Abstract
H84T-Banana Lectin (BanLec) CAR-NK cells bind high mannose glycosites that decorate the SARS-CoV-2 envelope, thereby decreasing cellular infection in a model of SARS-CoV-2. H84T-BanLec CAR-NK cells are innate effector cells, activated by virus. This novel cellular agent is a promising therapeutic, capable of clearing circulating SARS-CoV-2 virus and infected cells. Banana Lectin (BanLec) binds high mannose glycans on viral envelopes, exerting an anti-viral effect. A point mutation (H84T) divorces BanLec mitogenicity from antiviral activity. SARS-CoV-2 contains high mannose glycosites in proximity to the receptor binding domain of the envelope Spike (S) protein. We designed a chimeric antigen receptor (CAR) that incorporates H84T-BanLec as the extracellular moiety. Our H84T-BanLec CAR was devised to specifically direct NK cell binding of SARS-CoV-2 envelope glycosites to promote viral clearance. The H84T-BanLec CAR was stably expressed at high density on primary human NK cells during two weeks of ex vivo expansion. H84T-BanLec CAR-NK cells reduced S-protein pseudotyped lentiviral infection of 293T cells expressing ACE2, the receptor for SARS-CoV-2. NK cells were activated to secrete inflammatory cytokines when in culture with virally infected cells. H84T-BanLec CAR-NK cells are a promising cell therapy for further testing against wild-type SARS-CoV-2 virus in models of SARS-CoV-2 infection. They may represent a viable off-the-shelf immunotherapy for patients suffering from COVID-19.
Highlights
The prevalence and pathogenicity of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international pandemic that has placed healthcare systems under unprecedented stress
We investigated whether H84T-Banana Lectin (BanLec) chimeric antigen receptor (CAR)-natural killer (NK) cells could target S-protein pseudoviral transduced human ACE2 (hACE2).293T
In this study we show successful generation of chimeric antigen receptor natural killer (CAR-NK) cells expressing extracellular H84T-BanLec linked to intracellular activation domains (Figure 4)
Summary
The prevalence and pathogenicity of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international pandemic that has placed healthcare systems under unprecedented stress. Lack of prior exposure and a high fatality rate of coronavirus disease 2019 (COVID-19) [1], the disease caused by SARS-CoV-2 infection, have far resulted in almost four million deaths worldwide (as per the World Health Organization). Ill patients with COVID-19 have immune dysregulation with reduced number and function of effector cells, which impairs viral clearance [4,5,6,7,8,9,10,11]. A strategy to enhance, activate, and repopulate patient immune cells is necessary to better control SARS-CoV-2 infection
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