ABSTRACT
As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.
Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Humans , Immunoglobulin Fragments , SARS-CoV-2/genetics , Spike Glycoprotein, CoronavirusSubject(s)
Antibodies, Monoclonal/therapeutic use , C-Reactive Protein/metabolism , COVID-19/therapy , Interleukin-8/blood , SARS-CoV-2/drug effects , Serum Amyloid P-Component/metabolism , Ventilators, Mechanical , Acute Disease , Antineoplastic Agents, Immunological/therapeutic use , C-Reactive Protein/genetics , COVID-19/immunology , COVID-19/virology , Humans , Interleukin-8/antagonists & inhibitors , Prospective Studies , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Serum Amyloid P-Component/genetics , Survival Rate , COVID-19 Drug TreatmentABSTRACT
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
Subject(s)
C-Reactive Protein/genetics , COVID-19/genetics , Gene Expression Profiling/methods , Macrophages/metabolism , SARS-CoV-2/isolation & purification , Serum Amyloid P-Component/genetics , A549 Cells , Adult , C-Reactive Protein/metabolism , COVID-19/epidemiology , COVID-19/virology , Cell Line, Tumor , Cells, Cultured , Cohort Studies , Endothelial Cells/metabolism , Epidemics , Female , Humans , Male , Middle Aged , Monocytes/metabolism , Neutrophils/metabolism , Prognosis , SARS-CoV-2/physiology , Serum Amyloid P-Component/metabolismABSTRACT
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.