RESUMO
At least since March 2020, the multiorgan disease COVID-19 has a firm grip on the world. Although most of the cases are mild, patients from risk populations could develop a cytokine storm, which is characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper will introduce the small molecule MP1032, describe its mode of action, and give rationale why it is a promising option for prevention/treatment of SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-pthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting antioxidant activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, immune-regulatory and PARP-1 modulating properties, coupled with antiviral effects against SARS-CoV-2 were shown in various cell models. Efficacy has been preclinically elucidated in LPS-induced endotoxemia, a model with excessively activated immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-months daily administrations, no serious adverse drug reactions occurred highlighting the outstanding safety profile of MP1032.
RESUMO
The SARS-CoV-2 pandemic is continuing to impact the global population. This study was designed to assess the interplay of antibodies with the systemic cytokine response in SARS-CoV-2 patients. We demonstrate that significant anti-SARS-CoV-2 antibody production to Receptor Binding Domain (RBD), Nucleocapsid (N), and Spike S1 subunit (S1) of SARS-CoV-2 develops over the first 10 to 20 days of infection. The majority of patients produced antibodies against all three antigens (219/255 SARS-CoV-2 positive patient specimens, 86%) suggesting a broad response to viral proteins. Patient mortality, sex, blood type, and age were all associated with differences in antibody production to SARS-CoV-2 antigens which may help explain variation in immunity between these populations. To better understand the systemic immune response, we analyzed the production of 20 cytokines by SARS-CoV-2 patients over the course of infection. Cytokine analysis of SARS-CoV-2 positive patients exhibited increases in proinflammatory markers (IL-6, IL-8, IL-18) and chemotactic markers (IP-10, SDF-1, MIP-1{beta}, MCP-1, and eotaxin) relative to healthy individuals. Patients who succumbed to infection produced decreased IL-2, IL-4, IL-12, IL-13, RANTES, TNF-, GRO-, and MIP-1 relative to patients who survived infection. We also observed that the chemokine CXCL13 was particularly elevated in patients that succumbed to infection. CXCL13 is involved in B cell activation, germinal center development, and antibody maturation, and we observed that CXCL13 levels in blood trended with anti-SARS-CoV-2 antibody production. Furthermore, patients that succumbed to infection produced high CXCL13 and also tended to have high ratio of nucleocapsid to RBD antibodies. This study provides insights into SARS-CoV-2 immunity implicating the magnitude and specificity of response in relation to patient outcomes.