Methods of Purification and Application Procedures of Alpha1 Antitrypsin: A Long-Lasting History

Abstract

The aim of the present report is to review the literature addressing the methods developed for the purification of alpha1-antitrypsin (AAT) from the 1950s to the present. AAT is a glycoprotein whose main function is to protect tissues from human neutrophil elastase (HNE) and other proteases released by neutrophils during an inflammatory state. The lack of this inhibitor in human serum is responsible for the onset of alpha1-antitrypsin deficiency (AATD), which is a severe genetic disorder that affects lungs in adults and for which there is currently no cure. Being used, under special circumstances, as a medical treatment of AATD in the so-called “replacement” therapy (consisting in the intravenous infusion of the missing protein), AAT is a molecule with a lot of therapeutic importance. For this reason, interest in AAT purification from human plasma or its production in a recombinant version has grown considerably in recent years. This article retraces all technological advances that allowed the manufacturers to move from a few micrograms of partially purified AAT to several grams of highly purified protein. Moreover, the chronic augmentation and maintenance therapy in individuals with emphysema due to congenital AAT deficiency (current applications in the clinical setting) is also presented.

Technoeconomic Analysis of Intensified PEGylated Biopharmaceutical Recombinant Protein Production: Alpha Antitrypsin as a Model Case

“…Its primary function is to protect tissue from serine proteases released during inflammation, including neutrophil elastase and proteinase 3 [1]. Moreover, it has the ability to neutralize other proteases like cysteine proteinases and metalloproteases [2]. AAT protein is produced and secreted into the serum by hepatocytes with a mean concentration of 1-2 g/L.…”

“…The management protocol for the disease currently consists of life-long augmentation therapy with weekly infusions of 60 mg AAT/kg body weight [18][19][20]. Although authentic human AAT has been purified to a great extent from human plasma and Cohn fraction IV [2], limited resources for authentic human AAT from plasma or its derivates make this process unsustainable. For example, in the U.S., only 5000 severely deficient patients out of an estimated 60,000 PiZZ carriers receive a weekly dose based on the required amount mentioned earlier [5,16].…”

Pancreas Preservation with a Neutrophil Elastase Inhibitor, Alvelestat, Contributes to Improvement of Porcine Islet Isolation and Transplantation

“…In rats with hyperketonaemia, treatment with sivelestat sodium reduces serum cytokines and improves islet yields and functions in vitro [ 12 ]. α1-Antitrypsin is also a serine protease inhibitor that inhibits NE [ 20 , 21 , 22 , 23 ], prolongs islet graft survival [ 13 ], and reduces expression of proinflammatory mediators [ 14 ] in mice by binding to gp96 (a heat-shock protein) [ 24 ].…”