New antibody platform addresses viral mutations

Their findings, including preclinical studies in mice, introduce the Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nanobody Platform, a novel antibody approach to addressing how viruses like SARS-CoV-2, which causes COVID-19, 19, evolve to escape. vaccines and treatments. Details about the results were published on October 23 in the journal Cell.

Since the start of the COVID-19 pandemic, SARS-CoV-2 has mutated rapidly, making many vaccines and treatments less effective. To combat this, Yi Shi, PhD, and his team at Icahn Mount Sinai created AMETA, a versatile platform that uses engineered nanobodies to simultaneously target multiple stable regions of the virus that are less likely to mutate. This multi-target strategy, combined with a significant increase in binding strength, provides a more durable and resilient defense against evolving viruses, the researchers say.

“Mutational escape in SARS-CoV-2 has been a persistent challenge, with current vaccines and treatments struggling to keep up with the rapid evolution of the virus,” said Dr. Shi, lead corresponding author and associate professor of Pharmacological Sciences at Icahn Mount Sinai. “Most therapeutic antibodies target a single viral site and lose effectiveness within a year as new variants appear. AMETA, however, was designed to bind to multiple conserved regions of the virus at the same time, making it very more difficult for resistance to develop. This platform can potentially be adapted to other rapidly mutating pathogens, offering a durable and adaptable approach to managing infectious diseases worldwide.”

AMETA was designed by attaching specialized nanobodies to a human IgM scaffold, which is part of the immune system’s natural defense structure that helps fight infection. This allows AMETA to display more than 20 nanobodies at the same time, significantly increasing its ability to bind to the virus by targeting multiple stable regions on its surface, researchers say. As a result, AMETA is much more effective against advanced variants, offering up to a million times greater potency compared to traditional antibodies that focus on a single target.

Both laboratory tests and mouse experiments have shown that AMETA constructs are highly effective against a number of SARS-CoV-2 variants, including the heavily mutated Omicron sublineages and even the closely related SARS-CoV virus, of according to investigators. Collaborating with researchers at the University of Oxford and Case Western Reserve University, the team used advanced imaging tools such as cryo-electron microscopy and cryotomography to reveal that AMETA neutralizes the virus through several unexpected mechanisms. These include clumping viral particles together, binding to key regions of the spike protein, and disrupting the spike structure in ways not seen in other antiviral treatments, preventing the virus from infecting cells.

“Our goal with AMETA is to create a long-lasting platform that overcomes the rapidly evolving properties of viral pathogens,” says Adolfo Garcia-Sastre, PhD, co-senior author of the study, Irene and MD and Director of the Institute for Global Health and Emerging Pathogens at Icahn Mount Sinai. “This platform is not only a solution for COVID-19, but can also serve as a framework to combat other rapidly mutating human microbes, such as HIV, and to protect against future emerging viruses, including influenza viruses with pandemic potential. ”.

“AMETA’s flexible design allows it to be quickly adapted to target a wide range of pathogens, providing an agile and dynamic solution for emerging infections. Our findings represent a major step forward in overcoming mutational escape between antibiotic-resistant viruses and microbes “, adds Dr.

With its modular structure, AMETA also enables the rapid and cost-effective production of new nanobody constructs, making it an ideal candidate for tackling future pandemics, researchers say.

Drs. Shi and Garcia-Sastre’s teams are now preparing for preclinical trials and potential additional clinical trials to evaluate AMETA’s therapeutic potential in various diseases.