Targeting SARS‐CoV‐2 infection through CAR‐T‐like bispecific T cell engagers incorporating ACE2

OBJECTIVES: Despite advances in antibody treatments and vaccines, COVID‐19 caused by SARS‐CoV‐2 infection remains a major health problem resulting in excessive morbidity and mortality and the emergence of new variants has reduced the effectiveness of current vaccines. METHODS: Here, as a proof‐of‐concept, we engineered primary CD8 T cells to express SARS‐CoV‐2 Spike protein‐specific CARs, using the extracellular region of ACE2 and demonstrated their highly specific and potent cytotoxicity towards Spike‐expressing target cells. To improve on this concept as a potential therapeutic, we developed a bispecific T cell engager combining ACE2 with an anti‐CD3 scFv (ACE2‐Bite) to target infected cells and the virus. RESULTS: As in CAR‐T cell approach, ACE2‐Bite endowed cytotoxic cells to selectively kill Spike‐expressing targets. Furthermore, ACE2‐Bite neutralized the pseudoviruses of SARS‐CoV, SARS‐CoV‐2 wild‐type, and variants including Delta and Omicron, as a decoy protein. Remarkably, ACE2‐Bite molecule showed a higher binding and neutralization affinity to Delta and Omicron variants compared to SARS‐CoV‐2 wild‐type Spike proteins. CONCLUSION: In conclusion, these results suggest the potential of this approach as a variant‐proof, therapeutic strategy for future SARS‐CoV‐2 variants, employing both humoral and cellular arms of the adaptive immune response.