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Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein
Pablo Gonzalez-Garcia1, Juan P Muñoz-Miranda2, Ricardo Fernandez-Cisnal1
1Institute of Biomedical Research Cadiz (INIBICA), 11009 Cadiz, Spain.
Abstract:
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the Coronavirus Disease 2019 (COVID-19) pandemic, which is still a health issue worldwide mostly due to a high rate of contagiousness conferred by the high-affinity binding between cell viral receptors, Angiotensin-Converting Enzyme 2 (ACE2) and SARS-CoV-2 Spike protein. Therapies have been developed that rely on the use of antibodies or the induction of their production (vaccination), but despite vaccination being still largely protective, the efficacy of antibody-based therapies wanes with the advent of new viral variants. Chimeric Antigen Receptor (CAR) therapy has shown promise for tumors and has also been proposed for COVID-19 treatment, but as recognition of CARs still relies on antibody-derived sequences, they will still be hampered by the high evasion capacity of the virus. In this manuscript, we show the results from CAR-like constructs with a recognition domain based on the ACE2 viral receptor, whose ability to bind the virus will not wane, as Spike/ACE2 interaction is pivotal for viral entry. Moreover, we have developed a CAR construct based on an affinity-optimized ACE2 and showed that both wild-type and affinity-optimized ACE2 CARs drive activation of a T cell line in response to SARS-CoV-2 Spike protein expressed on a pulmonary cell line. Our work sets the stage for the development of CAR-like constructs against infectious agents that would not be affected by viral escape mutations and could be developed as soon as the receptor is identified.
Insights
This study introduces novel Chimeric Antigen Receptor (CAR)-like therapies targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). These ACE2-receptor-based CARs offer a potential solution against viral variants, unlike antibody-based treatments.
Area of Science:
- Immunology
- Virology
- Biotechnology
Background:
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, a global health concern due to its high contagiousness.
- Current antibody-based therapies and vaccines face challenges with emerging SARS-CoV-2 variants, diminishing efficacy.
- Chimeric Antigen Receptor (CAR) therapy, successful in oncology, has been explored for COVID-19 but is limited by antibody-derived recognition sequences susceptible to viral evasion.
Purpose of the Study:
- To develop and evaluate novel CAR-like constructs utilizing the Angiotensin-Converting Enzyme 2 (ACE2) viral receptor for recognizing SARS-CoV-2.
- To investigate the efficacy of CAR constructs based on both wild-type and affinity-optimized ACE2 against SARS-CoV-2.
- To establish a foundation for CAR-like therapies against infectious agents, resilient to viral escape mutations.
Main Methods:
- Designed CAR-like constructs incorporating ACE2 as the recognition domain, leveraging its interaction with the SARS-CoV-2 Spike protein.
- Developed a CAR construct featuring an affinity-optimized ACE2 variant.
- Tested the activation of a T cell line in response to SARS-CoV-2 Spike protein presented on a pulmonary cell line using both wild-type and optimized ACE2 CARs.
Main Results:
- ACE2-based CAR-like constructs demonstrated the ability to bind SARS-CoV-2, a crucial interaction for viral entry.
- Both wild-type and affinity-optimized ACE2 CAR constructs successfully induced T cell activation.
- The study confirmed that ACE2-based CARs can elicit an immune response against SARS-CoV-2 Spike protein.
Conclusions:
- CAR-like constructs utilizing the ACE2 receptor offer a promising therapeutic strategy against SARS-CoV-2, unaffected by viral escape mutations.
- The affinity-optimized ACE2 CAR construct shows potential for enhanced therapeutic efficacy.
- This approach paves the way for developing broadly applicable CAR-like therapies for various infectious diseases.
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