ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.
Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.
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Synergistic Anti-Fibrotic Effect of a First-in-Class PRS Inhibitor, DWN12088, and Standard-of-Care Therapeutic Agents for IPF
Session Title
TP126 - TP126 STRUCTURE AND FUNCTION IN PARENCHYMAL LUNG DISEASES
Abstract
A4645 - Synergistic Anti-Fibrotic Effect of a First-in-Class PRS Inhibitor, DWN12088, and Standard-of-Care Therapeutic Agents for IPF
Author Block: C. H. Lee, D. Bae, D. Kim, M. Cho, J. Kim, S. Shin, J. Lee, S. Kang, J. Jung, H. Koo, J. Park; Drug Discovery Center, Daewoong Pharmaceutical Co. Ltd., Yongin, Korea, Republic of.
Introduction: Glutamyl-Prolyl-tRNA synthetase (EPRS) is an enzyme that conjugates proline to its tRNA. Excessive deposition of collagen is the pathological hallmark of fibrosis, and proline is one of the major constituents of collagen. Hence, dysregulation of EPRS could drive excessive collagen formation. Daewoong is developing a novel, proprietary first-in-class prolyl-tRNA synthetase (PRS) inhibitor, DWN12088, and previous studies have shown anti-fibrotic effects by down-regulating collagen synthesis in various cellular and mouse pulmonary fibrosis models. Currently, Pirfenidone and Nintedanib serve as standard-of-care (SoC) therapies for Idiopathic Pulmonary Fibrosis (IPF), yet the treatment effects are limited. Thus, we investigated potential synergistic anti-fibrotic effects of DWN12088 in addition to SoC.
Method: Diseased human lung fibroblasts (DHLF) were co-treated with TGF-β1, DWN12088 and Nintedanib for 48 hours, then α-smooth muscle actin (α-SMA) and Collagen 1A1 (COL1A1) protein levels were assessed by western blot. The anti-fibrotic effect of DWN12088 and Pirfenidone co-treatment were investigated using Bleomycin (BLM)-induced mouse pulmonary fibrosis model. Mouse lung function was measured using pulse oximetry.
Results: Using dose-range finding study, the effective target concentration that can down-regulate approximately 50% of the α-SMA and COL1A1 were identified as 5 μM DWN12088 and 50 nM Nintedanib. Cells were co-treated with 50nM Nintedanib and titration of DWN12088, dose-dependent reduction of α-SMA and COL1A1 were observed. Cells were co-treated with 5 μM DWN12088 and titration of Nintedanib, dose-dependent reduction of α-SMA and COL1A1 were observed as well. Finally, co-treatment of 50 nM Nintedanib and 5 μM DWN12088 inhibited α-SMA and COL1A1better than 100 nM Nintedanib or 10 μM DWN12088 alone. In BLM-induced mouse pulmonary fibrosis model, co-treatment of DWN12088 and Pirfenidone significantly reduced total collagen amount and fibrotic index in the mouse lung tissues compared to treatment of each compound alone. Moreover, co-treatment of DWN12088 and Pirfenidone significantly improved lung function, as shown by pulse oximetry, compared to treatment of each compound alone.
Conclusion: Current standard of care for IPF, Pirfenidone and Nintedanib, show limited therapeutic effects in patients. Daewoong’s proprietary PRS inhibitor, DWN12088, has anti-fibrotic effects by inhibiting collagen synthesis and down-regulating pro-fibrotic markers. When combined with either Pirfenidone or Nintedanib, DWN12088 exhibits synergistic anti-fibrotic effect in both in vitro and in vivo IPF models. This suggests that DWN12088 has potential to become a novel therapeutic agent for IPF, either as monotherapy or combination therapy. DWN12088 has completed Phase I study in healthy volunteers, and is expected to enter Phase II clinical trial in 2021.
Author Block: C. H. Lee, D. Bae, D. Kim, M. Cho, J. Kim, S. Shin, J. Lee, S. Kang, J. Jung, H. Koo, J. Park; Drug Discovery Center, Daewoong Pharmaceutical Co. Ltd., Yongin, Korea, Republic of.
Introduction: Glutamyl-Prolyl-tRNA synthetase (EPRS) is an enzyme that conjugates proline to its tRNA. Excessive deposition of collagen is the pathological hallmark of fibrosis, and proline is one of the major constituents of collagen. Hence, dysregulation of EPRS could drive excessive collagen formation. Daewoong is developing a novel, proprietary first-in-class prolyl-tRNA synthetase (PRS) inhibitor, DWN12088, and previous studies have shown anti-fibrotic effects by down-regulating collagen synthesis in various cellular and mouse pulmonary fibrosis models. Currently, Pirfenidone and Nintedanib serve as standard-of-care (SoC) therapies for Idiopathic Pulmonary Fibrosis (IPF), yet the treatment effects are limited. Thus, we investigated potential synergistic anti-fibrotic effects of DWN12088 in addition to SoC.
Method: Diseased human lung fibroblasts (DHLF) were co-treated with TGF-β1, DWN12088 and Nintedanib for 48 hours, then α-smooth muscle actin (α-SMA) and Collagen 1A1 (COL1A1) protein levels were assessed by western blot. The anti-fibrotic effect of DWN12088 and Pirfenidone co-treatment were investigated using Bleomycin (BLM)-induced mouse pulmonary fibrosis model. Mouse lung function was measured using pulse oximetry.
Results: Using dose-range finding study, the effective target concentration that can down-regulate approximately 50% of the α-SMA and COL1A1 were identified as 5 μM DWN12088 and 50 nM Nintedanib. Cells were co-treated with 50nM Nintedanib and titration of DWN12088, dose-dependent reduction of α-SMA and COL1A1 were observed. Cells were co-treated with 5 μM DWN12088 and titration of Nintedanib, dose-dependent reduction of α-SMA and COL1A1 were observed as well. Finally, co-treatment of 50 nM Nintedanib and 5 μM DWN12088 inhibited α-SMA and COL1A1better than 100 nM Nintedanib or 10 μM DWN12088 alone. In BLM-induced mouse pulmonary fibrosis model, co-treatment of DWN12088 and Pirfenidone significantly reduced total collagen amount and fibrotic index in the mouse lung tissues compared to treatment of each compound alone. Moreover, co-treatment of DWN12088 and Pirfenidone significantly improved lung function, as shown by pulse oximetry, compared to treatment of each compound alone.
Conclusion: Current standard of care for IPF, Pirfenidone and Nintedanib, show limited therapeutic effects in patients. Daewoong’s proprietary PRS inhibitor, DWN12088, has anti-fibrotic effects by inhibiting collagen synthesis and down-regulating pro-fibrotic markers. When combined with either Pirfenidone or Nintedanib, DWN12088 exhibits synergistic anti-fibrotic effect in both in vitro and in vivo IPF models. This suggests that DWN12088 has potential to become a novel therapeutic agent for IPF, either as monotherapy or combination therapy. DWN12088 has completed Phase I study in healthy volunteers, and is expected to enter Phase II clinical trial in 2021.
