A novel platform for attenuating immune hyperactivity using EXO‐CD24 in COVID‐19 and beyond

Abstract

A small but significant proportion of COVID‐19 patients develop life‐threatening cytokine storm. We have developed a new anti‐inflammatory drug, EXO‐CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF‐kB pathway and the production of cytokines/chemokines. EXO‐CD24 discriminates damage‐from pathogen‐associated molecular patterns (DAMPs and PAMPs) therefore does not interfere with viral clearance. EXO‐CD24 was produced and purified from CD24‐expressing 293‐TREx™ cells. Exosomes displaying murine CD24 (mCD24) were also created. EXO‐CD24/mCD24 were characterized and examined, for safety and efficacy, in vitro and in vivo . In a phase Ib/IIa study, 35 patients with moderate–high severity COVID‐19 were recruited and given escalating doses, 10 8 –10 10 , of EXO‐CD24 by inhalation, QD, for 5 days. No adverse events related to the drug were observed up to 443–575 days. EXO‐CD24 effectively reduced inflammatory markers and cytokine/chemokine, although randomized studies are required. EXO‐CD24 may be a treatment strategy to suppress the hyper‐inflammatory response in the lungs of COVID‐19 patients and further serve as a therapeutic platform for other pulmonary and systemic diseases characterized by cytokine storm.

Serum‐derived extracellular vesicles: Novel biomarkers reflecting the disease severity of COVID‐19 patients

“…The identification of CD24 + EVs as potential biomarkers is especially interesting, since CD24 is known to exert anti‐inflammatory functions (Barkal et al., 2019) and is used as a marker for certain B cell subtypes, including regulatory B cells and B cells with class switch activities (Fu et al., 2020) whose presence has been correlated with COVID‐19 symptom duration (Newell et al., 2021). Furthermore, therapeutic application of CD24 loaded HEK‐EVs (Shapira al., 2022) has been reported to suppress severe COVID‐19 forms effectively in a registered Phase I clinical trial (Samara & Belle, 2021) (ClinicalTrials.gov: NCT04747574). Thus, the occurrence of CD24 + EVs in the sera of COVID‐19 patients with mild symptoms and the lack of those EVs in patients with severe symptoms might be linked causally.…”

“…Like in many other inflammatory diseases, EVs may not only serve as biomarkers but also provide therapeutic options for severe COVID‐19 patients (Börger et al., 2020). In addition to EVs released by mesenchymal stromal cells, CD24 containing EVs of engineered HEK cells appear as promising therapeutic agents for sever COVID‐19 patients (Börger et al., 2020; Samara & Belle, 2021, Shapira et al, 2022).…”

Update on Extracellular Vesicle-Based Vaccines and Therapeutics to Combat COVID-19

“…Consequently, exosomes derived from CD24-overexpressing 293T cells, T-Rex™ (EXO-CD24), are developed for the treatment of COVID-19 cytokine storms with the format of inhalation. The rationale of this new drug is that exosomes expressing CD24 can attenuate the cytokine storm via activating anti-inflammatory immune cells through CD24 signaling by over-activating innate immune responses of SARS-CoV-2 patients [ 19 ].…”

The Big Potential of Small Particles: Lipid-Based Nanoparticles and Exosomes in Vaccination

“…A fast and significant reduction in the inflammatory markers and in cytokine/chemokine levels confirmed the expected efficacy of EXO-CD24 in downregulating the cytokine storm. No adverse effects related to the drug were observed, indicating an excellent safety profile [ 70 ].…”