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Page 8 of 12 Chen et al. Rare Dis Orphan Drugs J 2022;1:15 https://dx.doi.org/10.20517/rdodj.2022.18

successfully reducing neutrophilic inflammation. However, more frequent episodes of exacerbation and
pneumonia infections were reported in the high-dose treatment arms, implying that retaining adequate
[74]
physiological responses is crucial for retaining host defence .

Neutrophil adhesion
An alternative approach to modulate neutrophil migration would be targeting endothelial adhesion. LTB4
mediates neutrophil adhesion by upregulating a b2-integrin (Mac-1) on endothelial cells as well as
promoting neutrophil chemotaxis and degranulation [75,76] . Although LTB4 receptor antagonists have been
studied in neutrophilic inflammatory diseases including cystic fibrosis and COPD, so far, no evident clinical
benefit has been reported , even though Gompertz and Stockley showed an anti-inflammatory effect. In
[78]
[77]
addition, directly blocking the adhesion molecules could have the same effect, although both strategies run
the risk of impairing this important secondary host defence as indicated above for CXCR2.

Proteinase production
A further approach would be to target upstream regulators required for maturating neutrophil serine
proteinases before packaging into granules, thereby reducing the proteinase payload delivered per
neutrophil. Cathepsin C (CatC) is an essential endopeptidase regulating the activation and subsequent
packaging of neutrophil serine proteinases. An uncleaved signal peptide in the zymogens is signalled for
degradation and when it is removed by CatC, the neutrophil serine proteinases become activated and
packaged into the azurophilic granules. This packaging process occurs early in neutrophil maturation .
[79]

Recently, it was discovered that azurophilic degranulation is also significantly enhanced in AATD
neutrophils through Rac2 signalling induced by elastase activity on the proteinase-activated receptor 2 on
the neutrophils , adding further amplification to neutrophil elastase release. CatC is therefore an appealing
[80]
target to simultaneously abrogate neutrophil serine proteinase activity and control the magnitude of
degranulation. More importantly, CatC inhibition does not seem to interfere with neutrophil migration and
antibacterial properties, as individuals with severe CatC deficiency (Papillion-Lefèvre syndrome) do not
experience increased susceptibility toward major bacterial infections . CatC blockade, therefore, should
[81]
cumulatively reduce the quantity of neutrophil elastase and Proteinase 3 packaged into each azurophilic
granule, lessen the amount of proteinase released and prevent excessive degranulation restoring a
proteinase/antiproteinase balance to a level consistent with AATD while retaining neutrophilic defence
properties. However, this should be balanced to avoid severe deficiency associated with the Papillion-Lefè
vre syndrome.

CatC inhibition as a strategy is supported by AZD7986 (Brensocatib), a reversible CatC inhibitor used in a
24-week phase 2 trial in non-cystic fibrosis bronchiectasis where it reduced sputum neutrophil elastase
activity by 40% while lowering exacerbation rates. In AATD, this approach may have not just been a
beneficial effect on emphysema decline targeting both neutrophil elastase and Proteinase 3 but also an
added benefit to the 30% of AATD patients with both emphysema and bronchiectasis .
[82]
SUMMARY
Neutrophil serine proteinases are responsible for driving inflammation and tissue destruction in the lung,
especially in chronic lung diseases, such as AATD. This process is partly modulated by AAT replacement in
AATD.