Based on experience of pathological research on SARS-CoV-1 infection, following Tocilizumab(anti IL-6) and Carelizumab(anti PD-1), Dupilumab(anti IL-4 & IL-13) may also improve inflammation and fibrosis associated with ACE2-decrease and Cytokine Storm in 2019nCoV(SARS-CoV-2) infection.
ACE2 is the binding site of the Spike proteins of SARS-CoV-1 and SARS-CoV-2[1], and ACE2 has important protective effects on myocardial cells, vascular endothelium and alveolar epithelium[2][3].
In the early stage of infection, the role of IL-4 in down-regulating ACE2 can protect cells from virus infection, but in the severe stage of the disease, ACE2 is too low to continue to exert protective effects on alveolar epithelium, blood vessels and myocardial cells[4].
Therefore, treatments that increase ACE levels in the body, such as infusion of GSK-2586881 [2] and inhibition of IL-4, are possible strategies to reduce cardiopulmonary damage in SARS-CoV-1 and SARS-CoV-2 infections.
And IL-4 induces differentiation of naive helper T cells (Th0 cells) to Th2 cells[5].
The increase of Th2 cells following infection of macrophages in SARS is an important factor in maintaining the Cytokine Storm[6]. This process is closely related to the activation of p38 MAPK, but extensive immunosuppression of p38 MAPK inhibitors may significantly increase the risk of new infections as same as glucocorticoids.
Therefore, reducing the production of Th2 cells by inhibiting IL-4 is also a possible way to reduce the Cytokine Storm.
In addition, IL-4 and IL-13 play main role in the initiation of inflammatory exudation and hyperfibrosis in which eosinophils are involved[7][8]. Inflammatory exudation and fibrosis in SARS-CoVs infections are the important cause of severe patients to be unable to separate from invasive ventilation or ECMO.
In summary, Dupilumab(anti IL-4 & IL-13) can be next immunomodulatory antibody drug that will be clinically tested for the treatment of severe patients with 2019nCoV(SARS-CoV-2) infection.
Of course, it should be noted that the expression of Spike protein on cells and the infection of macrophages by Viruses are the main factors that cause autoimmune attack in SARS-CoVs infection.
Therefore, these antibody drugs can only play the role of immunomodulatory therapy in severe patients based on the use of nucleotide antiviral drugs represented by Remdesivir.
References:
[1] Hoffmann M, Kleine-Weber H, Krueger N, et al. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells[J]. bioRxiv, 2020.
[2] Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome[J]. Critical Care, 2017, 21(1): 234.
[3] Keidar S, Kaplan M, Gamliel-Lazarovich A. ACE2 of the heart: from angiotensin I to angiotensin (1–7)[J]. Cardiovascular research, 2007, 73(3): 463-469.
[4] Reddy R, Asante I, Liu S, et al. Circulating angiotensin peptides levels in Acute Respiratory Distress Syndrome correlate with clinical outcomes: A pilot study[J]. PloS one, 2019, 14(3).
[5] Fallon P G, Jolin H E, Smith P, et al. IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13[J]. Immunity, 2002, 17(1): 7-17.
[6] de Lang A, Osterhaus A D M E, Haagmans B L. Interferon-γ and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells[J]. Virology, 2006, 353(2): 474-481.
[7] Schleimer R P, Sterbinsky S A, Kaiser J, et al. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1[J]. The Journal of Immunology, 1992, 148(4): 1086-1092.
[8] Passalacqua G, Mincarini M, Colombo D, et al. IL-13 and idiopathic pulmonary fibrosis: Possible links and new therapeutic strategies[J]. Pulmonary pharmacology & therapeutics, 2017, 45: 95-100.
