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

• Published in: Journal of translational autoimmunity (Online) Vol. 4; p. 100083
• Main Authors: Agresti, Nicholas, Lalezari, Jacob P., Amodeo, Phillip P., Mody, Kabir, Mosher, Steven F., Seethamraju, Harish, Kelly, Scott A., Pourhassan, Nader Z., Sudduth, C. David, Bovinet, Christopher, ElSharkawi, Ahmed E., Patterson, Bruce K., Stephen, Reejis, Sacha, Jonah B., Wu, Helen L., Gross, Seth A., Dhody, Kush
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Elsevier
• Subjects: Acute respiratory distress syndrome (ARDS); Coronavirus disease 2019 (COVID-19); Leronlimab (PRO 140); Review article; SARS-CoV-2; CDC; DVT; SARS-CoV; regulated on activation; ALT; hemophagocytic lymphohistiocytosis; TGF- α; CXCL2; immunoglobulin G4; COVID-19; interleukin 6; SARS-CoV-2; natural killer; Leronlimab (PRO 140); Acute respiratory distress syndrome (ARDS); eIND; per os (taken by mouth); intensive care unit; National Early Warning Score; CCR5; monocyte chemoattractant protein; ARDS; WHO; interferon gamma; positive end-expiratory pressure; platelet-derived growth factor AA/BB; letter of authorization; RT–PCR; VEGF-A; ACE2; Hydroxychloroquine; pulmonary nodular amyloidosis; RO; Coronavirus disease 2019 (COVID-19); CRP; T-reg RO; FDA; Middle East respiratory syndrome coronavirus; macrophage Inflammatory Proteins 1-beta; DPP4; Fi02, fraction of inspired oxygen; macrophage Inflammatory Proteins 1-alpha; CCL5; CCL4; CCL3; CCL2; WBC; monokine induced by IFN-γ (interferon gamma); BID; macrophage colony-stimulating factor encoded by the CCL22 gene; CCR1; obstructive sleep apnea; AST; interferon gamma-inducible protein (IP) 10 or CXCL10; not applicable; platelet-derived growth factor AA; Tregs; CK; EDTA; macrophage colony stimulating factor; CXCL10; interleukin 1 beta; TNF-α; TNF-β; hypertension; COPD; natural killer, OSA; platelet-derived growth factor AA, PDGF-AA/BB; EDTA, ethylenediaminetetraacetic acid; Fi02, fraction of inspired oxygen, IgG4; CDC, Centers for Disease Control; COPD, chronic obstructive pulmonary disease; T-reg RO, regulatory T cells – receptor occupancy; TNF-α, tumor necrosis factor alpha; macrophage colony-stimulating factor encoded by the CCL22 gene, MERS-CoV; Hydroxychloroquine, HLH; platelet-derived growth factor AA/BB, PEEP; VEGF-A, vascular endothelial growth factor A; SARS-CoV, severe acute respiratory syndrome coronavirus; pulmonary nodular amyloidosis, po; monokine induced by IFN-γ (interferon gamma), MIP-1α; RT–PCR, reverse transcriptase polymerase chain reaction; National Early Warning Score, NK; interleukin 1 beta, IFN-ƴ; CCR5, C–C chemokine receptor type 5; intensive care unit, IL-1β; CCL5, chemokine C–C motif ligand 5; not applicable, NEWS2; CCL2, chemokine C–C motif ligand 2; Tregs, regulatory T cells; interleukin 6, IP-10; obstructive sleep apnea, PDGF-AA; DVT, deep vein thrombosis; CRP, C-reactive protein; AST, aspartate aminotransferase; TNF-β, tumor necrosis factor beta; Middle East respiratory syndrome coronavirus, MIG; per os (taken by mouth), RANTES; positive end-expiratory pressure, PNA; eIND, emergency investigational new drug application; interferon gamma-inducible protein (IP) 10 or CXCL10, LOA; macrophage Inflammatory Proteins 1-alpha, MIP-1β; RO, receptor occupancy; CCL3, chemokine C–C motif ligand 3; hypertension, ICU; hemophagocytic lymphohistiocytosis, HTN; BID, bis in die (twice a day); ARDS, acute respiratory distress syndrome; interferon gamma, IL-6; letter of authorization, MCP; WHO, World Health Organization; CXCL10, chemokine C-X-C motif ligand 10; ALT, alanine aminotransferase; immunoglobulin G4, HCQ; regulated on activation, normal T expressed and secreted (also known as CCL5); TGF- α, transforming growth factor alpha; macrophage colony stimulating factor, MDC (CCL22); macrophage Inflammatory Proteins 1-beta, N/A; CCR1, C–C chemokine receptor type 1; DPP4, dipeptidyl peptidase-4; CK, creatine kinase; FDA, Food and Drug Administration; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; CXCL2, chemokine C-X-C motif ligand 2; COVID-19, coronavirus disease 2019; WBC, white blood cell; ACE2, angiotensin-converting enzyme 2; monocyte chemoattractant protein, M-CSF; CCL4, chemokine C–C motif ligand 4
• ISSN: 2589-9090; 2589-9090
• DOI: 10.1016/j.jtauto.2021.100083

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. •Leronlimab is a monoclonal antibody in clinical trials to treat the cytokine storm.•Critically ill patients received leronlimab through compassionate use and had remarkable recoveries measured objectively.•The CCR5 receptor is important in recruiting inflammatory cells mainly T cells and macrophages.•Leronlimab disrupted this signal and may have been responsible for restoration of the immune system, improved survival and decrease in IL-6.