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Highlights • Treatment with the anti-CCR5 humanized monoclonal antibody restored depressed CD8 counts which inversely correlated with decreases in plasma viral load (pVL) which went to undetectable by Day 14 of treatment. • CCL5/RANTES is elevated 3–5 fold in mild to moderate COVID patients and over 100-fold in critical COVID patients. • First report of highly sensitive, quantitative pVL by ddPCR in COVID patients. • Statistically significant drop in IL-6 by Day 14 during treatment. • Single cell transcriptome analysis revealed decreased IL-6 in myeloid cells., Objective Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now a global pandemic. Emerging results indicate a dysregulated immune response. Given the role of CCR5 in immune cell migration and inflammation, we investigated the impact of CCR5 blockade via the CCR5-specific antibody leronlimab on clinical, immunological and virological parameters in patients with severe COVID-19 disease. Methods In March 2020, ten terminally-ill, critical COVID-19 patients received two doses of leronlimab via individual emergency use indication (EIND). We analyzed changes in clinical presentation, immune cell populations, inflammation as well as SARS-CoV-2 plasma viremia before and 14 days after treatment. Results Over the 14 day study period 6/10 patients survived, 2 extubated, and 1 patient was discharged. We observed complete CCR5 receptor occupancy in all donors by day 7. Compared to baseline, we observed a concomitant statistically significant reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and resolution of SARS-CoV2 plasma viremia (pVL) compared to controls. Further, the increase in CD8% was inversely correlated with reduction in pVL (r = −0.77, p = 0.0013). Conclusions While the current study design precludes clinical efficacy inferences, these results implicate CCR5 as a therapeutic target for COVID-19 and form the basis for ongoing randomized clinical trials.

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.