Background:Astegolimab (anti-ST2/IL-33R) shows promise in reducing exacerbations & improving quality of life for a subset of moderate-severe COPD patients (n=81, NCT03615040). Our objective was to determine, concomitantly, the effect of astegolimab on blood leucocytes & proteins to identify IL-33-dependent pathways.

Method:Blood was collected at 0 (randomisation), 4 & 12 weeks from a subset of patients (n=30 placebo/n=29 astegolimab) during clinical stability. Non-/T2 cells were measured by cytometry (cells/100?l) & raw data analysed longitudinally by mixed effects model (?, [95%CI], FDR adj. p) & by Kruskal-Wallis for cross-sectional comparisons. Serum proteins (n=1463) were measured by Olink in 79 patients at week -2 (screening), week 4 (n=37/n=42, respectively) and week 24 (n=35/n=40, respectively) & those that passed QC (n=639) were analysed using a linear mixed model (FDR adj. p).

Results:Astegolimab, but not placebo, decreased eosinophils at week 4 (?=-0.58, [-0.86 to -0.31], p=0.0001) & week 12 (?=-0.83, [-1.13 to -0.53], p=2.0-7) vs week 0. Eosinophil levels in the astegolimab group were different from placebo at week 4 (p=0.04) & week 12 (p=0.002). Other leucocyte levels were not significantly altered by astegolimab compared to week 0. Of 639 serum proteins, only two were altered by astegolimab at week 4 & 24 vs week -2; soluble (s)ST2 (?=2.24, p=1.8x10-46 & ?=2.27, p=2x10-46, respectively) & Charcot-Leiden Crystal (?=-0.49, p=0.01 & ?=-0.47, p=0.016).

Conclusion:Astegolimab strongly decreased blood eosinophils & an eosinophil-associated protein (CLC) but had negligible effect on other cells or proteins beyond its target, sST2.