A monoclonal antibody to alpha1beta1 blocks antigen-induced airway responses in sheep.
The integrin alpha1beta1 (very late antigen-1; CD49a/CD29) is a major adhesion receptor for collagen I, IV, and VI, and its induced expression on activated monocytes and lymphocytes plays a central role in their retention and activation at inflammatory sites in autoimmune pathologies. However, the role of alpha1beta1 in allergic settings has not been explored. In this study, we show that a single 45-mg dose of aerosolized monoclonal antibody AQC2 to the alpha1 chain of human and sheep very late antigen-1, given 30 minutes before challenge, blocks both the allergen-induced late response and the associated airway hyperresponsiveness, functional indicators of allergen-induced inflammation, in sheep. AQC2 does not affect the early response. Consistent with these effects, AQC2 tended to reduce the cell response associated with local antigen instillation. An isotype-matched control antibody had no protective effects. Two humanized versions of AQC2, a wild-type IgG1 and an aglycosyl form of the same monoclonal antibody, which has reduced Fc receptor-mediated effector functions, are equally effective in blocking the antigen-induced late response and airway hyperresponsiveness in the sheep model. These data suggest that mononuclear leukocyte adhesion-dependent pathologies contribute to allergic lung disease and provide proof-of-concept that antagonists of alpha1 integrins may be useful in preventing these events.
Division of Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA. abraham@msmc.com
William M
WM
Abraham
Ashfaq
A
Ahmed
Irakli
I
Serebriakov
Amie N
AN
Carmillo
Janine
J
Ferrant
Antonin R
AR
de Fougerolles
Ellen A
EA
Garber
Philip J
PJ
Gotwals
Victor E
VE
Koteliansky
Fred
F
Taylor
Roy R
RR
Lobb
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D004195:Disease Models, Animal; D005260:Female; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D011336:Probability; D016029:Receptors, Very Late Antigen / Q000276:immunology*; D012016:Reference Values; D012680:Sensitivity and Specificity; D034561:Sheep, Domestic
D000911:Antibodies, Monoclonal; D016023:Integrins; D016029:Receptors, Very Late Antigen