Inhalation of IL-1 Receptor Antagonist (ALTA-2530) Achieves Stable and Prolonged Pulmonary Exposure in Nonclinical Studies Supportive of Development for Bronchiolitis Obliterans Syndrome
| Autor: | M. Palacios, J. Hastedt, S. Wring, C. McKernan, P. Kuehl, K. Crizer, M. Reed |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Pulmonary and Respiratory Medicine
Transplantation Lung Inhalation business.industry medicine.drug_class medicine.medical_treatment Bronchiolitis obliterans respiratory system Pharmacology medicine.disease Receptor antagonist Cytokine medicine.anatomical_structure In vivo medicine Potency Surgery Cardiology and Cardiovascular Medicine business Aerosolization |
| Zdroj: | The Journal of Heart and Lung Transplantation. 40:S373 |
| ISSN: | 1053-2498 |
| DOI: | 10.1016/j.healun.2021.01.1052 |
| Popis: | Purpose ALTA-2530 is a novel inhaled formulation of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in development for bronchiolitis obliterans syndrome (BOS). IL-1 overexpression in BOS drives chronic inflammation and fibroblast activation leading to airway remodeling and impaired oxygen transfer. Endogenous IL-1Ra is upregulated in response to IL-1 to limit cytokine signaling, but expression is inadequate to prevent BOS. Pharmacological IL-1 blockade is considered akin to restoration of physiologic immune regulation. Herein we determine if ALTA-2530 is stable during nebulization, achieves aerosol particle diameters consistent with distribution to distal airways, and pulmonary exposure commensurate with treatment of BOS. Methods Aerosolization and in vivo studies were performed with Aerogen Solo or Phillips InnospireGo vibrating mesh nebulizers. Rats (n=4/grp/timepoint) received ALTA-2530 by nose-only inhalation (0.63, 1.3, and 2.1mg/g lung). Serum and bronchioalveolar lavage (BAL) samples were collected for analysis by LC-MSMS. ALTA-2530 in lung epithelial lining fluid (ELF) was calculated using a BALF dilution factor. Results Nebulized ALTA-2530 delivered rhIL-1Ra particles with mass median aerodynamic diameters of ∼2.5-4 µm, consistent with delivery to small bronchioles. Impurity profiling by HPLC-UV and HPLC-SEC methods and an in vitro potency assay demonstrated rhIL-1Ra protein was stable during nebulization and retained full potency. ALTA-2530 achieved extensive and sustained exposure in lung ELF. The ratio of ELF to serum rhIL-1Ra was >2500X across all doses compared to 0.44X reported for lung tissue to plasma following a 5 hr IV infusion. Duration of lung exposure from a single inhaled dose exceeded 24 hr, in contrast to 1000X. Conclusion Nebulized ALTA-2530 delivers stable and active rhIL-1Ra protein, in a particle size for delivery to small airways of the lung and exposure duration predictive for once daily therapeutic dosing in BOS. |
| Databáze: | OpenAIRE |
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