Fate of aerosolized recombinant DNA-produced α1-antitrypsin: Use of the epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance

R. C. Hubbard, M. A. Casolaro, M. Mitchell, S. E. Sellers, F. Arabia, M. A. Matthay, R. G. Crystal

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Abstract

To evaluate the possibility of administering therapeutic proteins via the respiratory route, we administered an aerosol of recombinant DNA-produced human α1-antitrypsin (rAAT) to anesthetized sheep and measured levels of the protein in epithelial lining fluid (ELF), lung lymph, blood, and urine. Using a nebulizer that generated aerosol droplets with a mass median aerodynamic diameter of 2.7 μm (55% of droplets were < 3 μm, a particle size optimal for deposition on the alveolar epithelium), in vitro studies demonstrated that the aerosolized rAAT remained intact and fully functional as an inhibitor of neutrophil elastase. When aerosolized to sheep, the 45-kDa rAAT molecule diffused across the alveolar epithelium, as evidenced by its presence in lung lymph and in blood. Comparison of ELF, lymph, blood, and urine rAAT levels demonstrated that the process was concentration dependent, with highest levels in ELF and in descending concentrations with ~ 10-fold concentration differences in each consecutive compartment, respectively. Importantly, evaluation with aerosolized 125I-labeled rAAT-demonstrated that the rAAT molecules that reached the lung lymph and the systemic circulation remained intact as a 45-kDa protein. These results demonstrate the feasibility of using aerosolization to the pulmonary epithelial surface to administer sizeable proteins of therapeutic interest, thus circumventing the necessity of the traditional parenteral modes of administration of such molecules.

Original languageEnglish
Pages (from-to)680-684
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume86
Issue number2
DOIs
Publication statusPublished - 1 Jan 1989

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