Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab

Alessandro Rambaldi, Giuseppe Gritti, Maria Caterina Micò, Marco Frigeni, Gianmaria Borleri, Anna Salvi, Francesco Landi, Chiara Pavoni, Aurelio Sonzogni, Andrea Gianatti, Francesca Binda, Stefano Fagiuoli, Fabiano Di Marco, Luca Lorini, Giuseppe Remuzzi, Steve Whitaker, Gregory Demopulos

Research output: Contribution to journalArticlepeer-review

Abstract

In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway's effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.

Original languageEnglish
Pages (from-to)152001
JournalImmunobiology
Volume225
Issue number6
DOIs
Publication statusPublished - Nov 2020

Keywords

  • Antibodies, Monoclonal/immunology
  • C-Reactive Protein/immunology
  • COVID-19/complications
  • Complement Pathway, Mannose-Binding Lectin/drug effects
  • Endothelium, Vascular/drug effects
  • Female
  • Humans
  • Immunoglobulin G/immunology
  • Inflammation/complications
  • Interleukin-6/blood
  • Male
  • Mannose-Binding Protein-Associated Serine Proteases/antagonists & inhibitors
  • Middle Aged
  • Outcome Assessment, Health Care/methods
  • Retrospective Studies
  • SARS-CoV-2/immunology
  • Thrombotic Microangiopathies/complications

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