IMMUNOLOGICAL INSIGHTS INTO THE THERAPEUTIC ROLES OF CD24Fc AGAINST SEVERE COVID-19

Song, No-Joon; Allen, Carter; Vilgelm, Anna E.; Riesenberg, Brian P.; Weller, Kevin P.; Reynolds, Kelsi; Chakravarthy, Karthik B.; Kumar, Amrendra; Khatiwada, Aastha; Sun, Zequn; Ma, Anjun; Chang, Yuzhou; Yusuf, Mohamed; Li, Anqi; Zeng, Cong; Evans, John P.; Bucci, Donna; Gunasena, Manuja; Xu, Menglin; Liyanage, Namal P.M.; Bolyard, Chelsea; Velegraki, Maria; Liu, Shan-Lu; Ma, Qin; Devenport, Martin; Liu, Yang; Zheng, Pan; Malvestutto, Carlos D.; Chung, Dongjun; Li, Zihai

BACKGROUND. SARS-CoV-2 causes COVID-19 through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns (DAMPs) and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) can dampen the broad inflammatory response induced by DAMPs, and a recent randomized phase III trial evaluating impact of CD24Fc in patients with severe COVID-19 has shown encouraging clinical efficacy. METHODS. We studied peripheral blood samples obtained from 22 patients enrolled in the SAC-COVID trial (NCT04317040), which were collected before and at multiple time points after treatment with CD24Fc or placebo. We performed high dimensional spectral flow cytometry analysis and measured cytokine levels to discern the immunological impact of CD24Fc treatment on patients with COVID-19. RESULTS. Patient characteristics from the CD24Fc vs. placebo groups were clinically matched allowing us to compare results without apparent confounding factors. Using high-content spectral flow cytometry, we found systemic hyper-activation of multiple cellular compartments in the placebo group, including CD8(+) T cells, CD4(+) T cells, and CD56(+) NK cells in patients with untreated COVID-19. By contrast, CD24Fc-treated patient samples demonstrated blunted systemic inflammation, with a return to homeostasis in both NK and T cells within days. A single dose of CD24Fc significantly attenuated systemic IL-10 and IL-15 cytokines, and diminished the coexpression and networking among inflammatory cytokines associated with COVID-19. CONCLUSIONS. Our clinical and immunological data supports further development of CD24Fc as a novel therapeutic against severe COVID-19.