Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use

Abstract

Human alpha-1-proteinase inhibitor is a well-characterized protease inhibitor with a wide spectrum of anti-protease activity. Its major physiological role is inhibition of neutrophil elastase in the lungs, and its deficiency is associated with progressive ultimately fatal emphysema. Currently in the US, only plasma-derived human alpha-1-proteinase inhibitor is available for augmentation therapy, which appears to be insufficient to meet the anticipated clinical demand. Moreover, despite effective viral clearance steps in the manufacturing process, the potential risk of contamination with new and unknown pathogens still exists. In response, multiple efforts to develop recombinant versions of human alpha-1-proteinase inhibitor, as an alternative to the plasma-derived protein, have been reported. Over the last two decades, various systems have been used to express the human gene for alpha-1-proteinase inhibitor. This paper reviews the recombinant versions of human alpha-1-proteinase inhibitor produced in various hosts, considers current major safety and efficacy issues regarding recombinant glycoproteins as potential therapeutics, and the factors that are impeding progress in this area(1).

Expanding the Clinical Indications for α1-Antitrypsin Therapy

“…Recombinant AAT has been derived from plants, yeast, fungi, animals, insect cells, bacteria and mammalian cells and has been manipulated toward humanized systems, mutated at specific amino acids and conjugated with polyethylene glycol (PEG) (152). Bacterial nonglycosylated 44-kDa recombinant human AAT typically aggregates, is inactive and is also rapidly cleared from the circulation; the prolongation of its half-life by PEGylation may provide a solution to its inferiority (153).…”

Inhibition of airway proteases in cystic fibrosis lung disease

“…Prolastin is well tolerated and effective in vivo, but the purity of the preparation is only ,60% [124]. Novel a 1 -AT replacement preparations, such as Zemaira or Aralast, have shown equivalency with Prolastin in augmenting a 1 -AT serum and alveolar epithelial levels and provide greater purity than conventional preparations (Zemaira.Aralast.Prolastin) [124][125][126]. However, clinical data on the use of these preparations in CF patients are unavailable to date.…”

Recent Advances in the Research and Development of Alpha-1 Proteinase Inhibitor for Therapeutic Use

“…As evident from numerous reports, both from academic research and industry, the human gene for 1 -PI has been expressed in virtually all available hosts (E. coli, various yeasts, fungi, insect cells, CHO cells, human neuronal cells, and produced in transgenic plants and animals). For more details on research and development of recombinant 1 -PI (r-1 -PI) in different systems and advances and limitations of the recombinant approach for production of stable and biologically active 1 -PI, see our comprehensive 2006 review (Karnaukhova et al, 2006). More recently, the human gene for 1 -PI is available as a licensed therapeutic treatment.…”

“…In general, the essential criteria for the development of therapeutics for human use are safety, optimal clinical efficacy, and maximum cost-effectiveness. Among many efforts to develop r-1 -PI of therapeutic quality (see Karnaukhova et al, 2006), there appear to be only two examples of the r-1 -PIs for which development went far enough to get to clinical trials. The first was r-1 -PI produced in the yeasts Saccromyces cerevisiae and manufactured by Arriva Pharmaceuticals Inc. (Arriva) for several indications.…”

“…In order to be effective, therapeutic proteins have to be stable in vivo and in vitro (Karnaukhova et al, 2006). Reviewing the work performed over the last two decades to produce stable and biologically active r-1 -PI of therapeutic quality, one can see basically two major factors that were impeding the progress: (1) impurities that could induce antibody responses and cause adverse reactions in patients, and (2) lower stability than that of plasma counterpart, mainly caused by the lack of glycosylation or nonhuman type of glycosylation (the latter may also induce immune responses).…”