Summary

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and debilitating interstitial lung disease characterized by excessive extracellular matrix deposition within the pulmonary interstitium. The current understanding of IPF pathogenesis highlights the involvement of chemokine receptors, notably CXCR7. However, the anti-fibrotic effects of CXCR7 modulators in IPF have yet to be fully explored. In this study, we hypothesize that a novel compound with CXCR7 modulating properties may effectively impede the profibrotic processes in lung diseases.

Method: In the mouse IPF model, C57BL/6 mice were subjected to a single intra-tracheal (IT) dose of bleomycin (BLM, 1.5 U/kg) or control saline on day 0. IL1512 was administered orally at a dose of 30 mg/kg once daily (QD), while pirfenidone was administered orally at 100 mg/kg twice daily (BID) for 21 days in a prophylactic mode. After the termination of dosing, lung injury was evaluated through bronchoalveolar lavage (BAL) fluid analysis, differential cell counting, hydroxyproline level, and histological analysis. Pharmacokinetics (PK) for IL1512 was evaluated in mice.

Results: Mice treated with BLM exhibited a considerable increase in the total and differential cell counts in BALF compared to the normal control. The lung hydroxyproline level, Ashcroft score, and the expression of TGF-β and Col1a1 were significantly elevated in the BLM+vehicle group comparing with the normal control. However, IL1512 demonstrated a significant restoration of alveolar macrophage and lymphocyte counts, along with a substantial reduction in hydroxyproline level, when compared to the BLM+vehicle. Histological examination of lung sections stained with H&E revealed a significant decrease in the fibrosis score for the IL1512 group as compared to the disease group. In alignment with the Ashcroft score results, IL1512 exhibited a significant reduction in the expression of TGF-β and Col1A1 compared to the disease group. Pirfenidone showed an anti-fibrotic activity. The mouse PK revealed that the Cmax and the AUC for IL1512 were 5,347 ng/ml and 82,538 hr*ng/ml, respectively at a dose of 30 mg/kg orally.

Conclusion: IL1512 has been identified as a novel selective CXCR7 modulator. Prophylactic treatment with IL1512 in a BLM-induced IPF model exhibited robust efficacy superior to pirfenidone. Moreover, IL1512 demonstrated a good PK profile, delivering anti-fibrotic efficacy at a lower dose than pirfenidone, even with once-daily dosing. This study marks IL1512 as the first CXCR7 modulator to demonstrate significant efficacy in an animal model of pulmonary fibrosis.