Researchers have discovered that the PEGylation of alpha-1 antitrypsin (AAT) has the potential to achieve a prolonged half-life and greater therapeutic efficacy in patients with AAT deficiency (AATD), according to a study published in the International Journal of Pharmaceutics. 

AATD is characterized by a lack of AAT, which provides essential protection to the lungs. Currently, intravenous (IV) augmentation therapy is approved to treat AATD. However, IV augmentation therapy requires high doses (60 mg/kg weekly) because of the low fraction of the dose (2%) that reaches the lungs. The inhalation route of administration has only limited efficacy, likely due to the rapid clearance of AAT from the lungs if inhaled. This means the inhalation method of AAT administration can be improved if its residence time in the lungs is prolonged.

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PEGylation has commonly been used to prolong a protein serum’s half-life and hence enhance its therapeutic value. “In a few preclinical studies, conjugation of PEG to proteins also showed the potential to improve their local residence time in the lungs after pulmonary delivery,” Liu et al wrote in the current study. 

To study the characteristics and therapeutic potential of the PEGylation of AAT, the researchers produced, and later purified, PEGylated versions of glycosylated AAT in vitro. They used two PEGylated reactions, N-terminal and thiol PEGylation, as well as three polyethylene glycol (PEG) chains—linear 30kDa, linear 40 kDa, and 2-armed 40kDa. They then assessed biological activity by using a modified elastase inhibition assay. 

“The yields of mono-PEGylated AAT following purification by anion exchange chromatography were 40–50% for N-terminal PEGylation and 60–70% for thiol PEGylation,” wrote Liu and colleagues on the results of their study. “The PEG-AAT conjugates preserved the ability to form a protease-inhibitor complex with neutrophil elastase and proteinase 3 as well as the full inhibitory capacity to neutralize neutrophil elastase activity.”

The significance of this study is that it demonstrates that PEGylated AAT may have significant therapeutic potential, although more research needs to be conducted to ensure that it is safe. The authors of this study wrote, “PEGylated AAT needs to be thoroughly characterized for its immunogenicity, safety, and biodistribution before considering it for clinical use.”


Liu X, Vanvarenberg K, Guy Wilfried Kouassi K, Mahri S, Vanbever R. Production and characterization of mono-PEGylated alpha-1 antitrypsin for augmentation therapyInt J Pharm. 2021;121355. doi:10.1016/j.ijpharm.2021.121355