Researchers at the Icahn School of Medicine at Mount Sinai have identified three potent monoclonal antibodies that demonstrate complete protection against mpox in animal models, offering new hope for treating a disease that currently lacks approved therapeutic options. The antibodies, derived from a person previously infected with mpox, target the viral protein A35 and successfully blocked viral spread in laboratory tests while fully preventing death in rodents.
The findings, published August 22 in Cell, represent a significant breakthrough in addressing the ongoing mpox crisis. Since the global outbreak began in 2022, the World Health Organization has twice declared mpox a public health emergency of international concern, yet effective treatments remain elusive. Recent human clinical trials for the leading candidate therapy failed to demonstrate efficacy, leaving patients without approved therapeutic options.
Targeting a Critical Viral Vulnerability
The newly discovered antibodies bind to a region that is highly conserved across not only the orthopoxvirus genus, which includes mpox virus, but also the entire poxvirus family. This conservation means the targeted region is not prone to mutations or antibody escape, potentially providing durable protection against multiple related viruses.
"A previous study published in 2023 by our team showed that human antibodies targeting the viral protein A35 were unusually increased in sera in response to mpox infection compared with vaccination for smallpox or antibodies against other viral proteins," said Camila Coelho, PhD, MBA, Assistant Professor of Microbiology at the Icahn School of Medicine and senior author of the paper. "Based on this earlier finding, we hypothesized that antibodies targeting A35 from mpox-infected individuals would be highly protective against orthopoxviruses, since the viruses in this family share high genetic similarity."
Structural Insights Reveal Therapeutic Potential
The research team achieved a scientific first by determining the crystal structure of a human antibody bound to an mpox virus protein, providing detailed molecular insights into viral vulnerabilities. This structural analysis offers a roadmap for understanding how these antibodies neutralize the virus and could guide future therapeutic development.
"Ours is the first report of the crystal structure of a human antibody bound to an mpox virus protein, providing a detailed map of a vulnerability in the virus," said Raianna Fantin, PhD, the postdoctoral researcher who served as first author of the study. "It is also the first time that monoclonal antibodies against orthopoxviruses were quantified in human sera."
Natural Immunity Patterns Support Therapeutic Promise
The study revealed that humans previously infected with mpox consistently carry high levels of these protective antibodies in their blood. Importantly, the presence of these antibodies correlates with milder disease symptoms and reduced hospitalization rates, providing clinical validation for their therapeutic potential.
"We were surprised by how consistently people recovering from mpox infection produced antibodies targeting the same A35 epitope of the virus as the antibodies we discovered," Fantin noted.
Path to Clinical Development
The antibodies have been patented by the Icahn School of Medicine at Mount Sinai, and the research team plans to advance them into preclinical safety and efficacy testing. The ability of these antibodies to block viral spread, protect from severe disease, and fully prevent death in animal models positions them as promising drug candidates for human testing.
However, researchers emphasize that significant work remains before these antibodies could reach patients. Future human clinical trials will need to evaluate how the antibodies behave in the body, their duration of action, biodistribution, and their effectiveness in preventing orthopoxvirus infection in humans.
The research was conducted by multiple laboratories within Mount Sinai's Department of Microbiology, including teams led by Coelho, Schotsaert, Simon, Bajic, and Krammer. The collaborative effort addresses an urgent unmet medical need for a disease that causes painful rash, enlarged lymph nodes, and fever, and can result in severe illness and scarring.
Mpox is caused by an orthopoxvirus, the same family of viruses responsible for smallpox, which killed more than 300 million people in the 20th century alone. The virus spreads primarily through close contact with infected individuals and continues to pose a significant public health threat globally.
