Modified natural killer cells show neutralizing and multivalent potential against SARS-CoV-2 in vitro

A new study suggests that modified natural killer cells, which express a chimeric antigen receptor using S309 antibody, can bind to and inactivate SARS-CoV-2 spike protein in vitro.

The global scientific community’s effort to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) disease, includes vaccines, convalescent plasma, monoclonal antibody cocktails, and other repurposed drugs.

Study: CAR-NK Cells Effectively Target the D614 and G614 SARS-CoV-2-infected Cells. Image Credit: Numstocker / Shutterstock

Although some vaccines have already been approved for public use, their long-term effects are not yet known. Their efficacy against new and emerging variants of the virus is unknown, and some patients may even be unresponsive to the vaccines. Thus, there is a need for other strategies to combat the virus.

Natural killer (NK) cells are found in cord blood, peripheral blood, bone marrow, and embryonic stem cells, which can be isolated and modified to express a chimeric antigen receptor (CAR) for treating infectious diseases. Compared to CAR-T cells, CAR-NK cells have lower host cytotoxicity and are less likely to induce the cytokine release syndrome that is associated with severe COVID-19. Many CAR-NK therapies for COVID-19 are currently under development.

Memory B cells of recovered SARS-CoV patients, which have cross-reactivity to SARS-CoV-2, have yielded several antibodies. One such antibody, S309, has been shown to neutralize pseudotype and wild-type SARS-CoV-2 virus. It has a high binding affinity and neutralization potency to SARS-CoV-2 as it targets the most conserved epitope of the virus receptor-binding domain (RBD).

S309 antibody-derived CAR-NK cells can kill pseudotyped SARS-CoV-2 in vitro

In a new study published in the bioRxiv* preprint server, researchers report the generation of CAR-NK cells for SARS-CoV-2 from the scFv domain of S309. They cloned the scFv domain into an SFG retroviral vector, generating S309-CAR, from which they generated S309-CAR-NK using a human cell line.

NK cells are involved in fighting viral infections and, as innate immune response cells, can quickly respond to and target viral infections. The half-life of monoclonal antibody therapies is about 21 days. However, using NK cells can likely protect for longer by increasing their persistence in vivo. Thus, modified NK cells could be a potent therapy for COVID-19.

The authors studied the binding capability of S309-CAR-NK to the SARS-CoV-2 spike protein RBD using flow cytometry. They found that S309-CAR-NK binds strongly to the RBD of SARS-CoV-2 and SARS-CoV.

The team found that S309-CAR-NK cells bind to pseudotyped SARS-CoV-2 cells with a lower binding efficiency than that to recombinant spike protein. However, they bind more strongly to the virus than to cells expressing the human angiotensin-converting enzyme 2 (hACE2).

Using the 4-hour chromium-51 release assay, the authors found that S309-CAR-NK could kill cells from two different cell lines that express the SARS-CoV-2 RBD and spike protein. S309-CAR-NK had no effect on cells that did not have SARS-CoV-2, indicating it is highly specific to the virus. The team also found that S309-CAR-NK in cells expanded from the human primary NK cells from peripheral blood also kills the target cells expressing the virus. The S309-CAR-NK in expanded human blood cells was also effective against cells expressing the SARS-CoV-2 D614G mutant.

CR3022-CAR-NK is another natural killer cells generated from the neutralizing antibody CR3022, which binds only to the open configuration of the spike protein trimer. Testing this and S309-CAR-NK on cells expressing RBD and spike protein showed CR3022-CAR-NK had lower killing ability, suggesting conformation of the spike protein trimer is important in CAR recognition and binding. Thus, the data indicate S309-CAR-NK could be a potential therapeutic strategy to combat COVID-19.

Potential new approach to combat COVID-19

The use of the potent neutralizing antibody S309 indicates this new approach could work against new mutations of the virus that are quickly spreading worldwide. The use of NK-92 cells lines, which can be manufactured easily, and NK cells from expanded human blood for producing S309-CAR-NK allows producing enough quantities of CAR-NK cells.

However, the authors note that the results are only preliminary as they tested the approach on pseudotyped spike protein particles rather than the complete virus, and future studies will need to be done on the real virus. Further studies on the wild-type virus in vivo, in pre-clinical animal models, will be needed to test real-life efficacy and toxicity. This CAR-NK therapy for COVID-19 could be especially useful for treating patients whose immune systems are compromised and who may not generate sufficient immune response by vaccination.

*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:
Lakshmi Supriya

Written by

Lakshmi Supriya

Lakshmi Supriya got her BSc in Industrial Chemistry from IIT Kharagpur (India) and a Ph.D. in Polymer Science and Engineering from Virginia Tech (USA).

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