A new study has found that LQ059, an inhalable single domain antibody, shows promise in blocking Notch2, a protein involved in the production of excess mucus in cystic fibrosis (CF).
The study results, published in the American Journal of Respiratory Critical Care Medicine, were presented at the recent American Thoracic Society International Conference in Washington, DC.
“As reported, Notch2 plays an important role in mediating goblet cell metaplasia and mucus clearance,” the authors wrote. “Given the wide distribution of Notch2 across the body, it would be better to develop a drug antagonist of Notch2, which could be directly delivered to the lungs by inhalation for CF lung disease treatment.”
The research team developed LQ059 and used biolayer interferometry to determine its affinity to Notch2. They employed an enzyme-linked immunosorbent assay to assess its specificity and crossreactivity in vitro. An in vivo mouse model of interleukin 13-induced lung inflammation was used to measure the efficacy of LQ059 in reducing goblet cell metaplasia, mucus secretion, and mucin-related gene expression.
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The results showed that LQ059 bound to Notch2 and blocked its activity in a specific manner and did not bind to other Notch family members. In the mouse model, LQ059 significantly reduced goblet cell metaplasia in the lung and alleviated mucus production. LQ059 also significantly reduced the production of mucin-related genes.
Using the Next Generation Pharmaceutical Impactor, the research team found that LQ059 has the right particle size for effective delivery to the lungs via inhalation. The team was also able to produce LQ059 in significant quantities, enhancing its potential as an inhalable molecule.
Based on these findings, the team believes that LQ059 is an effective bivalent Notch2 neutralizing antibody that shows significant promise as a new treatment for CF lung disease.
Reference
Wan Y, Gai J, Zhu M, et al. First-in-class inhalable anti-notch2 single domain antibody for the treatment of cystic fibrosis lung disease. Am J Respir Crit Care Med. Published online May 21, 2023. doi:https://doi.org/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A1380
