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


CONCLUSIONS
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.
Department of Medicine, McMaster University, Hamilton, ON, Canada.
G M
GM
Gauvreau
L-P
LP
Boulet
D W
DW
Cockcroft
J M
JM
FitzGerald
I
I
Mayers
C
C
Carlsten
M
M
Laviolette
K J
KJ
Killian
B E
BE
Davis
M
M
Larché
C
C
Kipling
B
B
Dua
S
S
Mosesova
W
W
Putnam
Y
Y
Zheng
H
H
Scheerens
D
D
McClintock
J G
JG
Matthews
P M
PM
O'Byrne
D000328:Adult; D000485:Allergens / Q000276:immunology*; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004804:Eosinophils; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D000485:Allergens; D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D023201:CD40 Ligand; D007073:Immunoglobulin E
allergen inhalation challenge; anti-OX40L; mild atopic asthma; proof-of-activity