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Targeted Delivery of Antiprotease to the Epithelial Surface of Human Tracheal Xenografts

Department of Pediatrics, Washington University School of Medicine, St. Louis; Department of Veterinary Medicine and Surgery, College of Veterinary Medicine; Division of Biological Sciences; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri; and Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Dr. Thomas Ferkol, M.D., Division of Pediatric Allergy and Pulmonary Medicine, Department of Pediatrics, 660 South Euclid Avenue, Mailbox 8202, St. Louis, MO 63011. E-mail: ferkol_t{at}kids.wustl.edu

The cystic fibrosis (CF) lung is uniquely susceptible to Pseudomonas aeruginosa, and infection with this organism incites an intense, compartmentalized inflammatory response that leads to chronic airway obstruction and bronchiectasis. Neutrophils migrate into the airway, and released neutrophil elastase contributes to the progression of the lung disease characteristic of CF. We have developed a strategy that permits the delivery of antiproteases to the inaccessible CF airways by targeting the respiratory epithelium via the human polymeric immunoglobulin receptor (hpIgR). A fusion protein consisting of a single-chain Fv directed against secretory component, the extracellular portion of the pIgR, linked to human ₁-antitrypsin is effectively ferried across human tracheal xenografts and delivers the antiprotease to the apical surface to a much greater extent than occurs by passive diffusion of human ₁-antitrypsin alone. Targeted antiprotease delivery paralleled hpIgR expression in the respiratory epithelium in vivo and was not increased by escalating dose, so airway penetration was receptor-dependent, not dose-dependent. Thus, this approach provides us with the ability to deliver therapeutics, like antiproteases, specifically to the lumenal surface of the respiratory epithelium, within the airway surface fluid, where it will be in highest concentration at this site.

Key Words: polymeric immunoglobulin receptor • antiprotease • human tracheal xenograft • airway • epithelium

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