Evaluation of recombinant DNA-directed E.coli produced α1-antitrypsin as an anti-neutrophil elastase for potential use as replacement therapy of α1-antitrypsin deficiency

Sherwin D. Straus, Gerald A. Fells, Mark D. Wewers, Michael Courtney, Luc henri Tessier, Paul Tolstoshev, Jean Pierre Lecocq, Ronald Crystal

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Abstract

α1-antitrypsin (α1AT) deficiency is an inherited disorder almost always associated with the development of panacinar emphysema in the fourth to fifth decades. One source of α1AT for chronic replacement therapy of such individuals is that produced by E.coli directed by a cDNA coding for the human α1AT molecule. Using TG1(E.coli), an α1AT molecule produced by E.coli transformed with the plasmid-expressing vector pTG922, the present study shows that recombinant DNA-directed E.coli-produced α1AT is as an effective inhibitor of neutrophil elastase as α1AT purified from plasma. Importantly, TG1(E.coli) inhibited human neutrophil elastase with an association rate constant of 1.3±0.4×107 M-1 sec-1, similar to that of normal plasma α1AT (1.1±0.1, p>0.2). Furthermore, when TG1(E.coli) was added to α1AT-deficient plasma obtained from homozygous α1AT type Z individuals, the TG1(E.coli) remained functional and augmented the anti-neutrophil elastase activity of the serum proportional to the amount of TG1(E.coli) added. These observations suggest that if sufficient amounts of recombinant DNA methodology-produced α1AT molecules could be safely delivered to the alveolar structures of α1AT-deficient individuals, they would function to protect the alveolar walls from elastolytic attack.

Original languageEnglish
Pages (from-to)1177-1184
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume130
Issue number3
DOIs
Publication statusPublished - 15 Aug 1985
Externally publishedYes

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ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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