Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling
Mohit Ojha, … , Samuel A. Ammerman, Brian M. Varisco
Mohit Ojha, … , Samuel A. Ammerman, Brian M. Varisco
Published January 9, 2024
Citation Information: JCI Insight. 2024;9(1):e169189. https://doi.org/10.1172/jci.insight.169189.
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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 2

Protection of Cela1–/– mice in 3 emphysema models.

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Protection of Cela1–/– mice in 3 emphysema models. (A) At 21 days after ...
(A) At 21 days after airway administration of porcine pancreatic elastase (PPE), Cela1–/– and WT mice had a similar level of emphysema. However, at 42 and 84 days, WT mice experienced progression of emphysema as evidenced by greater mean linear intercept (MLI) values, while Cela1–/– mice did not. P < 0.001 by 1-way ANOVA and Holm-Šidák post hoc comparisons are shown by **P < 0.01. Dashed line represents average MLI of WT PBS-treated mice. n is the number of mice per group. (B) Representative 42-day photomicrographs of WT and (C) Cela1–/– lungs are shown. Scale bars: 100 μm. (D) Cela1–/– mice exposed to 4 hours of cigarette smoke 5 days per week for 8 months had almost no detectable airspace simplification, while such emphysema was detected in WT mice. FA, filtered air. P < 0.0001 by 1-way ANOVA and Holm-Šidák post hoc comparisons are shown by ****P < 0.0001. (E) Representative tile-scanned images of middle lobes of WT and (F) Cela1–/– mice are shown. Scale bars: 2,500 μm. (G) In comparing lung images of untreated mice aged 72 to 75 weeks, the MLI of WT mice was significantly increased, while that of Cela1–/– mice was not significantly larger (NS = not significant) and aged Cela1–/– mice had less age-related alveolar simplification than WT. P < 0.001 by 1-way ANOVA and Holm-Šidák post hoc comparisons are shown by ***P < 0.001.