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Targeting SARS-CoV-2 infection through CAR-T-like bispecific T cell engagers incorporating ACE2
Mikail Dogan1, Lina Kozhaya1, Lindsey Placek1
1Jackson Laboratory for Genomic Medicine Farmington CT USA.
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.
Insights
Researchers engineered T cells to target SARS-CoV-2 variants. A novel ACE2-Bite molecule effectively neutralizes and binds to variants like Delta and Omicron, offering a potential therapeutic strategy against future strains.
Area of Science:
- Immunology
- Virology
- Biotechnology
Background:
- COVID-19 remains a significant global health threat due to SARS-CoV-2 infection, causing high morbidity and mortality.
- Emerging SARS-CoV-2 variants diminish the efficacy of existing vaccines and antibody treatments.
Purpose of the Study:
- To develop a novel therapeutic strategy for combating SARS-CoV-2 and its variants.
- To engineer T cells and create a bispecific molecule targeting SARS-CoV-2 Spike protein and infected cells.
Main Methods:
- Engineered primary CD8 T cells to express SARS-CoV-2 Spike protein-specific chimeric antigen receptors (CARs) using the ACE2 extracellular region.
- Developed a bispecific T cell engager (ACE2-Bite) combining ACE2 with an anti-CD3 single-chain variable fragment (scFv).
Main Results:
- Engineered T cells demonstrated potent and specific cytotoxicity against Spike-expressing target cells.
- ACE2-Bite effectively neutralized SARS-CoV, SARS-CoV-2 wild-type, and variant pseudoviruses (Delta, Omicron).
- ACE2-Bite exhibited enhanced binding and neutralization affinity towards Delta and Omicron variants compared to the wild-type.
Conclusions:
- The engineered T cell and ACE2-Bite approaches show promise as variant-proof therapeutic strategies.
- This strategy leverages both humoral and cellular arms of the adaptive immune response against SARS-CoV-2.
- The findings suggest a potential for broad-spectrum protection against current and future SARS-CoV-2 variants.
