Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19

Abstract

28Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of 29 coronavirus disease 2019 , is now pandemic with nearly three million cases 30 reported to date 1 . Although the majority of COVID-19 patients experience only mild or 31 moderate symptoms, a subset will progress to severe disease with pneumonia and acute 32 respiratory distress syndrome (ARDS) requiring mechanical ventilation 2 . Emerging results 33 indicate a dysregulated immune response characterized by runaway inflammation, 34including cytokine release syndrome (CRS), as the major driver of pathology in severe 35 -19 3,4 . With no treatments currently approved for COVID-19, therapeutics to 36 prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 37 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we 38 report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell 39 levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with 40 the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor 41 occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the 42 CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent 43 with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in 44 transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These 45 results demonstrate a novel approach to resolving unchecked inflammation, restoring 46 immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of 47 COVID MAIN TEXT 51 52Since the initial cases of COVID-19 were reported from Wuhan, China in December 53 2019 2 , SARS-CoV-2 has emerged as a global pandemic with an ever-increasing number 54 of severe cases requiring invasive external ventilation that threatens to overwhelm health 55

Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts

“…In another study, the CCL5‐CCR5 axis was found to contribute to immunopathology 106 in critically ill COVID‐19 patients with elevated levels of CCL5 (RANTES), as compared with patients who had mild or moderate cases of disease. Blocking the CCR5 antibody with Leronlimab reduced IL‐6 levels in critically ill COVID‐19 patients and restored the CD4/CD8 ratio, leading to a marked reduction in SARS‐CoV‐2 plasma viremia 106 . Deng and colleagues have also suggested that upstream targets, such as cyclic guanosine monophosphate (GMP) – adenosine monophosphate (AMP) synthase (cGAS), anaplastic lymphoma kinase (ALK), and stimulator of interferon genes (STING), may help reduce cell activation and cytokine release 118 .…”

C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis

“…In COVID-19 patients, disruption of the CCL5-CCR5 axis through CCR5 blocking antibody leronlimab was shown to reduce plasma IL-6, and SARS-CoV-2 plasma viremia [34]. For that reason, leronlimab is currently under investigation in a Phase2b/3 for severely ill COVID-19 patients [35].…”

C-C chemokine receptor type 5 links COVID-19, Rheumatoid arthritis, and Hydroxychloroquine: In silico analysis 

“…In COVID-19 patients, disruption of the CCL5-CCR5 axis through CCR5 blocking antibody leronlimab was shown to reduce plasma IL-6, and SARS-CoV-2 plasma viremia [35]. For that reason, leronlimab is currently under investigation in a Phase2b/3 for severely ill COVID-19…”