new-drugs-aim-disarm-immune-system-s-atomic-bomb-cells

https://www.sciencemag.org/news/2020/03/new-drugs-aim-disarm-immune-system-s-atomic-bomb-cells

Interfering with neutrophils is an audacious idea. Neutrophils make up some 70% of the white cells in blood, with billions spawned every day by stem cells nestled in the bone marrow.

Neutrophils can also malfunction. In some conditions, such as chronic obstructive pulmonary disease (COPD), they seem to lose their sense of direction: Instead of homing in on bacteria, they wander. Researchers suspect these vagrant neutrophils release neutrophil elastase and other molecules at the wrong spots, including the lungs, causing the tissue damage seen in COPD.

“We are now beginning to understand that neutrophils are linked to many diseases that blight our population,” says pulmonologist Elizabeth Sapey of the University of Birmingham in the United Kingdom. With that realization has come optimism that these cells aren’t off-limits for medical interventions. Researchers have been cautious about targeting neutrophils, fearing that doing so would leave patients at the mercy of pathogens. “The age-old idea was that you couldn’t touch neutrophils,” Sapey says. But a series of clinical trials has offered reassurance that it can be safe to restrain the cells.

More than 10 years ago, such disease links prompted some companies to begin to develop compounds that inhibit neutrophil elastase. Others tried to restore neutrophils’ navigational abilities, which are faulty in COPD and other conditions, by blocking the protein PI3K, an enzyme involved in controlling cell movement.

More than a dozen clinical trials scrutinized these potential drugs in many conditions. The good news is that the compounds didn’t cripple defenses against infections. But most of the trials found minimal benefits. As a result, several big pharmaceutical companies have given up. In 2019, GlaxoSmithKline jettisoned danirixin and nemiralisib, the two neutrophil-targeting drug candidates it had been developing for lung diseases. Merck and AstraZeneca have also recently abandoned once-promising compounds.

But researchers say there’s still hope, arguing they haven’t yet pinned down what doses to use, how best to deliver potential drugs, and which aspects of neutrophil biology to target. In trials for COPD and other lung disorders, Sapey notes, patients inhaled the compounds. But because most neutrophils ply the bloodstream, inhaled drugs may not reach faulty cells, she says. Nervous about side effects, investigators may also have kept doses too low.

And as scientists dig deeper into the cells’ biology, they may find new ways to keep these immune soldiers in check, Fessler says. “There is hope that with increasing understanding of neutrophils, we will have more sophisticated approaches down the line.”