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

Nicholas Agresti; Jacob P Lalezari; Phillip P Amodeo; Kabir Mody; Steven F Mosher; Harish Seethamraju; Scott A Kelly; Nader Z Pourhassan; C David Sudduth; Christopher Bovinet; Ahmed E ElSharkawi; Bruce K Patterson; Reejis Stephen; Jonah B Sacha; Helen L Wu; Seth A Gross; Kush Dhody

doi:10.1016/j.jtauto.2021.100083

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

J Transl Autoimmun. 2021:4:100083. doi: 10.1016/j.jtauto.2021.100083. Epub 2021 Jan 6.

Authors

Nicholas Agresti¹, Jacob P Lalezari², Phillip P Amodeo¹, Kabir Mody³, Steven F Mosher¹, Harish Seethamraju⁴, Scott A Kelly², Nader Z Pourhassan², C David Sudduth¹, Christopher Bovinet⁵, Ahmed E ElSharkawi¹, Bruce K Patterson⁶, Reejis Stephen¹, Jonah B Sacha⁷, Helen L Wu⁷, Seth A Gross⁸, Kush Dhody⁹

Affiliations

¹ Southeast Georgia Health System, 2415 Parkwood Drive, Brunswick, GA, 31520, USA.
² CytoDyn, 1111 Main Street, Suite 660 Vancouver, WA, 98660, USA.
³ Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 3222, USA.
⁴ Montefiore Medical Center, Albert Einstein University, 1695A Eastchester Rd, Bronx, NY, 10467, USA.
⁵ Spine Center of Southeast Georgia, 1111 Glynco Pkwy Ste 300, Brunswick, GA, 31525, USA.
⁶ IncellDx, 1541 Industrial Rd, San Carlos, CA, 94070, USA.
⁷ Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, 505 N.W. 185th Avenue, Beaverton, OR, 97006, USA.
⁸ NYU Langone Gastroenterology Associates, 240 East 38th Street, 23rd Floor New York, NY, 10016, USA.
⁹ Amarex Clinical Research, 20201 Century Blvd, Germantown, MD, 20874, USA.

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).

Publication types

Review