Immune NK T-cells may be therapeutic target for IPF

GRI Bio shares data about the potential role of natural killer T-cell suppressor GRI-0621

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Certain immune cells called natural killer (NK) T-cells are present at higher numbers in the lungs of people with idiopathic pulmonary fibrosis (IPF) than in the lungs of healthy people, according to data announced by GRI Bio.

Also, the more NK T-cells, the greater the number of macrophages, a type of immune cell that contributes to IPF-related inflammation and scarring, or fibrosis. This supports the therapeutic potential of the company’s NK T-cell suppressor, GRI-0621, in IPF.

“These data add to our growing belief in the key role of NKT cells [NK T-cells] in the [underlying mechanisms] of IPF and bolsters our confidence in GRI-0621’s ability to provide a much-needed therapeutic option for patients,” Marc Hertz, PhD, GRI Bio’s CEO, said in a press release.

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Emily Calamita, a GRI Bio collaborator at Imperial College London in the U.K., presented the data at the 2023 Pittsburgh-Ireland International Lung Conference, held last month in Dublin, Ireland, in a poster titled “Altered NKT cell populations in the airways of patients with IPF.”

“Supported by a growing body of data, we are on track to launch our Phase 2a biomarker study before year end to evaluate GRI-0621 as a potential treatment option for this devastating disease,” Hertz said.

Pulmonary fibrosis causes lung tissue to thicken and stiffen and form scars over time. Scarred lungs make it difficult to breathe, leading to shortness of breath and a dry, hacking cough. When the cause remains unknown, the disease is said to be idiopathic.

NK T-cells play an important role in the body’s first immune response to invading microorganisms or other threats. A recent review study co-authored by Hertz concluded that a subset of NK T-cells, type 1 invariant NK T-cells, may trigger a cascade of events leading up to inflammation and fibrosis both in mice and people with IPF.

Examining NK T-cells from bronchoalveolar lavage samples

Now, GRI Bio, Calamita, and other researchers investigated the NK T-cell population in samples of bronchoalveolar lavage (BAL) from deep in the airways of IPF patients and healthy people.

The number and proportion of NK T-cells were significantly higher in BAL samples from people with IPF than from healthy controls. NK T-cells from IPF patients also showed significantly higher activity in the genes coding for TGF-beta, osteopontin, and collagen type I — all involved in pro-fibrotic events seen in IPF.

Significant production of IFN-gamma in IPF patients

IPF patients also showed a significantly higher proportion, by nearly five times, of NK T-cells producing IFN-gamma, a signaling molecule that promotes further immune responses, compared with healthy people.

In people with IPF, a higher number of NK T-cells was associated significantly with higher counts of airway macrophages, another immune cell type involved in IPF, but not with forced vital capacity (FVC), a measure of lung function.

“The number of NKT cells positively correlates with the number of airway macrophages in IPF patients. However, there is no correlation with lung function parameters,” the researchers wrote in the poster. “Our data implicate NKT cell populations in the [underlying mechanisms] of IPF.”

GRI-0621 is a patented, orally-available small molecule designed to mimic the action of retinoid acid receptor (RAR) beta and gamma, two molecules known to suppress the activity of type 1 invariant NK T-cells.

In disease models, it was shown to reduce fibrosis. In a small placebo-controlled Phase 2a trial (NCT02949375) involving 14 people with a chronic liver disease also marked by fibrosis, the oral therapy improved liver function and reduced markers of inflammation and injury, according to GRI Bio.

According to a May press release, the upcoming Phase 2a biomarker study may include up to 36 people with IPF who are already receiving treatment for the disease. Participants will be assigned randomly to receive either GRI-0621 or a placebo for about three months.

Its main goal may be to check if GRI-0621 is safe and well tolerated based on lab tests and side effects. Secondary goals may include changes in blood biomarkers, as well as the therapy’s pharmacokinetics (the therapy’s movement in, through, and out of the body) and suppressing effects on NK T-cells. Changes in lung function also may be assessed as an exploratory measure.