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
View: Text | PDF
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

×

Figure 4

Immune cells in Cela1-deficient mice.

Options: View larger image (or click on image) Download as PowerPoint
Immune cells in Cela1-deficient mice. (A) In lung sections from WT and C...
(A) In lung sections from WT and Cela1–/– (KO) mice treated with tracheal PBS or porcine pancreatic elastase (PPE, n = 8 for all groups) immunostained for the leukocyte marker CD45, the only notable difference was fewer immune cells in KO-PBS mice compared with WT-PPE. Neg is the number of cells identified with secondary antibody staining alone. (B) After 8 months of cigarette smoke exposure, the number of leukocytes was increased in KO mice (n = 19) compared with WT (n = 20). (C) Similarly, in 72- to 75-week-old mouse lungs, more immune cells were present in KO (n = 9) compared with WT (n = 7). (D) In a different experiment, we used flow cytometry to quantify immune cell populations. Two hundred and fifty thousand cells were analyzed for each mouse. n = 7, 8, 8, and 9 for WT-PBS, WT-PPE, KO-PBS, and KO-PPE, respectively. More CD45-positive cells were present in KO lungs. (E and F) In analysis of immune cell populations, only the fractional increases in neutrophils and eosinophils were notable. For all analyses, P < 0.05 by Kruskal-Wallis test and *P < 0.05, **P < 0.01, ***P < 0.001 by Dunn’s post hoc test.