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Polyethylene Glycol Conjugation at Cys²³² Prolongs the Half-Life of 1 Proteinase Inhibitor

Pulmonary Research Unit and Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec; and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada

Address correspondence to: André M. Cantin, M.D., Pulmonary Research Unit, Faculty of Medicine, University of Sherbrooke, 3001 12ième Avenue Nord, Fleurimont, PQ, J1H 5N4 Canada. E-mail: Andre.Cantin{at}usherbrooke.ca

1 Proteinase inhibitor (1PI), a natural inhibitor of the serine proteinase leukocyte elastase, is also an intravenous therapeutic agent used to treat hereditary emphysema and may be useful in other respiratory disorders. However, to achieve sustained suppression of leukocyte elastase, 1PI must be given frequently and in large amounts, thus limiting its clinical use. We hypothesized that conjugating 1PI with polyethylene glycol (PEG) at Cys²³² could extend the in vivo half-life of 1PI in blood and lung. We present evidence that site-specific conjugation with either 20 or 40 kD PEG at Cys²³² of nonglycosylated recombinant human 1PI (rh1PI) results in an active inhibitor with prolonged in vivo stability. In addition, 72 h after airway instillation PEG-rh1PI was found to be significantly better than glycosylated 1PI in protecting the lung against leukocyte elastase–mediated lung hemorrhage. We conclude that thiol-specific PEGylation markedly improves the in vivo pharmacokinetic profile of rh1PI and represents a simple, novel strategy to address the therapeutic goal of human leukocyte elastase inhibition.

Abbreviations: 1 proteinase inhibitor, 1PI • bronchoalveolar lavage fluid, BALF • cystic fibrosis, CF • human leukocyte elastase, HLE • human neutrophil elastase, HNE • isopropyl ß-D-thiogalactoside, IPTG • relative molecular mass, M_r • N-ethylmaleimide, NEM • polyethylene glycol, PEG • recombinant human 1PI, rh1PI • sodium dodecyl sulfate–polyacrylamide gel electrophoresis, SDS-PAGE

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