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Targeting SARS-CoV-2 Infection Through CAR-T Like Bispecific T Cell Engagers Incorporating ACE2
42 Pages Posted: 21 Apr 2022
More...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 proofof-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.
Funding: National Institute of Health (NIH) grant U19 AI142733-01 (DU) and Achelis and Bodman Foundation (DU)
Declaration of Interest: M.D. and D.U. are inventors in a provisional patent application. All other authors have nothing to declare.
Keywords: SARS-CoV-2 CAR-T, COVID-19, ACE2 CAR, ACE2-Bite, Delta, Omicron
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