title: Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy.
abstract: Human plasma-derivedα1-antitrypsin (AAT) delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting in deficiency of AAT. Inhalation is an alternative route of administration that can potentially increase the efficacy and convenience of treatment. This study was conducted to determine whether delivery to the lungs, initially via the intratracheal (IT) route of administration, would deliver efficacious levels of a recombinant AAT (rAAT) to the site of action in the lungs in mice.125I-radiolabeled rAAT, fluorophore-conjugated rAAT (rAAT-Alexa488), and NE680 (neutrophil elastase 680, a silent fluorescent substrate of neutrophil elastase which fluoresces in the near-infrared range upon activation by neutrophil elastase) were used to characterize the pharmacokinetics and tissue distribution profile, distribution of rAAT within the lung, and efficacy of rAAT to inhibit neutrophil elastase at the site of action, respectively. The study has demonstrated that rAAT was able to gain access to locations where neutrophil elastase was localized. The histochemical quantification of rAAT activity relative to dose at the site of action provided here will improve confidence in predicting the human dose via the inhalation route.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Andover, MA, USA.
authors.forename: Mengmeng
authors.identifier: 0000-0002-8278-734X
authors.initials: M
authors.lastname: Wang
authors.affiliation: Drug Safety R&D, Pfizer Inc., Andover, MA, USA.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Clinical R&D, Pfizer Inc., Cambridge, MA, USA.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Andover, MA, USA.
authors.forename: Haojing
authors.initials: H
authors.lastname: Rong
authors.affiliation: Drug Safety R&D, Pfizer Inc., Andover, MA, USA.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: O'Neil
authors.affiliation: Molecular Imaging Laboratory, Pfizer Inc., Andover, MA, USA.
authors.forename: Brahma
authors.initials: B
authors.lastname: Ghosh
authors.affiliation: Drug Safety R&D, Pfizer Inc., Andover, MA, USA.
authors.forename: Vuong
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Rare Disease RU, Pfizer Inc., Cambridge, MA, USA.
authors.forename: Jane
authors.identifier: 0000-0002-4916-7202
authors.initials: J
authors.lastname: Owens
authors.affiliation: Rare Disease RU, Pfizer Inc., Cambridge, MA, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Andover, MA, USA.
authors.forename: Denise M
authors.identifier: 0000-0003-3266-041X
authors.initials: DM
authors.lastname: O'Hara