Development of synthetic molecules that can bridge T cells with SARS-CoV-2 infected cells

The coronavirus disease 2019 (COVID-19) pandemic has been caused by a rapid outbreak of a novel RNA virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). To date, this virus has claimed more than 5.6 million lives and caused a chronic debilitating condition called Post-Acute COVID-19 Syndrome (PACS) worldwide.

Study: Targeting SARS-CoV-2 infection through CAR T cells and bispecific T cell engagers. Image Credit: Kateryna Kon/ShutterstockStudy: Targeting SARS-CoV-2 infection through CAR T cells and bispecific T cell engagers. Image Credit: Kateryna Kon/Shutterstock

Background

Scientists have worked at a record speed to develop COVID-19 vaccines and therapeutics to contain the pandemic. To date, all the vaccines and therapeutics (e.g., monoclonal antibodies) that received emergency use authorization from the global regulatory bodies have been designed against the spike protein of the original SARS-CoV-2 strain. However, the efficacy of the COVID-19 vaccines and therapeutics has been threatened due to mutations in the spike protein in the newly emerged SARS-CoV-2 strains. 

Mutations have increased the affinity of the spike protein for angiotensin-converting enzyme 2 (ACE2), which has brought about an increase in the infection rate. Additionally, some SARS-CoV-2 variants, such as the Delta strain, can evade the immune protection induced via natural infection and immunization targets. Hence, developing a new treatment that would remain effective against SARS-CoV-2 variants is urgently required. Generally, the spike protein of SARS-CoV-2 binds to ACE2 and, eventually, the virus enters the cell. After the virus enters the host cell, it captures its protein synthesis machinery and initiates viral replication.

Previously, researchers have evaluated the CAR-T approach against various infectious diseases, including Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV) Hepatitis C virus (HCV), Cytomegalovirus (CMV), and Aspergillus fumigatus. Conceptually the development of engineered CAR-T cells to target SARS-CoV-2 infected cells in the form of prophylaxis to treat severely infected COVID-19 patients, immunocompromised individuals, or the elderly seems plausible. However, scientists revealed that this strategy is not practical to use as a treatment for COVID-19 infection.

A new study

Scientists have recently used synthetic biology to design primary human CD8 T cells to express Spike protein-specific chimeric antigen receptors (ACE2 CAR or anti-Spike CAR). They used ACE2 or anti-Spike antibody on the extracellular domain to target SARS-CoV-2 infected cells. Researchers also engineered a novel ACE2/anti-CD3 bispecific T cell engager antibody (ACE2-Bite) to target SARS-CoV-2 infected cells and the SARS-CoV-2 virus. This study has been published on the bioRxiv* preprint server.

The current study describes the development of bispecific T cell engager antibodies (Bites). Bites have been designed using chimeric molecules, which bind with CD3 on T cells through an antiCD3 single-chain variable fragment (ScFv). Therefore, the main idea of this study has been associated with targeting infected cells via a target-specific molecule. After T cells are bridged with target cells, Bites activate T cells and trigger target cell cytotoxicity.

Main findings

A previous study reported that a Bites-based treatment, i.e., Bbinatumomab (CD19-CD3 Bite), received accelerated approval for B-cell lymphomas in 2018. Many other studies have indicated that Bites could be used against CD20, EGFR, Her2, and PDL1 expressing cancers.

Researchers revealed that ACE2-CAR and anti-Spike CAR-expressing CD8 T cells get activated. These cells eliminate different target cells, i.e., cells expressing SARS-CoV-2 Spike protein on their surface. As stated above, ACE2-Bite antibodies can activate T cells in the presence of Spike-expressed targets and promote cytotoxicity in these cells. Importantly, the ACE2-Bite antibodies act as a bait receptor and could neutralize both mutated and unmutated SARS-CoV-2 pseudotyped virus. 

Scientists revealed that the neutralization mechanism of the ACE2-Bite molecule is promising for preventive treatments. The findings of this study are in line with previous studies which reported that infusion of soluble recombinant human ACE2 molecule in a COVID-19 patient (45-year-old) caused a significant decrease in viral load in the patient plasma. 

Conclusion

The current study indicated that the novel chimeric antigen receptors and bispecific antibodies could effectively identify the cell surface expression of virus Spike protein and redirect cytotoxic immune cells towards COVID-19 infected cells. Compared to current treatments, the ACE2-Bite strategy could be effective both at the early and later stages of the infection. One of the major advantages of ACE2-Bite based treatment is the utilization of ACE2, which is the key host receptor of SARS-CoV-2. This strategy could be used to neutralize the SARS-CoV-2 original strain and its variants effectively.

The author’s previous study indicated that ACE2-Bite or ACE2 CAR might interact with its physiologic ligands and affect the renin-angiotensin system. The authors stated that before implementing this potential strategy to treat COVID-19 patients, more studies are required to assess the side effects of CAR-T cells or ACE2-Bite treatments.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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