Tozorakimab exerts distinct dual pharmacology to reduce COPD epithelial remodelling

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Background: COPD patients exhibit epithelial remodelling characterized by goblet cell hyperplasia and excessive mucus accumulation. Tozorakimab, an anti-IL-33 mAb which has shown efficacy in COPD, inhibits both IL-33red and IL-33ox activity through ST2 and RAGE/EGFR signalling pathways, respectively. Objective: To understand the extent to which signalling pathways with suggested clinical benefit in COPD have an impact on epithelial remodelling and wound healing. Methods: Anti-IL-33/ST2 mAbs were evaluated for their ability to reduce COPD epithelial remodelling in vitro. In addition, effects of anti-IL-4R and anti-TSLP on MUC5AC expression were determined. Results: Tozorakimab was the only anti-IL-33/ST2 mAb, including itepekimab and astegolimab, that reduced mucus secretion in differentiated, bronchial COPD ALI cultures (Table). mAbs targeting IL-4R and TSLP signalling did not alter MUC5AC expression. An IL-33ox/RAGE/EGFR-dependent epithelial scratch wound assay was used to compare pharmacology between mAbs, with only tozorakimab showing the ability to promote repair (Table). Epitope competition assays revealed a distinct binding epitope for tozorakimab binding to IL-33red versus other anti-IL-33 mAbs. Conclusion: Of the anti-IL-33/ST2 mAbs tested, only tozorakimab demonstrated the ability to reduce epithelial remodelling and promote repair. Tozorakimab is under clinical investigation in COPD and other respiratory diseases. erj;66/suppl_69/OA6527/F1 F1 F1

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