Journal Article

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies

Van Tassell, Benjamin W., Cremer, Paul C., Rajendram, Prabalini, Wang, Tisha S., Lee, Elinor, Vecchié, Alessandra, Bonaventura, Aldo, Hudock, Kristin M., Carey, Brenna, Korbee, Leslie, Abbate, Antonio, Dagna, Lorenzo

2020

Overview

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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Alveoli / Animal models / Animals / Antibodies, Monoclonal, Humanized - therapeutic use / Antigens / Arthritis / Betacoronavirus - immunology / Cell differentiation / Clinical trials / Coronavirus Infections - drug therapy / Coronavirus Infections - immunology / Coronavirus Infections - pathology / COVID-19 / cytokine release syndrome / Cytokine storm / Disease / Disease Models, Animal / Drug Delivery Systems / Fibroblasts / GM-CSF / Granulocyte-macrophage colony-stimulating factor / Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors / Granulocyte-Macrophage Colony-Stimulating Factor - immunology / Granulocytes / Humans / IL-6 / Immune response / Immunology / Immunomodulation / Inflammation / Inflammation - drug therapy / Inflammation - immunology / Inflammation - pathology / Interferon / Interleukin 6 / Intranasal administration / Kinases / Leukocytes (granulocytic) / Ligands / Lymphocytes / Lymphocytes T / Macrophages / Macrophages, Alveolar - immunology / Macrophages, Alveolar - pathology / mavrilimumab / Mechanical ventilation / Medical prognosis / Monoclonal antibodies / Monocytes / Neutrophils / Pandemics / Pneumonia / Pneumonia, Viral - drug therapy / Pneumonia, Viral - immunology / Pneumonia, Viral - pathology / Proteins / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - immunology / Respiratory failure / Respiratory tract infection / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Signal Transduction - drug effects / Signal Transduction - immunology / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Tumor necrosis factor-TNF / Viral infections / γ-Interferon