Omalizumab increases the intrinsic sensitivity of human basophils to IgE-mediated stimulation

Abstract

Background: Treatment of allergic patients with omalizumab results in a paradoxical increase in their basophil histamine release (HR) response ex vivo to cross-linking anti-IgE antibody. It is not known whether this change in response is associated with an increase in intrinsic cellular sensitivity, which would be a paradoxical response.

Objective: We sought to determine whether the increase in response to anti-IgE antibody is a reflection of an increased cellular sensitivity expressed as molecules of antigen-specific IgE per basophil required to produce 50% of the maximal response.

Methods: Patients were treated with omalizumab or placebo for 12 weeks (NCT01003301 at ClinicalTrials.gov), and the metric of basophil sensitivity was assessed at 4 time points: baseline, 6 to 8 weeks, 12 weeks (after which treatment stopped), and 24 weeks (12 weeks after the end of treatment).

Results: As observed previously, treatment with omalizumab resulted in a marked increase in the maximal HR induced by cross-linking anti-IgE antibody. This change was accompanied by a marked shift in intrinsic basophil sensitivity, ranging from 2.5- to 125-fold, with an average of 6-fold at the midpoint of the treatment to 12-fold after 12 weeks. The magnitude of the increase in cellular sensitivity was inversely related to the starting sensitivity or the starting maximum HR. The increased cellular sensitivity also occurred when using leukotriene C4 secretion as a metric of the basophil response. Twelve weeks after the end of treatment, cellular sensitivity was found to shift toward the baseline value, although the return to baseline was not yet complete at this time point.

Conclusions: Treatment with omalizumab results in a markedly increased sensitivity of basophils to IgE-mediated stimulation in terms of the number of IgE molecules required to produce a given response. These results provide a better quantitative sense of the phenotypic change that occurs in basophils during omalizumab treatment, which has both mechanistic and clinical implications.

Keywords: ED(50); Effective density for 50% maximum response; Fc receptors; HR; HSA; Histamine release; Human; Human serum albumin; IL-3 receptor; IL-3R; LTC(4); Leukotriene C(4); PAG; PIPES; PIPES-albumin-glucose; Piperazine-N,N′-bis(2-ethanesulfonic acid); Spleen tyrosine kinase; Syk; allergy; basophil.