Targeting SARS-CoV-2 infection through CAR T cells and bispecific T cell engagers

Dogan, M.; Kozhaya, L.; Placek, L.; Karabacak, F.; Yigit, M.; Unutmaz, D.

doi:10.1101/2022.01.19.476940

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bioRxiv · 10.1101/2022.01.19.476940

Targeting SARS-CoV-2 infection through CAR T cells and bispecific T cell engagers

Dogan, M.·Kozhaya, L.·Placek, L.·Karabacak, F.·Yigit, M.·Unutmaz, D.

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Abstract

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. Here, as a proof-of-concept we engineered primary CD8 T cells to express SARS-CoV-2 Spike protein-specific CARs, using 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. Similar to 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, suggesting 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.

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Dogan, M., Kozhaya, L., Placek, L., Karabacak, F., Yigit, M., Unutmaz, D.. 2022-01-20. Targeting SARS-CoV-2 infection through CAR T cells and bispecific T cell engagers. https://doi.org/10.1101/2022.01.19.476940

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