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Development of ACE2-tropic-betacoronavirus therapeutics for future pandemic preparedness
Ashley Utz1,2,3, Matt Armbrust4, Thuy-Tien T Nguyen2,5
1Stanford Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
A major challenge during viral pandemics is the ability to develop therapeutics whose efficacy can withstand viral genetic evolution. During the COVID-19 pandemic, five SARS-CoV-2 monoclonal antibody (mAb) therapeutics were rendered ineffective within a period of 2 years, leading to the U.S. FDA revoking their emergency use authorization. Here, we describe ReconnAb-multimers, a new therapeutic design that broadly and potently neutralize all tested betacoronaviruses that use host ACE2 as their receptor to enter cells. These ReconnAb-multimers have potent neutralization efficacy via avidity, enhanced breadth via a new pan-betacoronavirus-binding antibody that targets a highly conserved epitope on SARS-CoV-2 spike protein, and the potential for clinical development by using a catalytically inactive ACE2 component. We demonstrate that ReconnAb-multimers neutralize all SARS-CoV-2 pseudoviruses and authentic viral variants of concern (VOC) tested, with similar or higher potency than mAbs previously approved by the FDA; neutralize related pandemic-potential betacoronaviruses, including SARS-CoV, WIV1-CoV, PRD-0038, and merbecovirus HKU5-CoV-2; and despite a short half-life, protect female mice against authentic viral challenge with Omicron variant XBB.1.5. Our results highlight ReconnAb-multimers as a broad and highly potent therapeutic that could potentially withstand viral escape against current and future betacoronaviruses that require host ACE2 as a receptor.
Insights
New ReconnAb-multimers offer broad neutralization against diverse betacoronaviruses, including SARS-CoV-2 variants. This therapeutic design shows potential to overcome viral evolution challenges and protect against future pandemics.
Area of Science:
- Virology
- Immunology
- Therapeutic Design
Background:
- Viral genetic evolution poses a significant challenge for developing effective therapeutics during pandemics.
- The emergence of SARS-CoV-2 variants rendered several monoclonal antibody (mAb) therapeutics ineffective, leading to FDA emergency use authorization revocations.
Purpose of the Study:
- To introduce ReconnAb-multimers, a novel therapeutic strategy designed for broad and potent neutralization of betacoronaviruses.
- To assess the efficacy of ReconnAb-multimers against SARS-CoV-2 variants and other pandemic-potential betacoronaviruses.
Main Methods:
- Development of ReconnAb-multimers incorporating a pan-betacoronavirus antibody targeting a conserved spike protein epitope and a catalytically inactive ACE2 component.
- Evaluation of neutralization potency against SARS-CoV-2 pseudoviruses and authentic viral variants of concern (VOC).
- Testing neutralization against related betacoronaviruses (SARS-CoV, WIV1-CoV, PRD-0038, HKU5-CoV-2) and in vivo protection studies in mice.
Main Results:
- ReconnAb-multimers demonstrated potent neutralization of all tested SARS-CoV-2 pseudoviruses and authentic VOCs, comparable or superior to FDA-approved mAbs.
- Broad neutralization was observed against SARS-CoV, WIV1-CoV, PRD-0038, and HKU5-CoV-2.
- ReconnAb-multimers provided protection in mice against authentic Omicron variant XBB.1.5 challenge, despite a short half-life.
Conclusions:
- ReconnAb-multimers represent a promising broad-spectrum therapeutic candidate against current and future ACE2-dependent betacoronaviruses.
- This design has the potential to overcome viral escape mechanisms and mitigate pandemic threats.
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