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Birmingham in the United Kingdom. With
that realization has come optimism that
these cells aren’t off-limits for medical in-
terventions. Researchers have been cau-
tious 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 of-
fered reassurance that it can be safe to re-
strain the cells.
Although some of those trials yielded
mediocre results, researchers have pressed
on—and their persistence may be paying
off. Two clinical trials with neutrophil-
focused drug candidates reported encour-
aging findings last year; one could lead to
the approval of the first medication tar-
geting these immune cells, in a rare auto-
immune condition. The trial Ferro and his
colleagues are conducting, the first to at-
tempt to stem cardiovascular disease by

interfering with neutrophils, is expected to
have results by 2021 or 2022. And a burst of
new findings about the cells’ diversity and
behavior is likely to inspire new ways to ma-
nipulate them. “There is real hope in this
field,” Sapey says.

NEUTROPHILS FLOCK to the site of an injury
or infection, wherever it occurs. The cells
navigate to trouble spots with the help
of receptors on their surface, such as one
known as CXCR2, which detects a trail of
alarm molecules released by damaged tis-
sue. If the cells happen upon microbes,
they launch a multipronged attack, gob-
bling the pathogens, spilling corrosive
chemicals, and sometimes launching webs
of DNA, known as neutrophil extracellular
traps (NETs), that snag and kill the invad-
ers. Hematopoietic stem cell transplants
given to some cancer patients to replace
their bone marrow underscore the im-

portance of these defenses. “If the graft
doesn’t take, you will have no neutrophils,
and that is not survivable,” says immuno-
logist Klaus Ley of the La Jolla Institute
for Immunology.
Yet studies over the past 2 decades have
darkened their image. The cells in effect
“drop atomic bombs” in the body, says
immunologist Paul Kubes of the Univer-
sity of Calgary. Neutrophil elastase and
other chemicals they discharge may drive
inflammation and damage to the airways
in cystic fibrosis and intractable cases of
asthma. NETs, for their part, can provoke
the immune system to attack a patient’s
own cells in the autoimmune disease lupus,
and they spur formation of blood clots in
the potentially lethal condition deep-vein
thrombosis. NETs can also worsen arterial
plaques by promoting inflammation, cell
biologist Venizelos Papayannopoulos of
the Francis Crick Institute in London and
colleagues found in 2015. Neutrophils can
even abet cancer, spurring growth of new
blood vessels that feed tumors and helping
the abnormal cells spread to other parts of
the body.
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 con-
trolling cell movement.
More than a dozen clinical trials scru-
tinized these potential drugs in many con-
ditions. The good news is that the com-
pounds didn’t cripple defenses against
infections. But most of the trials found min-
imal benefits. As a result, several big phar-
maceutical 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, ar-
guing 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.
Hematologist and oncologist Steven
Pavletic of the U.S. National Cancer Insti-
tute and his colleagues think they can do
better. In a phase I safety trial, Pavletic and
his team have started to give larger amounts PHOTO: TOMASZ SZUL AND DEREK W. RUSSELL

Blunting the attack

Ongoing clinical trials aim to treat a range of diseases by targeting proteins that abet tissue damage by neutrophils.
Earlier tests had reassured researchers that the strategy would not leave patients defenseless against infections.


ANCA vasculitis C5a (molecule that helps switch
on neutrophils)

Avacopan Phase III completed ChemoCentryx

Chronic obstructive
pulmonary disease

CXCR2 (receptor that helps guide
neutrophils to damaged tissue)

Danirixin Phase II completed GlaxoSmithKline

Cardiovascular disease CXCR2 AZD5069 Phase II underway AstraZeneca

Asthma PI3K (protein that helps
control neutrophil migration)

Nemiralisib Phase II completed GlaxoSmithKline

Cystic fibrosis Neutrophil elastase
(tissue-damaging enzyme)

POL6014 Phase I/II underway Santhera

Pulmonary arterial

Neutrophil elastase Elafin Phase I underway Proteo Biotech

Released by neutrophils, vesicles (yellow) carrying
protein-degrading enzymes can bind to and damage
collagen fibrils (blue) in connective tissue.

1068 6 MARCH 2020 • VOL 367 ISSUE 6482

Published by AAAS
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