ATYR1923, a candidate therapy for pulmonary sarcoidosis, binds specifically to the neuropilin-2 (NRP2) receptor protein, which is located at the surface of immune cells responsible for inflammation and granuloma formation in lung sarcoidosis, the treatment’s developer, aTyr Pharma, has announced.
These findings are described in two posters, titled “ATYR1923 Specifically Binds to Neuropilin-2, a Novel Therapeutic Target for the Treatment of Immune-Mediated Diseases”and “Neuropilin-2, the Specific Binding Partner to ATYR1923, Is Expressed in Sarcoid Granulomas and Key Immune Cells,” to be presented at the 2020 ATS International Conference — which will be held virtually due to the COVID-19 pandemic — and later published in the American Journal of Respiratory and Critical Care Medicine.
“We are very pleased to have these abstracts, which were originally accepted for presentation at the ATS International Conference, published in the highly-regarded American Journal of Respiratory and Critical Care Medicine,” Sanjay Shukla, MD, president and CEO of aTyr, said in a press release.
ATYR1923 is an immunomodulatory molecule that binds to a receptor protein, called NRP-2. Specifically, ATYR1923 was designed to downregulate the immune responses in inflammatory disease states.
In a previous study in mice, ATYR1923 was shown to have a potent immunomodulatory activity, lessening lung inflammation by halting the infiltration of immune cells called neutrophils into the lungs.
However, “to date, little is known about the role of NRP2 in immune regulation and disease, in particular very little is known about the expression of NRP2 in sarcoidosis patients,” researchers wrote.
The first study assessed the presence and pattern of NRP2 in cells from sarcoidosis patients.
“We report for the first time that NRP2 is expressed in samples obtained from lung and skin of sarcoidosis patients,” the researchers wrote.
In particular, NRP2 was detected on myeloid cells — immune cells that play a crucial role in granuloma formation and inflammation. Using mice, the team confirmed NRP2 presence in different myeloid cells, including macrophages, dendritic cells, neutrophils, and T-cells.
“We clearly show that NRP2 expression can be detected on key immune cells known to play an important role in inflammation and granuloma formation,” the researchers wrote. “These findings highlight the potential of ATYR1923 to exert its effect on various immune cells directly related to the pathology of the target patient population.”
In the second study, scientists characterized the specificity of ATYR1923 for the NRP2 receptor. In lab tests with more than 4,500 human plasma membrane proteins, they observed a specific interaction between ATYR1923 protein and the NRP2 receptor. This was later confirmed in a cell line, called HEK293, which was modified to have higher-than-normal levels of NRP2, and also in immune cells in which NRP2 is found at the cell’s surface (including THP-1 polarized M1 macrophages).
“ATYR1923 specifically and selectively binds to NRP2 on the cell surface,” the researchers wrote, adding that NRP2 is a “receptor known to be expressed on a number of different immune cell types and play a key role in regulating inflammatory responses.”
Together, the findings support the immune modulatory properties of ATYR1923 and its potential for mitigating immune-mediated diseases such as pulmonary sarcoidosis.
“The findings summarized in these abstracts confirm the significant role of NRP2 in serious inflammatory diseases, and further elucidate the mechanism of action of ATYR1923 in its ability to selectively bind to this unique target,” said Shukla.
ATYR1923 is being investigated in a Phase 1b/2a clinical trial in patients with pulmonary sarcoidosis in the United States. The trial (NCT03824392) is currently recruiting adult participants (for more information, visit this link), but due to the COVID-19 pandemic, aTyr is expecting a delay in completing enrollment.
“While some of our investigational sites for our ongoing trial of ATYR1923 in pulmonary sarcoidosis have remained active, our timeline has been impacted by the [COVID-19] pandemic and we expect a delay in the completion of enrollment,” Shukla said in another press release. “We are encouraged by our recent interactions with our investigators as they implement procedures to allow them to safely re-engage during the second quarter and complete our Phase 1b/2a trial study.”
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