Innovative drug reduces inflammation in rats by inhibiting neutrophil activation

A newly developed compound that reduces harmful inflammation caused by overactive neutrophils in rats shows great potential as a safer treatment for various inflammatory diseases in humans.

Neutrophils are the most abundant white blood cells in the human body and play a crucial role in the immune response. These immune cells help fight infections by capturing pathogens and releasing enzymes that kill the invaders. Although they are essential for fighting infections, neutrophils can also become overactive, leading to various inflammatory diseases. When activated by an infection, neutrophils can release neutrophil extracellular traps (NETs), web-like structures made of DNA and proteins that capture and kill pathogens as part of the host's normal defense mechanism. However, too much NET formation can cause significant tissue damage, contributing to inflammation.

A team of researchers from Hokkaido University and Alivexis, Inc. investigated a recently developed drug candidate, MOD06051, that reduces harmful inflammation in rat models by targeting neutrophils. The results of their joint research were recently published in Nature Communications.

We found that MOD06051 acts as a selective inhibitor of cathepsin C (CatC), a key regulator that activates several enzymes in neutrophils known as neutrophil serine proteases (NSPs). One such NSP is neutrophil elastase, an enzyme involved in pathogen killing but also an essential factor in NET formation.”

Yoh Terada, co-author of Alivexis, Inc.

The scientists found that inhibiting CatC reduces the active form of neutrophil elastase and decreases the ability of neutrophils to form NETs. Excessive NET formation is linked to several diseases, including vasculitis, lupus, rheumatoid arthritis and diabetes.

“When we tested the compound in rats suffering from a specific type of vasculitis, it reduced the severity of the disease, as evidenced by reduced inflammation and damage to blood vessels, particularly the kidneys and lungs,” says Professor Akihiro Ishizu, who led the study. “Our results suggest that CatC inhibition holds promise as a new treatment strategy to reduce neutrophil overactivation and improve the condition in diseases in which overactive neutrophils and excessive NET formation play a crucial role. This approach differs from current treatments that may have broader immunosuppressive effects.”

Glucocorticoids and immunosuppressants are currently widely used in the treatment of inflammatory diseases, which suppress overall immune system activity and can lead to secondary immunodeficiency, increasing the risk of opportunistic infections. By targeting multiple NSPs through CatC inhibition without comprehensive immune system suppression, MOD06051 may offer a safer alternative that could reduce the risk of infections and other side effects.

These findings pave the way for further research and clinical trials to evaluate the safety and efficacy of MOD06051 in humans. The team is optimistic that this novel approach will provide safer and more effective therapies for patients around the world suffering from a variety of inflammatory diseases, thereby improving their quality of life.