Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19
bioinformatics clinical drug discovery/repurposing immunology/immunity therapeutics
Authors: B. Pattterson et al.
Link to paper: https://www.researchsquare.com/article/rs-26517/v1
Journal/ Pre-Print: Research Square
Tags: Immunology/Immunity, Bioinformatics, Drug repurposing, Therapeutics, Clinical/ Diagnostics
1. Disrupting the CCL5-CCR5 axis by CCR5 blocking antibody (leronlimab) treatment may reduce serum IL-6, increase the CD8/CD4 ratio and reduce viremia levels in critical COVID-19 patients.
2. Single-cell RNAseq on 2 critically ill patients before and after leronlimab treatment revealed a reduction of IL-6, chemokine and IFN-related gene transcripts in myeloid cells.
3. Compared to healthy controls, COVID-19 patients had higher serum IL-1b, IL-6, IL-8 and CCL5. Moreover, IL-6 and CCL5 levels correlated with severity.
In this pilot study, 10 critically ill COVID-19 patients (6/10 renal transplant recipients) were given compassionate emergency use of Leronlimab, a CCR5-blocking antibody. The authors show a stepwise increase in serum concentrations of CCL5 (RANTES) from healthy controls, mild/moderate and critical patients. A single subcutaneous dose of Leronlimab bound to CCR5 on T cells and monocytes with high efficiency for over 14 days. The patients demonstrated a reduction in their plasma IL-6 level, a higher frequency of circulating CD8+ T cells and lower plasma viremia over 14 days. However, the lack of a control patient population and clinical outcomes prevents conclusions concerning efficacy.
Impact for SARS-CoV2/COVID19 research efforts
Postulates Leronlimab as a potential treatment of COVID-19 patients.
· In silico study / bioinformatics study
· Clinical Cohort study (e.g. drug trials) – Pilot study
Strengths and limitations of the paper
Novelty: Introduction of Leronlimab as COVID-19 treatment. Controlled clinical trials necessary and ongoing.
Standing in the field: [How does this study compare to existing knowledge]
Appropriate statistics: No control or alternative treatments used in this study therefore it is not clear if there is any efficacy. Too small number of patients included in the study. Non-parametric statistical tests used.
Viral model used: SARS-CoV-2 infected patients (New York City, USA) in critical care.
Translatability: Yes. Randomised, double blind, controlled trials have been registered to test Leronlimab in mild, moderate, severe and critical patients to test the efficacy.
- Limited number of patients and no control patient population included; therefore drug efficacy cannot be assessed.
- Needs inclusion of patient clinical outcomes.
- No information on the protein expression/functional status of CD8+ T cells/myeloid cells, or the therapeutic impact on humoral immunity.
- Would benefit from more information about patient recruitment (time from onset, time spent in ICU before recruitment, dates of recruitment).
- Needs inclusion of the criteria classifying mild, moderate and severe cases. Inclusion of information about mild/moderate patients (e.g. time from onset). Also needs a comment on the collection and virus status of the healthy control blood.