Last year, around the Thanksgiving holiday, the Omicron SARS-CoV-2 variant emerged, harboring “many more mutations in the spike protein and seemed to be more infectious,” Dr. Taran Gujral, part of the Human Biology Division, explains. His group previously found that the Spike protein could promote cytokine release from monocytes- a type of white blood cell that fights off germs. This cytokine storm occurs when an infection triggers your immune system to flood your bloodstream with inflammatory proteins called cytokines, termed cytokine storm. While cytokines serve as crucial signals to help your immune system do its job, a large release of cytokines can cause damage. In the case of COVID-19, 15-20% of patients face increased inflammation induced by this massive cytokine storm that ultimately can lead to lung damage and respiratory failure. So in mid-December, the Gujral team “set out to determine whether the Spike from Omicron (with many mutations) could also promote cytokine release and whether we could find existing drugs/medicine that could suppress this cytokine storm.” In their recently published EMBO Molecular Medicine study led by Dr. Marina Chan and with help from Dr. Eric Holland, the researchers identified how the SARS-CoV-2 Omicron variant also causes cytokine release, and then identified drugs that were able to inhibit this cytokine storm.
The Omicron variant carries more than 50 mutations, including more than 25 mutations in the Spike protein alone, many of which are present in the N-terminal domain (NTD) of the protein. Dr. Chan first sought to determine whether the mutations in the NTD of the Omicron variant affect its ability to promote the secretion of inflammatory cytokines and how this compared to other variants. The researchers stimulated human peripheral blood mononuclear cells (PBMCs) from healthy donors obtained from Bloodworks NW, with the NTD of different SARS-CoV-2 variant spike proteins. They found that the Omicron variant was able to stimulate cytokine release as efficiently as other variants. The Gujral team then asked if they could identify a drug that would be able to inhibit cytokine release, and thus could prove for an effective COVID-19 therapy. Previously, the group identified Ponatinib, an FDA-approved leukemia drug in a machine learning-based drug screen as a potent inhibitor of cytokine release in PBMCs. The researchers then asked if Ponatinib could inhibit cytokine release mediated by the Omicron NTD, in addition to evaluating Baricitinib, an FDA-approved COVID-19 drug and Olverembatinib, a clinical-stage multi-kinase inhibitor that is structurally similar to Ponatinib. While Baricitinib only inhibited three of the seven cytokines measured, both Ponatinib and Olverembatinib inhibited the release of all cytokines, even at low concentrations. As Olverembatinib treatment showed the most substantial suppression of the Omicron NTD-mediated cytokine release, they next tested the response of Olverembatinib in PBMCs from nine COVID-19 patients. Excitingly, the Gujral team found that the drug was able to inhibit Omicron NTD-mediated cytokine release in these patient samples.
Altogether, these important findings support that targeting multiple kinases essential for SARS-CoV-2-mediated cytokine release, such as Olverembatinib, may present an attractive therapeutic option for treating moderate-to-severe COVID-19. As such, this works has also been recognized by national media outlets, highlighting the potential for this drug to be used as a COVID-19 treatment. Drs. Gujral and Chan add that, “the persistent upregulation of cytokines is also associated with long-covid symptoms. Therefore, we hope to trial Olverembatinib in COVID-19 patients in the long covid.” Furthermore, Drs. Gujral and Chan explain they “are working with a team from Ascentage Pharmaceuticals, who has been committed to providing the drug (Olverembatinib) and funding a clinical trial on COVID-19 patients. Drs. Rachel Bender Ignacis and Vivian Oehler from Fred Hutch are leading these efforts.”
This work was supported by the Fred Hutch COVID-19 Pilot Fund.
UW/Fred Hutch Cancer Consortium members Taran Gujral and Eric Holland contributed to this research.
Chan M, Holland EC, Gujral TS. Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release in human peripheral blood mononuclear cells. EMBO Mol Med. 2022 Jun 8;14(6):e15919. doi: 10.15252/emmm.202215919. Epub 2022 May 17. PMID: 35579119.