Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab

Abstract

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

Keywords: ACE2, angiotensin-converting enzyme 2; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; Acute respiratory distress syndrome (ARDS); BID, bis in die (twice a day); CCL2, chemokine C–C motif ligand 2; CCL3, chemokine C–C motif ligand 3; CCL4, chemokine C–C motif ligand 4; CCL5, chemokine C–C motif ligand 5; CCR1, C–C chemokine receptor type 1; CCR5, C–C chemokine receptor type 5; CDC, Centers for Disease Control; CK, creatine kinase; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CXCL10, chemokine C-X-C motif ligand 10; CXCL2, chemokine C-X-C motif ligand 2; Coronavirus disease 2019 (COVID-19); DPP4, dipeptidyl peptidase-4; DVT, deep vein thrombosis; EDTA, ethylenediaminetetraacetic acid; FDA, Food and Drug Administration; Fi02, fraction of inspired oxygen, IgG4; Hydroxychloroquine, HLH; Leronlimab (PRO 140); Middle East respiratory syndrome coronavirus, MIG; National Early Warning Score, NK; RO, receptor occupancy; RT–PCR, reverse transcriptase polymerase chain reaction; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; T-reg RO, regulatory T cells – receptor occupancy; TGF- α, transforming growth factor alpha; TNF-α, tumor necrosis factor alpha; TNF-β, tumor necrosis factor beta; Tregs, regulatory T cells; VEGF-A, vascular endothelial growth factor A; WBC, white blood cell; WHO, World Health Organization; eIND, emergency investigational new drug application; hemophagocytic lymphohistiocytosis, HTN; hypertension, ICU; immunoglobulin G4, HCQ; intensive care unit, IL-1β; interferon gamma, IL-6; interferon gamma-inducible protein (IP) 10 or CXCL10, LOA; interleukin 1 beta, IFN-ƴ; interleukin 6, IP-10; letter of authorization, MCP; macrophage Inflammatory Proteins 1-alpha, MIP-1β; macrophage Inflammatory Proteins 1-beta, N/A; macrophage colony stimulating factor, MDC (CCL22); macrophage colony-stimulating factor encoded by the CCL22 gene, MERS-CoV; monocyte chemoattractant protein, M-CSF; monokine induced by IFN-γ (interferon gamma), MIP-1α; natural killer, OSA; not applicable, NEWS2; obstructive sleep apnea, PDGF-AA; per os (taken by mouth), RANTES; platelet-derived growth factor AA, PDGF-AA/BB; platelet-derived growth factor AA/BB, PEEP; positive end-expiratory pressure, PNA; pulmonary nodular amyloidosis, po; regulated on activation, normal T expressed and secreted (also known as CCL5).

Fig. 1

Immune restoration as measured by CD4% (a), CD8% (b), and CD4+/CD8+ T cell ratio (c); IL-6 levels (d); CRP levels (e); T cell and monocyte receptor occupancy (f); and vasopressor use (g) at Days 3, 7, and 14.