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

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date1. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation2. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-193,4. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.

The COVID-19 Pandemic and its Impact on the Cardio-Oncology Population

“…Due to its immune system restorative properties, leronlimab is being investigated for compassionate use in the treatment of COVID-19 patients [96,97]. Studies examining receptor blockade in leronlimab preliminarily have shown decreases in IL-6, restoration of CD4/CD8 ratios, and reduction in overall COVID-19 viremia [98]. These collective findings suggest possible therapeutic role in establishing immune reconstitution in patients that are critically ill and may provide dual benefit in patients with shared cancer diagnoses.…”

Repurposing anticancer drugs for the management of COVID-19

“…PRO 140 has shown a promising antiviral potency with a high barrier to resistance and encouraging shortterm safety and tolerability [189]. A recently published Preprint suggested that leronlimab disrupts the CCL5/ RANTES-CCR5 axis and restores immune homeostasis in COVID-19 patients [133]. The authors observed a marked CCR5 receptor occupancy on macrophages and T lymphocytes, rapid drop of circulating IL-6, CD4/ CD8 ratio restoration and a significant decrease of patients' viremia [133].…”

“…A recently published Preprint suggested that leronlimab disrupts the CCL5/ RANTES-CCR5 axis and restores immune homeostasis in COVID-19 patients [133]. The authors observed a marked CCR5 receptor occupancy on macrophages and T lymphocytes, rapid drop of circulating IL-6, CD4/ CD8 ratio restoration and a significant decrease of patients' viremia [133]. These encouraging findings boosted the rapid entrance of leronlimab into two clinical trials for mild to moderate and severe COVID-19 infection (NCT04343651 and NCT04347239).…”