Document Type

Article

Publication Date

1-1-2022

Publication Title

Clin Transl Immunology

Keywords

JGM

JAX Source

Clin Transl Immunology. 2022;11(10):e1421

Volume

11

Issue

10

First Page

1421

Last Page

1421

ISSN

2050-0068

PMID

36285327

DOI

https://doi.org/10.1002/cti2.1421

Grant

The research in this study was supported by the National Institute of Health (NIH) grant U19 AI142733-01 (DU) and the Achelis and Bodman Foundation (DU).

Abstract

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.

Comments

This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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