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CHIT1 is a novel therapeutic target in idiopathic pulmonary fibrosis (IPF): anti-fibrotic efficacy of OATD-01, a potent and selective chitinase inhibitor in the mouse model of pulmonary fibrosis

Barbara Dymek, Piotr Sklepkiewicz, Michal Mlacki, Agnieszka Zagozdzon, Robert Koralewski, Marzena Mazur, Magdalena Paplinska-Goryca, Patrycja Nejman-Gryz, Malgorzata Proboszcz, Katarzyna Gorska, Marta Maskey-Warzechowska, Natalia Przysucha, Rafal Krenke, Adam Golebiowski, Pawel Dobrzanski, Karolina Dzwonek
European Respiratory Journal 2018 52: OA5361; DOI: 10.1183/13993003.congress-2018.OA5361
Barbara Dymek
1OncoArendi Therapeutics SA, Warsaw, Poland
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Piotr Sklepkiewicz
1OncoArendi Therapeutics SA, Warsaw, Poland
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Michal Mlacki
1OncoArendi Therapeutics SA, Warsaw, Poland
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Agnieszka Zagozdzon
1OncoArendi Therapeutics SA, Warsaw, Poland
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Robert Koralewski
1OncoArendi Therapeutics SA, Warsaw, Poland
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Marzena Mazur
1OncoArendi Therapeutics SA, Warsaw, Poland
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Magdalena Paplinska-Goryca
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Patrycja Nejman-Gryz
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Malgorzata Proboszcz
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Katarzyna Gorska
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Marta Maskey-Warzechowska
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Natalia Przysucha
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Rafal Krenke
2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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Adam Golebiowski
1OncoArendi Therapeutics SA, Warsaw, Poland
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Pawel Dobrzanski
1OncoArendi Therapeutics SA, Warsaw, Poland
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Karolina Dzwonek
1OncoArendi Therapeutics SA, Warsaw, Poland
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Abstract

Rationale: Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases in humans. CHIT1 has been implicated in the pathogenesis of interstitial lung diseases (ILDs) including IPF.

Methods: Chitinolytic activity was assessed in induced sputum (IS) and serum from IPF patients and controls (n=20-28) and CHIT1 expression was evaluated in bronchoalveolar lavage (BAL) cells from IPF patients. The therapeutic efficacy of OATD-01 – a selective chitinase inhibitor was evaluated in the mouse model of bleomycin-induced pulmonary fibrosis. Mice were dosed with OATD-01 or nintedanib (100 mg/kg, po, qd) in a therapeutic scheme.

Results: The chitinolytic activity in serum and IS from IPF patients was significantly elevated when compared to controls. Additionally, CHIT1 was shown to be highly expressed in BAL macrophages from IPF patients. OATD-01 - a potent chitinase inhibitor (hAMCase IC50=9nM, hCHIT1 IC50=26nM) significantly reduced lung fibrosis in the bleomycin-induced fibrosis model, comparably to nintedanib, as assessed by modified Ashcroft scoring. The anti-fibrotic activity of OATD-01 was associated with pharmacodynamic effect: plasma chitinolytic activity was significantly reduced in mice dosed with OATD-01 as compared to control group.

Conclusion: We have demonstrated that expression of CHIT1 is increased in IPF and that inhibition of chitinases with OATD-01 provided significant therapeutic efficacy, comparable to nintedanib, in the bleomycin-induced pulmonary fibrosis model. These data support further development of OATD-01 as a first-in-class therapy for IPF.

Footnotes

Cite this article as: European Respiratory Journal 2018 52: Suppl. 62, OA5361.

This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).

  • Copyright ©the authors 2018
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CHIT1 is a novel therapeutic target in idiopathic pulmonary fibrosis (IPF): anti-fibrotic efficacy of OATD-01, a potent and selective chitinase inhibitor in the mouse model of pulmonary fibrosis
Barbara Dymek, Piotr Sklepkiewicz, Michal Mlacki, Agnieszka Zagozdzon, Robert Koralewski, Marzena Mazur, Magdalena Paplinska-Goryca, Patrycja Nejman-Gryz, Malgorzata Proboszcz, Katarzyna Gorska, Marta Maskey-Warzechowska, Natalia Przysucha, Rafal Krenke, Adam Golebiowski, Pawel Dobrzanski, Karolina Dzwonek
European Respiratory Journal Sep 2018, 52 (suppl 62) OA5361; DOI: 10.1183/13993003.congress-2018.OA5361

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CHIT1 is a novel therapeutic target in idiopathic pulmonary fibrosis (IPF): anti-fibrotic efficacy of OATD-01, a potent and selective chitinase inhibitor in the mouse model of pulmonary fibrosis
Barbara Dymek, Piotr Sklepkiewicz, Michal Mlacki, Agnieszka Zagozdzon, Robert Koralewski, Marzena Mazur, Magdalena Paplinska-Goryca, Patrycja Nejman-Gryz, Malgorzata Proboszcz, Katarzyna Gorska, Marta Maskey-Warzechowska, Natalia Przysucha, Rafal Krenke, Adam Golebiowski, Pawel Dobrzanski, Karolina Dzwonek
European Respiratory Journal Sep 2018, 52 (suppl 62) OA5361; DOI: 10.1183/13993003.congress-2018.OA5361
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