Novel monoclonal antibodies show promise in preventing severe mpox disease

A team from the Microbiology Department at the Icahn School of Medicine at Mount Sinai has discovered three powerful monoclonal antibodies from a person who had previously been infected with mpox (formerly known as monkeypox).

These antibodies, which target the viral protein A35, blocked viral spread in laboratory in vitro tests and, most importantly, protected rodents from severe disease and fully prevented death. The findings, published August 22 in Cell, also reveal that humans previously infected with mpox carry high levels of these protective antibodies in their blood, and that their presence is associated with milder symptoms and the absence of hospitalization.

Mpox is a viral disease caused by an orthopoxvirus (the family of viruses that causes smallpox, which killed more than 300 million people in the 20th century alone). This virus spreads mainly through close contact with an infected individual. The virus causes a painful rash, enlarged lymph nodes, and fever. It can make people very sick and leave scars.

A global outbreak of mpox began in 2022 and continues to this day. In the last three years, the World Health Organization twice declared the disease a public health emergency of international concern, yet effective treatment for this virus family is lacking. Recent human clinical trials for the leading candidate therapy did not show it to have efficacy. Thus, there is currently no approved drug to treat mpox. This study from Mount Sinai might change that.

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. 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. We aimed to address the urgent unmet need for effective treatments for orthopoxviruses, and with the help of our outstanding collaborators, I am very proud to say that we are close to achieving that goal."

Camila Coelho, PhD, MBA, Assistant Professor of Microbiology at the Icahn School of Medicine and senior author of the paper

The newly discovered antibodies bind to a region that is highly conserved across not only the orthopoxvirus genus, to which MPXV belongs to, but also the entire poxvirus family, which means the region is conserved among different viruses and is not prone to mutations or antibody escape. The ability of these antibodies to block viral spread, protect from severe disease, and fully prevent death suggests that they are promising drug candidates that could be tested in humans for the prevention or treatment of mpox. The antibodies have been patented by the Icahn School of Medicine at Mount Sinai.

"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 is the first author of the study. "It is also the first time that monoclonal antibodies against orthopoxviruses were quantified in human sera. 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."

While the researchers see this as a promising next-generation therapy against mpox in humans, it is important to note that this is still in the research stage. Future testing in human clinical trials is needed to evaluate how the antibodies behave in the body, how long they last, where they go after being administered to the human body, and how well they prevent orthopoxvirus infection.

The research team plans to move the newly discovered antibodies into advanced preclinical safety and efficacy testing. Simultaneously, they are using the structural and immunological insights from the study to guide future work on understanding and enhancing the human immune response to mpox.

The study was conducted by the following laboratories from Mount Sinai's Department of Microbiology: Coelho, Schotsaert, Simon, Bajic, and Krammer.