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Leronlimab Treatment Inhibits CCR5 in Critically Ill COVID-19 Patients--Decreasing Inflammatory Cytokines, Increasing CD8 T-Cells, and Decreasing SARS-CoV-2 RNA in Plasma by Day 14

Researchers have reported that treatment of ten critically ill COVID-19 patients with the anti-CCR5 monoclonal antibody leronlimab restored depressed CD8 counts which correlated inversely with decreases in plasma viral load of SARS-CoV-2, which moved to undectable by Day 14 of treatment, and that 6 of 10 treated patients showed significant improvement during the 14-day test period. The scientists noted that levels of the normal CCR5-binding immunomodulatory molecule CCL5/RANTES is elevated 3- to 5-fold in mild to moderate COVID patients and over 1000-fold in critical COVID patients, suggesting that blocking the binding of this immunomodulatory molecule might have an influence in COVID-19. The newly reported results include the first report of the highly sensitive measurement of quantitative plasma viral load by droplet digital PCR (ddPCR) in COVID patients. The researchers also described a statistically significant drop in interleukin-6 (IL-6) by Day 14 of leronlimab treatment. In addition, single-cell transcriptome analysis revealed decreased in IL-6 in myeloid cells. The work was reported online on November 9, 2020, in the International Journal of Infectious Diseases. The open-access article is titled “CCR5 Inhibition in Critical COVID-19 Patients Decreases Inflammatory Cytokines, Increases CD8 T-Cells, and Decreases SARS-CoV2 RNA in Plasma by Day 14” (https://www.ijidonline.com/article/S1201-9712(20)32305-5/fulltext). The authors conclude that, while the current study design precludes clinical efficacy inferences, the results implicate CCR5 as a therapeutic target for COVID-19 and form the basis for ongoing randomized clinical trials. Leronlimab is produced by CytoDyn, Inc., a Vancouver, Washington-based, late-stage biotechnology company (https://www.cytodyn.com/). The authors include first and corresponding author Bruce Patterson (brucep@incelldx.com), MD, Chief Executive Officer and Founder of IncellDx, a diagnostics company headquartered in San Carlos, California, and former Medical Director of Diagnostic Virology at Stanford University Hospitals and Clinics.

The second author is Harish Seethamraju, MD, Medical Director for Advanced Lung Failure and Lung Transplant, at the Montefiore Medical Center, the primary teaching hospital of the Albert Einstein College of Medicine in the Bronx, New York City. Dr. Seethamraju is recognized as an international expert in lung transplantation. He was twice awarded as "Best Attending of the Year," at the Baylor College of Medicine, Pulmonary Section. It was Dr. Seethamraju who first contacted CytoDyn CEO Dr. Nader Pourhassan to request the use of leronlimab for his critically ill COVID-19 patients. He told Dr. Pourhassan that he “was just watching them die.”

Co-senior authors are Lishomwa Ndhlovu, MD, PhD, Assistant Professor (Interim) of Immunology in Medicine at Weill Cornell Medicine in the Division of Infectious Diseases, and Jonah Sacha, PhD, Professor, Vaccine & Gene Therapy Institute (VGTI) and Oregon National Primate Research Center, Oregon Health & Science University.

BACKGROUND & CLINICAL DETAILS

In their abstract, the authors noted that Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now a global pandemic. Emerging results have indicated a dysregulated immune response. Given the known role of CCR5 in immune cell migration and inflammation, the authors 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. This humanized monoclonal antibody was originally developed in the HIV/AIDs research effort as a means to block CCR5, which is a cell-surface co-receptor for HIV, in addition to its normal roles in the immune system.

In March 2020, ten terminally-ill, critical COVID-19 patients, under the care of Montefiore’s Dr. Seethamraju, received two injected doses of leronlimab via individual emergency use indication (EIND). The authors analyzed changes in clinical presentation, immune cell populations, inflammation, as well as SARS-CoV-2 plasma viremia before and 14 days after treatment.

Over the 14-day study period, 6 of 10 patients survived, with 2 being extubated, and 1 patient discharged. The researchers observed complete CCR5 receptor occupancy in all donors by day 7. Compared to baseline, they observed a concomitant statistically significant reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and resolution of SARS-CoV-2 plasma viremia [plasma viral load (pVL)] compared to controls. Further, the increase in CD8% was inversely correlated with reduction in pVL (r = −0.77, p = 0.0013).

The authors concluded that, while the current study design precludes clinical efficacy inferences, the results implicate CCR5 as a therapeutic target for COVID-19 and form the basis for ongoing randomized clinical trials.

DISCLOSURE

Michael D. O’Neill, Editor & Publisher of BioQuick News, has a very small amount of equity in CytoDyn. That small holding had no effect in the selection and publication of this article. This article was selected and published solely on a consideration of its news value for the BioQuick News audience.

[International Journal of Infectious Diseases article]