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

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.

• Authors: Aldo Bonaventura, Alessandra Vecchié, Tisha S Wang, Elinor Lee, Paul C Cremer, Brenna Carey, Prabalini Rajendram, Kristin M Hudock, Leslie Korbee, Benjamin W Van Tassell, Lorenzo Dagna, Antonio Abbate
• Journal: Frontiers in immunology (Front Immunol) Vol. 11 Pg. 1625 ( 2020) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 32719685 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2020 Bonaventura, Vecchié, Wang, Lee, Cremer, Carey, Rajendram, Hudock, Korbee, Van Tassell, Dagna and Abbate.

Chemical References

• Antibodies, Monoclonal, Humanized
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• mavrilimumab
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Betacoronavirus (immunology)
• COVID-19
• Coronavirus Infections (drug therapy, immunology, pathology)
• Disease Models, Animal
• Drug Delivery Systems
• Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors, immunology)
• Humans
• Inflammation (drug therapy, immunology, pathology)
• Macrophages, Alveolar (immunology, pathology)
• Pandemics
• Pneumonia, Viral (drug therapy, immunology, pathology)
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors, immunology)
• SARS-CoV-2
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes (immunology, pathology)