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 5

CELA1 in human lung and stretch-dependent binding and elastase activity.

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CELA1 in human lung and stretch-dependent binding and elastase activity....
(A) Immunofluorescence imaging for human tropoelastin (green) and CELA1 (red) demonstrated CELA1 protein found near elastin fibers in the airspace walls. Scale bar: 100 μm. (B) Proximity ligation assay (PLA) was performed in human lung using anti-tropoelastin and anti-CELA1 antibodies. Red signal is obtained when antibodies are located within 40 nm of each other. This red signal was observed in the alveolar interstitium. (C) Using fluorophore-conjugated CELA1, human lung tissue sections demonstrated little binding of CELA1 (red) to lung tissue (blue) in the absence of strain. Tissue section is 100 μm thick and each tick mark represents 200 μm. Dashed line highlights a comparison region. (D) When subjected to biaxial strain, CELA1 binding to lung tissue increased. The dashed line highlights the same region as the prior panel. (E) Fluorophore-conjugated albumin binding to lung tissue did not increase with strain. This channel was omitted from images for clarity. (F) Quantification of CELA1 binding in 4 independent lung specimens shows that binding increases with increasing levels of strain to approximately 5-fold. *P < 0.05, **P < 0.01 by 2-tailed Welch’s t test. (G) Using a fluorophore-conjugated and quenched soluble elastin substrate for in situ zymography, human lung tissue (white) does not have appreciable elastase activity (green) at baseline. Scale bars: 250 μm. (H) When subjected to biaxial strain, there is an increase in lung elastase activity. (I) Lung elastase activity increases with strain by approximately 8-fold. *P < 0.05, **P < 0.01 by 2-tailed Welch’s t test.