Development of Single Domain Antibody (sdAb)-Based Therapeutics Targeting SARS-CoV-2 Spike Protein for the Treatment of COVID-19
Abstract
Severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, was identified as the cause of viral pneumonia (COVID-19), and patients with COVID-19 are at risk for acute respiratory distress syndrome (ARDS) and death from respiratory failure. Since its emergence at the end of 2019 in Wuhan, China, SARS-CoV-2 has spread across the globe, infecting more than 4 million people, resulting in over 250 thousand deaths. Unfortunately, this is likely to be just the beginning of the pandemic, with numbers anticipated to rise dramatically. The emergence of a new pathogen requires development of novel therapeutics to counteract this urgent threat. Infectivity of SARS-CoV-2 is driven by binding of the viral spike protein to lung epithelial cells. This application proposes to create a therapeutic antibody targeting SARS-CoV-2 spike protein that blocks SARS-CoV-2 spike protein binding to lung cells. As such, the topic areas addressed are Emerging Viral Diseases and Respiratory Health. Our company has developed a platform for developing antibodies that bind multiple targets simultaneously. Using this technology, we propose to develop a therapeutic antibody that blocks the interaction of SARS-CoV-2 with lung cells. Blocking of this interaction with a multi-specific antibody therapeutics may provide a novel treatment option for COVID-19. In this application, we propose to screen a library of antibodies to select ones that bind to SARS-CoV-2 spike-RBD and block the interaction with lung cells. Candidate antibodies will be identified and screened for their ability to bind and block the Spike protein. Due to their non-human origin, all animal-derived antibodies have the potential to generate an immune response against them. In order to limit this immune response, candidate antibodies will be humanized. Multiple humanized anti-Spike protein antibody variants will be produced and binding to their protein targets and blocking will be determined. To create optimized therapeutic antibodies, we will investigate combinations of candidate antibodies that work together to block Spike protein. The individual antibodies in the combinations that provide enhanced blocking will be used to construct multi-specific antibodies. To identify a single lead therapeutic candidate, multi-specific candidates will be compared for their ability to block Spike protein and neutralization viral entry into human cells. At the conclusion of this project, we will have identified a lead humanized multi-specific therapeutic antibody candidate with Spike protein blocking capabilities, which will be rapidly taken forward for development as a treatment for COVID-19. This strategy of virus neutralization is independent of therapies aimed at modulating the patient’s immune system, and may be combined with alternative therapies to potentially reduce the severity of critical COVID-19 pneumonia and ARDS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110155
Entities
People
- Andrew Hollands
Organizations
- Inhibrx (United States)
- United States Army