Combination Therapy of Anti-Inflammatory Apadenoson or Regadenoson, Immunoglobulin M Antibody, and Anti-Viral Remdesivir for Mitigating the COVID-19 Cytokine Storm and Improving Clinical Outcomes

P. Chhabra, M. Ma, B. Mann, S. Feldman, J. Linden, K.Brayman
University of Virginia, Virginia, United States

Keywords: Apadenoson, Regadenoson, Immunoglobulin M Antibody, Remdesivir, Type 1 Diabetes, COVID-19

A life-threatening manifestation of COVID-19 infection is the cytokine storm that necessitates hospitalization and supplemental oxygen. Despite vaccines, the ongoing pandemic has fueled interest in complementary therapeutics. We have shown that potent agonists of adenosine A2A receptors (A2AR), such as Apadenoson and Regadenoson, improved outcomes in SARS-CoV-2 infected mice by decreasing weight loss, improving clinical symptoms, reducing proinflammatory cytokines and chemokines in bronchial lavage fluid, and enhancing the survival of K18-hACE2 transgenic mice. Hospitalized COVID-19 patients receiving Regadenoson showed increased oxygen saturation, decreased D-dimer levels, lowered CRP levels, reduced iNKT cell activation, and lowered plasma proinflammatory cytokines. Although several antibody-based therapies are approved for emergency use, viral resistance remains a challenge with new variants emerging. Our studies demonstrated that Immunoglobulin M inhibits SARS-CoV-2 replication in vitro and prevents the interaction between the viral surface protein S-RBD and the ACE2 receptor by binding to S-RBD. A single low dose of IgM administered pre-challenge delays disease progression in diabetic infected mice. We conclude a combination therapy comprising Apadenoson or Regadenoson, IgM therapy, and the antiviral Remdesivir would effectively mitigate cytokine storms, prevent coagulation abnormalities, restore glucose control, and reduce mortality in diabetic COVID-19 patients, and could be used both preemptively or post-exposure.