OX40L blockade and allergen-induced airway responses in subjects with mild asthma

Abstract

Background: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells.

Objective: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma.

Methods: Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability.

Results: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups.

Conclusion and clinical relevance: Pharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.

Keywords: allergen inhalation challenge; anti-OX40L; mild atopic asthma; proof-of-activity.

© 2013 The Authors Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.

Figures

Figure 1

Study schematic.

Figure 2

Mean (SEM) allergen-induced change in FEV1 during the screening period, and 56 and 113 days post-dosing with placebo and anti-OX40L MAb.

Figure 3

Mean (bars) and individual subject (circles) total IgE (a and b) and allergen-challenge-specific IgE (c and d) measured at baseline (a and c), and post-dosing, expressed as a percentage of baseline (b and d) with placebo (open circles) and anti-OX40L MAb (closed circles). *P < 0.05

Figure 4

The mean (SEM) level of peripheral blood eosinophils measured at baseline and 113 days post-dosing.

Figure 5

Median (bars) and individual (circles) sputum eosinophils measured at baseline and 56 and 112 days post-dosing with placebo (open circles) and anti-OX40L MAb (closed circles) treatment. *P < 0.05.