Alpha-1 antitrypsin-IgG1 Fc-fusion protein (AAT-Fc) may provide a new therapeutic option for people with emphysema caused by alpha-1 antitrypsin (AAT) deficiency as well as cigarette smoke.

Currently, the treatment option for emphysema is plasma-derived AAT. However, this only provides modest clinical improvements in some patients. Moreover, patients have to have weekly intravenous infusions, making the treatment cumbersome.

In order to assess the effect of AAT-Fc, which should have a longer half-life after infusion, and therefore require fewer infusions, researchers led by Erwin W. Gelfand, MD, the chairman of the Department of Pediatrics at National Jewish Health, in Denver, Colorado, used 2 mouse models of emphysema.


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In the first model, the team used elastase to induce emphysema while in the second they exposed the mice to cigarette smoke daily, 5 days a week, for 6 months.

Researchers treated the animals with either AAT-Fc or plasma-derived AAT or a vehicle 1 day before or 3 weeks after elastase instillation, in the elastase-induced emphysema model. They then assessed the lung function and histology of the animals 7 and 32 days after instillation.

In the cigarette smoke-induced emphysema model, they administered AAT-Fc or plasma-derived AAT, or a vehicle every 10 days during the last 3 months of cigarette smoke exposure.

The results showed that both elastase instillation and exposure to cigarette smoke led to alveolar enlargement and increased lung compliance. They also led to an increase in markers of inflammation.

Importantly, AAT-Fc led to better protection against alveolar enlargement, lung dysfunction, and airway inflammation compared to plasma-derived AAT in both models of emphysema regardless of when it was administered. 

In terms of immune reactivity, the researchers have shown that the spleen mononuclear cells of elastase-exposed mice produced IFNγ and IL-17 in a dose-dependent manner, suggesting immune reactivity and that AAT-Fc treatment inhibited this production.

The researchers concluded that AAT-Fc could more effectively prevent or attenuate emphysema caused by elastase instillation of cigarette smoke compared to plasma-derived AAT and that this effect was immunomodulatory in nature.

“AAT-Fc may provide a therapeutic option to individuals with AAT-[deficiency] and [cigarette smoke]-induced emphysema,” they wrote.

Emphysema is a condition where the inner walls of the alveoli in the lungs weaken and rupture forming enlarged air spaces. It can be caused by genetic conditions such as AAT deficiency or cigarette smoke.

Reference

Takeda K, Kim SH, Joetham A, Petrache I, Gelfand EW. Therapeutic benefits of recombinant alpha1-antitrypsin IgG1 Fc-fusion protein in experimental emphysema. Respir Res. 2021;16;22(1):207. doi:10.1186/s12931-021-01784-y