Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling
Mohit Ojha, Noah J. Smith, Andrew J. Devine, Rashika Joshi, Emily M. Goodman, Qiang Fan, Richard Schuman, Aleksey Porollo, J. Michael Wells, Ekta Tiwary, Matthew R. Batie, Jerilyn Gray, Hitesh Deshmukh, Michael T. Borchers, Samuel A. Ammerman, Brian M. Varisco
Mohit Ojha, Noah J. Smith, Andrew J. Devine, Rashika Joshi, Emily M. Goodman, Qiang Fan, Richard Schuman, Aleksey Porollo, J. Michael Wells, Ekta Tiwary, Matthew R. Batie, Jerilyn Gray, Hitesh Deshmukh, Michael T. Borchers, Samuel A. Ammerman, Brian M. Varisco
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Research Article Aging Pulmonology

Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling

Abstract

There are no therapies to prevent emphysema progression. Chymotrypsin-like elastase 1 (CELA1) is a serine protease that binds and cleaves lung elastin in a stretch-dependent manner and is required for emphysema in a murine antisense oligonucleotide model of α-1 antitrypsin (AAT) deficiency. This study tested whether CELA1 is important in strain-mediated lung matrix destruction in non–AAT-deficient emphysema and the efficacy of CELA1 neutralization. Airspace simplification was quantified after administration of tracheal porcine pancreatic elastase (PPE), after 8 months of cigarette smoke (CS) exposure, and in aging. In all 3 models, Cela1–/– mice had less emphysema and preserved lung elastin despite increased lung immune cells. A CELA1-neutralizing antibody was developed (KF4), and it inhibited stretch-inducible lung elastase in ex vivo mouse and human lung and immunoprecipitated CELA1 from human lung. In mice, systemically administered KF4 penetrated lung tissue in a dose-dependent manner and 5 mg/kg weekly prevented emphysema in the PPE model with both pre- and postinjury initiation and in the CS model. KF4 did not increase lung immune cells. CELA1-mediated lung matrix remodeling in response to strain is an important contributor to postnatal airspace simplification, and we believe that KF4 could be developed as a lung matrix–stabilizing therapy in emphysema.

Authors

Mohit Ojha, Noah J. Smith, Andrew J. Devine, Rashika Joshi, Emily M. Goodman, Qiang Fan, Richard Schuman, Aleksey Porollo, J. Michael Wells, Ekta Tiwary, Matthew R. Batie, Jerilyn Gray, Hitesh Deshmukh, Michael T. Borchers, Samuel A. Ammerman, Brian M. Varisco

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Figure 9

KF4 treatment in mouse models of alveolar simplification.

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KF4 treatment in mouse models of alveolar simplification. (A) Left: Conf...
(A) Left: Confocal image of a mouse that was administered fluorophore-labeled KF4 (red) at a dose of 5 mg/kg 24 hours before tissue harvest. The lung section was counterstained for tropoelastin (green). KF4 signal is present throughout the interstitium. Scale bar: 100 μm. Right: Magnified image showing a cell with increased binding of KF4, but also red signal throughout the lung matrix seemingly de-silhouetting cells suggested by central nuclei without red signal surrounding them. (B) Intraperitoneal administration of 5 mg/kg KF4 once weekly at the time of treatment with tracheal PPE resulted in a significant improvement in airspace simplification. Comparison by 2-tailed Welch’s t test. (C) Representative ×10 photomicrographs of IgG- and (D) KF4-treated mice are shown. (E) Initiating the same KF4 therapy 7 days after PPE administration still resulted in reduced airspace simplification. Comparison by 2-tailed Welch’s t test. (F) Representative ×10 photomicrographs of IgG- and (G) KF4-treated mice are shown. (H) KF4 administration to litter-matched WT mice exposed to cigarette smoke (CS) for 8 months reduced the amount of emphysema compared with IgG administration. P < 0.0001 by 1-way ANOVA and selected Tukey’s post hoc comparisons are shown. (I) Representative ×10 photomicrographs of IgG-treated and (J) KF4-treated mice are shown. (K) Quantitative image analysis of CS exposure alone, CS exposure with IgG treatment, and CS exposure with KF4 treatment showed no differences in the number of CD45-positive cells. Neg is analysis of secondary alone–treated lung section. **P < 0.01, ***P < 0.001, ****P < 0.00001.