Reductions in eosinophil biomarkers by benralizumab in patients with asthma. (February 2016) - Pham, Tuyet-Hang
Abstract: Background: Eosinophilic inflammation is frequently associated with increased asthma severity. Benralizumab is a humanized, afucosylated, anti–interleukin-5Rα monoclonal antibody that selectively depletes eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity. Objective: To study effects of benralizumab on eosinophil counts and activity following administration to asthma patients. Methods: Sera were collected from asthma patients enrolled in two clinical studies. Placebo or benralizumab was subcutaneously administered to patients in Phase I (100 or 200 mg, multiple doses; N = 14; NCT00659659) and Phase IIa (25, 100, or 200 mg every 4 weeks; N = 24; NCT00783289) studies. Sera were also collected from healthy volunteers ( N = 20) for comparison. Blood eosinophils, IL-5, eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), eotaxin/chemokine (C–C motif) 11 (CCL11), eotaxin-2/CCL24, tumor necrosis factor (TNF), and interferon-γ (IFN-γ) were measured at baseline and post-treatment. Results: Increased EDN concentrations were observed in sera of patients from both studies relative to healthy volunteers ( p < 0.05). At baseline, sera EDN concentrations correlated with blood eosinophil counts (rs = 0.5; p < 0.05). Benralizumab reduced blood eosinophil numbers and sera EDN and ECP relative to baseline ( p < 0.05). No changes in TNF or IFN-γ were observed, while serum IL-5, eotaxin/CCL11, and eotaxin-2/CCL24 increased after benralizumab administration vs. placebo ( p < 0.05). Conclusions: In two independent studies, serum IL-5, EDN, and ECP were modulated following benralizumab. Eosinophil depletion after benralizumab also resulted in significant reductions in EDN and ECP concentrations, suggesting that cytotoxic granule proteins were not released after eosinophil reduction. Highlights: Upon activation, eosinophils may release the cytotoxic proteins EDN and ECP. Benralizumab, a humanized anti–IL-5Rα mAb, depletes eosinophils by enhanced ADCC. EDN and ECP concentrations were measured after benralizumab or placebo treatment. Eosinophil depletion by ADCC reduced serum EDN and ECP concentrations from baseline. This suggests that cytotoxic proteins were not released after eosinophil depletion.