Effect of benralizumab and mepolizumab on the AHR to histamine
Both benralizumab and mepolizumab inhibited the AHR mediated by the histaminergic tone in passively sensitized bronchi.
The Emax elicited by the CRC to histamine was significantly reduced when passively sensitized airways were incubated with benralizumab at concentrations ≥1 μg/ml (-1348.33±126.51 mg/100mg bronchial tissue, P<0.001 vs. C+; Figure 2A), whereas at least 3 μg/ml of mepolizumab were necessary to significantly inhibit the histamine mediated AHR (-954.59±333.13 mg/100mg bronchial tissue, P<0.001 vs. C+; Figure 2B). When either benralizumab or mepolizumab were administered at concentrations ≥10 μg/ml, the AHR induced by CRC to histamine in passively sensitized bronchi was completely prevented, with the contractile response of hyperresponsive ASM reduced at the same level of that detectable in C- airways (P>0.05 vs. C-), or even significantly lower for benralizumab administered at 100 μg/ml (P<0.05 vs. C-) (Figure 2A and B). Benralizumab administered at concentrations ≥10 μg/ml significantly (delta pEC50 0.65±0.20, P<0.05 vs. C+) reduced the potency of histamine in passively sensitized airways, whereas 100 μg/ml of mepolizumab were necessary to elicit the same significant impact (delta pEC50 0.65±0.22, P<0.05 vs. C+) on the pEC50 of histamine. Details on the effect of different concentrations of benralizumab and mepolizumab on the pharmacological characteristics of CRC to histamine (Emax and pEC50) in passively sensitized bronchi are reported in Table 1.
The CRCs to either benralizumab or mepolizumab modulated the contractile plateau to specific concentrations of histamine in hyperresponsive airways (Figure 3A-F). Specifically, both benralizumab and mepolizumab prevented the AHR in passively sensitized airways contracted by histamine administered at EC50 (Figure 3A,D), EC70 (Figure 3B,E), and EC90 (Figure 3C,F) in a potent concentration-dependent manner. Benralizumab resulted 0.73±0.10 logarithm significantly (P<0.05) more potent than mepolizumab (Table 2).