Scientists headed by a team at the Icahn School of Medicine at Mount Sinai have developed an antibody-based platform, which they’ve called adaptive multi-epitope targeting with enhanced avidity (AMETA), to address a key challenge in treating rapidly evolving viruses such as SARS-CoV-2, which is the viral ability to mutate and evade existing vaccines and treatments.
AMETA has been developed as a modular, multivalent platform that uses engineered nanobodies (Nbs) to simultaneously target multiple stable regions of a virus that are less likely to mutate. The technology conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold. The researchers suggest this multi-targeting strategy, paired with a significant boost in binding strength, provides a more durable and resilient defense against evolving viruses.
In their newly published paper in Cell, lead corresponding author Yi Shi, PhD, and colleagues outlined preclinical tests in mice, which demonstrated effectiveness of the AMETA constructs against sarbecoviruses, including the most recent Omicron variants of SARS-CoV-2. “AMETA’s flexible design allows it to be quickly adapted to target a diverse range of pathogens, providing an agile and dynamic solution for emerging infections,” said Shi, who is associate professor of pharmacological sciences at Icahn Mount Sinai. “Our findings represent a major step forward in overcoming mutational escape across viruses and antibiotic-resistant microbes.”
In their report, titled “Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy,” the researchers commented, “Altogether, these results underscore AMETA as a modular, effective, and enduring strategy against challenging pathogens.”
Pathogens such as viruses and bacteria often have high genetic diversity and share the ability to develop escaping mutations that undermine the effectiveness of host immunity and therapeutics, the authors noted. Since the start of the COVID-19 pandemic, SARS-CoV-2 has quickly mutated, making many vaccines and treatments less effective. “Mutational escape in SARS-CoV-2 has been a persistent challenge, with current vaccines and treatments struggling to keep pace with the virus’s rapid evolution,” added Shi. “Most therapeutic antibodies target a single viral site and lose effectiveness within a year as new variants appear.” As the authors further noted, “The development of durable countermeasures requires targeting multiple neutralizing and ideally evolutionarily conserved epitopes.”
Nanobodies have emerged as a promising solution for antiviral therapy, the team continued. “Affinity-matured Nbs can specifically bind a variety of neutralizing epitopes, including conserved and cryptic sites, employing diverse mechanisms to thwart viral infections.”
Using the AMETA platform, specialized nanobodies are attached to a scaffold of human IgM, part of the immune system’s natural defenses that help fight infections. This allows for the display of more than 20 nanobodies at once, significantly boosting the ability to bind to the virus by targeting multiple stable regions on its surface, the investigators noted. As a result, AMETA is far more effective against advanced variants, offering up to a million times greater potency compared to traditional antibodies that focus on a single target.
![AMETA treatment effectively clumps the virus and disarms its spike structures, which are essential for infecting host cells. [Jialu Xu, PhD, University of Oxford.]](https://www.genengnews.com/wp-content/uploads/2024/10/low-res-9-300x164.jpeg)
Both lab tests and experiments in mice showed that AMETA constructs are highly effective against a range of SARS-CoV-2 variants, including the heavily mutated Omicron sublineages and even the closely related SARS-CoV-2 virus, according to the investigators. “By leveraging multi-epitope SARS-CoV-2 nanobodies and structure-guided design, AMETA constructs exponentially enhance antiviral potency, surpassing monomeric nanobodies by over a million-fold,” the team stated. “Utilizing murine infection models, we have demonstrated the robust in vivo efficacy of a representative AMETA construct for both prophylaxis and therapeutic applications … These constructs demonstrate ultrapotent, broad, and durable efficacy against pathogenic sarbecoviruses, including Omicron sublineages, with robust preclinical results.”
Collaborating with researchers at the University of Oxford and Case Western Reserve University, the team used advanced imaging tools like cryo-electron microscopy and cryotomography to reveal that AMETA constructs neutralize the virus through several unexpected mechanisms. “Through cryo-ET analysis, we discovered a plethora of antiviral mechanisms by AMETA beyond the classical mechanism of neutralization by competition with binding to the receptor,” they wrote. These include clumping viral particles together, binding to key regions of the spike protein, and disrupting the spike’s 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 fast-evolving properties of viral pathogens,” noted Adolfo Garcia-Sastre, PhD, co-senior author of the study, Irene and Dr. Arthur M. Fishberg Professor of Medicine, and director of the Global Health and Emerging Pathogens Institute at Icahn Mount Sinai. “This platform is not just a solution for COVID-19 but could also serve as a framework for combating other rapidly mutating human microbes, like HIV, and for protection from future emerging viruses, including influenza viruses with pandemic potential.”
The authors commented, “Our findings broaden the scope of therapeutic strategies against infectious diseases and drug-resistant systems, paving the way for innovative approaches to combat a wide array of pathogens.”
Added Shi, “AMETA’s flexible design allows it to be quickly adapted to target a diverse range of pathogens, providing an agile and dynamic solution for emerging infections. Our findings represent a major step forward in overcoming mutational escape across viruses and antibiotic-resistant microbes.”
With its modular structure, AMETA also enables rapid and cost-effective production of new nanobody constructs, making it an ideal candidate for addressing future pandemics, the investigators suggest. “AMETA’s modularity enables rapid, cost-effective production and adaptation to evolving pathogens,” they stated. Shi and Garcia-Sastre’s teams are now preparing for additional preclinical and potential clinical trials to evaluate AMETA’s therapeutic potential across various diseases.
