S309 CAR-NK Cells Targeting Coronavirus Spike Protein
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Solution Overview
Problem
Current treatments for COVID-19, including antiviral and immunosuppressive therapies, face challenges in effectively managing severe immune responses and providing targeted antiviral mechanisms, particularly in immunocompromised patients or those with comorbidities, due to limitations in specificity and safety.
Innovation Solution
Development of CAR-NK cells expressing the scFv domain of S309 antibody, which specifically targets the coronavirus spike protein, incorporating a hinge, transmembrane, and intracellular domains, and optionally an IL-15 domain, to enhance killing activity against SARS-CoV-2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antiviral and immunosuppressive treatments are used, then broad coverage against coronavirus is achieved, but specificity and safety are reduced due to limitations in targeted mechanisms
Solution Approach 1:
The treatment approach is segmented into two distinct functional components: (1) the scFv domain for specific antigen recognition and binding, and (2) the CAR signaling domains for targeted immune cell activation. This segmentation allows each component to perform its specialized function, improving overall safety and efficacy while reducing unnecessary immune suppression.
Solution Approach 2:
The invention applies local quality by endowing NK cells with localized specificity through the scFv domain that targets only the coronavirus spike protein. This localized targeting ensures that immunosuppressive effects are confined to virus-infected cells expressing the spike antigen, rather than causing broad immunosuppression, thereby improving safety.
2Reliability
If natural killer cells are used for antiviral defense, then broad antiviral activity is achieved, but specificity against coronavirus spike protein is reduced
Solution Approach 1:
The invention merges two previously separate functions into a single chimeric receptor: the antigen-specific binding function of the scFv domain (providing coronavirus spike protein specificity) and the immune activation function of the CAR signaling domains (providing potent antiviral activity). This merging allows NK cells to achieve both high specificity and high efficacy simultaneously.
Solution Approach 2:
The S309-CAR construct serves multiple functions within a single molecular entity: (1) specific recognition of coronavirus spike protein via scFv, (2) membrane anchoring and structural support via hinge and transmembrane domains, and (3) immune cell activation via intracellular signaling domains. This multi-functionality enables NK cells to achieve both specificity and broad antiviral activity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
S309-CAR-NK cells demonstrate superior killing activity against pseudotyped SARS-CoV-2 virus and show potential for preventing infection and treating immunocompromised patients by providing targeted antiviral mechanisms with reduced host cytotoxicity.
Implementation Method 1
an antigen binding domain that specifically binds coronavirus spike protein, such as an scFv of antibody S309
Implementation Method 2
induction of apoptosis through the interaction of TNF-related apoptosis induction ligand (TRAIL) on NK cells to the death receptors on the target cells
Data Source
AI summary
Chimeric antigen receptors (CARs) including an scFv binding to coronavirus spike protein (S309 scFv), nucleic acids encoding the CARs, vectors including nucleic acids encoding the CARs, and cells expressing the CARs are provided. Methods of treating a subject with coronavirus are also provided, including administering to the subject a modified immune cell expressing a disclosed CAR.