 …”

Section: Ccl5/ccr5 and Diseasesmentioning

confidence: 99%

CCL5/CCR5 axis in human diseases and related treatments

et al. 2022

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To defense harmful stimuli or maintain the immune homeostasis, the body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, chemokines act as crucial regulators in defense systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, as well as inducing the adhesion and migration of different T cell subsets in immune responses. In addition, recent studies have shown that the interaction between CCL5 and CCR5 is involved in various pathological processes including inflammation, chronic diseases, cancers as well as the infection of COVID-19. This review focuses on how CCL5/CCR5 axis participates in the pathological processes of different diseases and their relevant signaling pathways for the regulation of the axis. Moreover, we highlighted the gene therapy and chemotherapy studies for treating CCR5-related diseases, including the ongoing clinical trials. The barriers and perspectives for future application and translational research were also summarized.

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were reduced. 86 Furthermore, 17 years ago, patients with SARS also had shown elevated CCL5 level. 87 …”

Section: Ccl5/ccr5 and Diseasesmentioning

confidence: 99%

CCL5/CCR5 axis in human diseases and related treatments

et al. 2022

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“…Leronlimab is a monoclonal IgG4 antibody which also has CCR5 as a therapeutic target. Leronlimab successfully reduced the IL-6 levels in patients with severe COVID 19 manifestations [131]. Taking into consideration the role of CCR5 in the COVID-19 pathogenesis and their expression by the endothelial cells, the CCR5 antagonism might represent a therapeutic option in the treatment of SARS-CoV-2-induced endotheliopathy.…”

Section: Therapeutic Targets For the Treatment Of Covid-19mentioning

confidence: 99%

Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19—Mechanisms and Therapeutic Targets

Fodor

Tiperciuc

et al. 2021

Oxidative Medicine and Cellular Longevity

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The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.

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“…However, several of these dysregulated molecules shared by COVID-19 and HLH have been successfully investigated for the treatment of SARS-CoV-2 infection, supporting our findings. For instance, inhibition of the CCR5-CCL4 axis by Leronlima (anti-CCR5 monoclonal antibody) 98 , or blockade of cytokine signaling by Tocilizumab (anti-IL-6R) 99 , Adalimumab (anti-TNF) 100 , or Anakinra (anti-IL1R) 101 Cytokine/chemotaxis and neutrophil-mediated immunity genes with a correlation of ≥ 0.7 or ≤ -0.7 are colored in green and blue, respectively, while those with a correlation of < 0.7 or > -0.7 are gray in both groups. (C) Scatter plots with marginal boxplots display the relationship between variables (genes).…”

Section: Discussionmentioning

confidence: 99%

“…However, several of these dysregulated molecules shared by COVID-19 and HLH have been successfully investigated for the treatment of SARS-CoV-2 infection, supporting our findings. For instance, inhibition of the CCR5-CCL4 axis by Leronlima (anti-CCR5 monoclonal antibody) 98 , or blockade of cytokine signaling by Tocilizumab (anti-IL-6R) 99 , Adalimumab (anti-TNF) 100 , or Anakinra (anti-IL1R) 101 All original codes used for data analysis have been deposited at github (https://github.com/lschimke/COVID19-and-HLH-paper) and are publicly available as of the date of publication. R packages are listed in the key resources table.…”

Section: Discussionmentioning

confidence: 99%

Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states

Schimke

Marques

Baiocchi

et al. 2021

Preprint

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Clinical and hyperinflammatory overlap between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) has been reported. However, the underlying mechanisms are unclear. Here we show that COVID-19 and HLH have an overlap of signaling pathways and gene signatures commonly dysregulated, which were defined by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) using microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq). COVID-19 and HLH share pathways involved in cytokine and chemokine signaling as well as neutrophil-mediated immune responses that associate with COVID-19 severity. These genes are dysregulated at protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins which converge to neutrophil hyperactivation in COVID-19 patients admitted to intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.

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Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab

Cited by 41 publications

References 39 publications

CCL5/CCR5 axis in human diseases and related treatments

CCL5/CCR5 axis in human diseases and related treatments

Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19—Mechanisms and Therapeutic Targets

Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states

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