title: The ability of serum from alpha 1-antitrypsin-deficient patients to inhibit PRT-201, a recombinant human type I pancreatic elastase.
abstract: PRT-201 is a recombinant human pancreatic elastase under development as a treatment for blood vessels to promote hemodialysis access patency. Proteases such as elastase are normally inactivated by antiproteases such as alpha 1-antitrypsin. It is unknown if serum from patients with alpha 1-antitrypsin deficiency will inhibit PRT-201 elastase activity. An assay for PRT-201 elastase activity in the presence of serum was developed and validated. PRT-201 elastase activity inhibition curves were developed using serum and also using purified alpha 1-antitrypsin and alpha 2-macroglobulin. Serum from 15 patients with documented alpha 1-antitrypsin deficiency, some of whom were receiving alpha 1-antitrypsin augmentation therapy, and four normal volunteers was analyzed. Serum from normal volunteers and patients with alpha 1-antitrypsin deficiency completely inactivated PRT-201 elastase activity in vitro. In the alpha 1-antitrypsin-deficient patients, the volume of serum necessary to inhibit elastase activity was related to the serum concentration of alpha 1-antitrypsin and augmentation therapy. Purified alpha 1-antitrypsin and alpha 2-macroglobulin were each alone capable of completely inhibiting PRT-201 elastase activity. It is unlikely that the use of PRT-201 will be associated with negative outcomes in patients with alpha 1-antitrypsin deficiency.
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Qamar
authors.forename: Steven K
authors.initials: SK
authors.lastname: Burke
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lafleur
authors.forename: Bee C
authors.initials: BC
authors.lastname: Ding
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Bland
authors.forename: Marco D
authors.initials: MD
authors.lastname: Wong
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Gustafson
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Blair
authors.forename: F Nicholas
authors.initials: FN
authors.lastname: Franano
mesh_terms: D000328:Adult; D000368:Aged; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D044967:Serum; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood* / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D010196:Pancreatic Elastase