Effect of Aerosolized Anti-IgE (E25) on Airway Responses to Inhaled Allergen in Asthmatic Subjects

Abstract

Intravenous administration of a humanized monoclonal antibody of IgE (E25) attenuates the early and late phase response to inhaled allergen in allergic asthmatic subjects. To test whether direct delivery of E25 to the airway might have the same effect, we conducted a randomized, double-blind, three group study in 33 subjects with mild allergic asthma (20 to 46 yr of age, 21 men, FEV(1) > 70% predicted). The airway responses to aerosolized allergen were determined at baseline, after 2 and 8 wk of once daily treatment with aerosolized placebo (n = 11), aerosolized E25 1 mg (n = 12), or aerosolized E25 10 mg (n = 10), and after 4 wk of treatment withdrawal. We found that E25 was detectable in the serum during aerosol treatment, although serum IgE did not change significantly in any of the three groups during treatment. In addition, both doses of E25 were no more effective than placebo in attenuating the early phase responses to allergen at both times during treatment. Although aerosolized E25 was generally well tolerated, one subject receiving aerosolized E25 10 mg daily was found to have serum IgG and IgA antibodies to E25. We conclude that aerosol administration of an anti-IgE monoclonal antibody does not inhibit the airway responses to inhaled allergen in allergic asthmatic subjects. We speculate that the observed lack of efficacy may be due to the inability of aerosol route of delivery to result in high enough concentrations of E25 in the tissue compartments surrounding IgE effector cells to neutralize IgE arising from local airway and pulmonary sources and IgE arising from the vascular space. Additionally, the aerosol route of delivery of monoclonal antibodies may be more immunogenic than the parenteral route.

Elicitation of allergic asthma by immunoglobulin free light chains

“…Indeed, mast cell numbers are increased in the lungs of individuals with atopic as well as nonatopic variants of adult asthma, and the extent of degranulation of these cells is directly related to disease severity (6,7). Although antigen-specific mast cell activation results from crosslinking of the high-affinity IgE receptor, FcRI, this effect can also occur in the absence of IgE antibodies (8)(9)(10)(11)(12); furthermore, anti-IgE antibody therapy has been of limited benefit in asthma (13)(14)(15)(16)(17)(18).…”

Anti‐IgE treatment: an update

“…In the entire clinical programme, encompassing earlierphase studies, there were no positive antio-malizumab titres in patients receiving omalizumab administered intravenously or subcutaneously, including an extension of the US study in ragweed-sensitive SAR in which 287 patients were readministered omalizumab during the following pollen season (52). In a pilot study of aerosolized administration to the lungs mentioned previously (43), one patient developed serum IgG and IgA antibodies to omalizumab. The clinical safety database shows that omalizumab has an excellent safety profile and was well tolerated in the asthma and SAR patients studied.…”

“…Part of the early clinical research involved a pilot study of aerosol administration topically to the lungs. The results from this study showed instances of anti-omalizumab antibody formation, and the topical route of administration would thus probably not be clinically practicable (43). In the phase III work, patients were assigned to one of the dosing strata according to body weight and baseline free IgE.…”

Pharmacocinétique des anticorps monoclonaux

“…La voie inhalée a également été testée car le FcRn est exprimé dans les poumons [2,12]. Après administration d'omalizumab par aérosol chez des patients asthmatiques, des concentrations sériques ont pu être mesurées mais l'effet thérapeutique était insuffisant [13]. La voie pulmonaire a également été testée pour l'administration de protéines de fusion comportant une portion Fc, telles que l'érythropoïétine-Fc [14].…”