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2.
Mol Med ; 27(1): 49, 2021 05 22.
Article in English | MEDLINE | ID: covidwho-1238700

ABSTRACT

A SARS-like coronavirus 2 (SARS-CoV-2) has caused a pandemic Coronavirus Disease 2019 (COVID-19) that killed more than 3.3 million people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its spike protein to bind a host receptor, the angiotensin-converting enzyme 2 (ACE2), to gain entry. Currently, several mRNA or adenoviral vaccines encoding for the spike protein of SARS-CoV-2 are being used to boost antibodies capable of inhibiting spike-ACE2 interaction and viral entry. However, recent evidence has also suggested an anti-inflammatory effect of spike-reactive antibodies, suggesting that some SARS-CoV-2 spike-based vaccines may elicit protective antibodies capable of inhibiting GM-CSF production and COVID-19 progression.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/metabolism , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Neutralizing/immunology , COVID-19/metabolism , COVID-19/virology , COVID-19 Vaccines/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Host-Pathogen Interactions/drug effects , Humans , Protein Binding/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization/drug effects , Virus Replication/drug effects
3.
Mayo Clin Proc ; 95(11): 2382-2394, 2020 11.
Article in English | MEDLINE | ID: covidwho-912419

ABSTRACT

OBJECTIVE: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death. RESULTS: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P=.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab. CONCLUSION: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , SARS-CoV-2 , Aged , COVID-19/epidemiology , COVID-19/metabolism , Dose-Response Relationship, Drug , Female , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Infusions, Intravenous , Male , Middle Aged , Pandemics , Treatment Outcome
4.
Proc Natl Acad Sci U S A ; 117(44): 27141-27147, 2020 11 03.
Article in English | MEDLINE | ID: covidwho-834980

ABSTRACT

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.


Subject(s)
Coronavirus Infections/therapy , Cytokines/antagonists & inhibitors , Nanoparticles/therapeutic use , Pneumonia, Viral/therapy , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Cell Membrane/chemistry , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , HEK293 Cells , Humans , Interleukin-6/antagonists & inhibitors , Mice , Mice, Inbred ICR , Monocytes , Nanoparticles/chemistry , Pandemics , Peptidyl-Dipeptidase A/metabolism , Receptors, Cytokine/metabolism , SARS-CoV-2 , THP-1 Cells
5.
Front Immunol ; 11: 1625, 2020.
Article in English | MEDLINE | ID: covidwho-688729

ABSTRACT

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections , Drug Delivery Systems , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Pandemics , Pneumonia, Viral , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
6.
Immunotherapy ; 12(15): 1121-1126, 2020 10.
Article in English | MEDLINE | ID: covidwho-602002

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) is a novel disease associated with a cytokine-mediated, severe, acute respiratory syndrome. Tocilizumab and lenzilumab are recombinant monoclonal antibodies against IL-6 and granulocyte macrophage colony-stimulating factor, respectively, and have been proposed as a potential treatment for acute, hypoxic respiratory failure associated with COVID-19. Results & methodology: We present the case of a 68-year-old man with COVID-19 who was initially treated with hydroxychloroquine and lenzilumab, but continued to develop hypoxemia, requiring an increase in respiratory support with an associated rise in serum inflammatory markers. He was subsequently treated with tocilizumab with marked clinical improvement and a decrease in acute phase reactants within 48 h. Discussion & conclusion: This case demonstrates the effective use of tocilizumab in the treatment of COVID-19 and suggests the superiority of tocilizumab over lenzilumab in the management of this cytokine-mediated syndrome.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Aged , Betacoronavirus , COVID-19 , Combined Modality Therapy , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/therapy , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Male , Pandemics , Pneumonia, Viral/pathology , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Insufficiency/pathology , Respiratory Insufficiency/therapy , SARS-CoV-2 , Treatment Outcome
7.
Lancet Respir Med ; 8(8): 822-830, 2020 08.
Article in English | MEDLINE | ID: covidwho-599200

ABSTRACT

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Immunologic Factors/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/prevention & control , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Disease Progression , Humans , Immunomodulation , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Respiratory Distress Syndrome/virology , SARS-CoV-2
8.
J Immunother Cancer ; 8(1)2020 05.
Article in English | MEDLINE | ID: covidwho-220167

ABSTRACT

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Immunotherapy , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/drug therapy , Societies, Medical , Adoptive Transfer , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/complications , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/antagonists & inhibitors , Interleukin-1/antagonists & inhibitors , Interleukin-17/antagonists & inhibitors , Interleukin-23/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Janus Kinases/antagonists & inhibitors , Neoplasms/immunology , Neoplasms/therapy , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , STAT Transcription Factors/antagonists & inhibitors , Severe Acute Respiratory Syndrome/pathology , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors
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