An lab discovers novel nasal treatment for influenza
New data from researchers at the Brown Foundation Institute of Molecular Medicine exploring novel therapeutic approaches to treating Influenza A viruses has been published in Nature Communications.
The paper, titled “An intranasally administered IgM protects against antigenically distinct subtypes of influenza A viruses,” is published by Zhiqiang An, PhD, professor of molecular medicine and the Robert A. Welch Distinguished University Chair in Chemistry at the Texas Therapeutics Institute at the Brown Foundation Institute of Molecular Medicine and vice president of Drug Discovery at UTHealth Houston, and leading authors Ashwin Kumar Ramesh, PhD; Jwala Sivaccumar, PhD; and Xiaohua Ye, PhD.
“Traditional flu treatments and vaccines often struggle to keep up with how quickly the virus mutates,” the researchers said. “So, we explored an alternative therapeutic approach: engineered IgM antibodies with broader neutralizing activities that can be delivered through the nose.”
IgM, or immunoglobulin M, are normally the first line of defense against influenza viruses. “Unlike traditional IgG antibodies, IgM antibodies are naturally multivalent, meaning they can bind to multiple sites on a virus simultaneously,” the researchers said. “This makes them especially effective at neutralizing even mutated or resistant strains.”
The lab began the research by selecting a panel of 18 broadly neutralizing IgG monoclonal antibodies previously identified against various influenza A types. Each was chosen to represent diverse binding specificities, particularly centering around the hemagglutinin protein, with some binding to the receptor-binding site while others bound to non-receptor-binding site regions like the stem or lateral patch of the hemagglutinin.
The antibodies were reformatted from their IgG isotype into corresponding IgM isotype using recombinant DNA technology, which allowed the lab to evaluate both their binding and neutralization capabilities against a variety of recombinant HA proteins and live influenza viruses.
“Recombinant HA proteins from Influenza subtypes H1 and H3 were focused on this study due to their predominance as currently circulating subtypes,” the researchers said. “Our antigen panel comprised over 80 years of antigenic diversity. This diversity ensured we could assess neutralization breadth across seasonal and potentially pandemic strains.”
The lab identified the IgM antibody F045-092 as a leading candidate. The antibody was designed to target the receptor-binding spot (RBS) of the influenza virus’ hemagglutinin protein, which is critical in infecting human cells. Since the RBS is an essential spot for viral entry, the lab said it represents a “sweet spot” for broad-spectrum antiviral defense.
“What sets this therapy apart is its intranasal delivery,” the researchers said. “Administered as a simple nasal spray, the IgM antibody directly coats the respiratory tract — the primary site of flu infection.”
The therapy showed robust protection in preclinical murine models against lethal doses of both the H1N1 and H3N2 influenza viruses with just a single dose of the nasal IgM. The IgM neutralized a wide range of Influenza A strains, including those evading current treatments.
“This approach combines the precision of antibody therapy with the convenience of immediacy of nasal delivery,” Ramesh said. “It’s a promising step toward a self-administered, broad-spectrum flu treatment that could be used at home or in outbreak settings.”
The research proved that engineering broadly neutralizing influenza IgG antibodies into the IgM isotypes and administering them intranasally significantly enhances their protective capabilities against various Influenza A viruses. IgM antibodies also improved mucosal retention, remaining in the nasal passages and lungs longer than IgG antibodies. The findings underscore the potential of intranasally delivered IgM antibodies as a broadly protective and practical approach to influenza prevention and treatment.
Additional authors include Yan Xu, PhD; Ningyan Zhang, PhD; and Kai Xu, PhD, at UTHealth Houston; Luona Yang, and Xinli Liu, PhD, at the University of Houston; Hailong Guo, PhD; Chen-Ni Chin, PhD; Sha Ha, PhD; John W. Shiver, PhD; William R. Strohl, PhD; and Tong-Ming Fu, PhD, at IGM Biosciences Inc., and Haijuan Du, PhD; and Tongqing Zhou, PhD, at the National Institutes of Health.
Grants from IGM Biosciences In, the National Institutes of Health, and the Welch Foundation partly supported the work.