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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

See all articles by Mikail Dogan

Mikail Dogan

The Jackson Laboratory

Lina Kozhaya

The Jackson Laboratory

Lindsey Placek

The Jackson Laboratory

Fatih Karabacak

The Jackson Laboratory

Mesut Yigit

The Jackson Laboratory

Derya Unutmaz

The Jackson Laboratory

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

Suggested Citation

Dogan, Mikail and Kozhaya, Lina and Placek, Lindsey and Karabacak, Fatih and Yigit, Mesut and Unutmaz, Derya, Targeting SARS-CoV-2 Infection Through CAR-T Like Bispecific T Cell Engagers Incorporating ACE2. Available at SSRN: https://ssrn.com/abstract=4087366 or http://dx.doi.org/10.2139/ssrn.4087366

Mikail Dogan

The Jackson Laboratory ( email )

600 Main Street
Bar Harbor, ME 04609
United States

Lina Kozhaya

The Jackson Laboratory ( email )

600 Main Street
Bar Harbor, ME 04609
United States

Lindsey Placek

The Jackson Laboratory ( email )

Fatih Karabacak

The Jackson Laboratory ( email )

600 Main Street
Bar Harbor, ME 04609
United States

Mesut Yigit

The Jackson Laboratory ( email )

Derya Unutmaz (Contact Author)

The Jackson Laboratory ( email )

600 Main Street
Bar Harbor, ME 04609
United States