Scientists have created a groundbreaking antibody platform designed to confront a significant challenge in treating swiftly changing viruses such as SARS-CoV-2, the virus responsible for COVID-19. This new strategy responds to the virus’s ability to mutate and avoid current vaccines and treatments.
Researchers at the Icahn School of Medicine at Mount Sinai, working alongside other experts in the field, have introduced a cutting-edge antibody platform focused on one of the major difficulties in treating rapidly mutating viruses such as SARS-CoV-2: the virus’s capability to change and escape the defenses provided by existing vaccines and therapies.
Their research, including mouse studies, presents the Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nanobody Platform, a novel antibody solution to combat how viruses like SARS-CoV-2 evolve to dodge vaccines and treatments. The results of this study were published on October 23 in the journal Cell.
Since the emergence of the COVID-19 pandemic, SARS-CoV-2 has rapidly adapted, resulting in many vaccines and therapies becoming less effective. To address this, Dr. Yi Shi and his team at Icahn Mount Sinai developed AMETA, a flexible platform that utilizes engineered nanobodies to target multiple stable areas of the virus that are less prone to mutation. This approach allows for targeting multiple sites simultaneously, along with a notable increase in binding strength, hence providing a stronger and more lasting defense against evolving viruses, the researchers explain.
“The phenomenon of mutational escape in SARS-CoV-2 has been a continuous issue, with current vaccines and therapies unable to keep up with the virus’s swift evolution,” states Dr. Shi, who is the lead author and an Associate Professor of Pharmacological Sciences at Icahn Mount Sinai. “Most therapeutic antibodies focus on a single viral location, losing their effectiveness within a year as new variants emerge. In contrast, AMETA is engineered to attach to multiple stable regions of the virus simultaneously, significantly reducing the chance for resistance to occur. This platform could also be modified for other rapidly mutating pathogens, thereby offering a sustainable and adaptive approach to managing infectious diseases on a global scale.”
AMETA works by linking specialized nanobodies to a human IgM scaffold, a component of the immune system’s natural defenses that fights infections. This design permits AMETA to present over 20 nanobodies at once, greatly enhancing its capability to bind to the virus by addressing multiple stable regions on its surface. Consequently, AMETA shows up to a million times greater effectiveness compared to traditional antibodies that target a single site.
Laboratory tests and mouse experiments have demonstrated that AMETA constructs are significantly effective against various SARS-CoV-2 variants, including the extensively mutated Omicron sublineages, and even the closely related SARS-CoV virus, as per the researchers. Collaborating with teams from the University of Oxford and Case Western Reserve University, the researchers utilized advanced imaging techniques like cryo-electron microscopy and cryotomography that illustrated how AMETA neutralizes the virus via several novel mechanisms. These strategies involve clustering viral particles, binding to critical regions of the spike protein, and altering the spike’s structure in unique ways compared to other antiviral treatments, which prevents the virus from infecting cells.
“With AMETA, we aim to build a long-lasting platform that can manage the rapidly evolving nature of viral pathogens,” explains Dr. Adolfo Garcia-Sastre, co-senior author of the study, Professor of Medicine, and Director of the Global Health and Emerging Pathogens Institute at Icahn Mount Sinai. “This platform is not only a response to COVID-19 but could also provide a foundation for tackling other rapidly mutating human pathogens, such as HIV, and supply protection against future emerging viruses, including potential pandemic influenza viruses.”
“The versatile design of AMETA allows for quick adaptability to target a wide array of pathogens, making it a responsive and dynamic solution for emerging infections. Our results signify significant progress in overcoming mutational escape across viruses and antibiotic-resistant microbes,” Dr. Shi adds.
The modular nature of AMETA also facilitates the swift and economical production of new nanobody constructs, making it a prime candidate for managing future pandemics, as noted by the researchers.
Teams led by Drs. Shi and Garcia-Sastre are currently gearing up for further preclinical and possible clinical trials to assess AMETA’s therapeutic capabilities across different diseases.
