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Published ahead of print on October 24, 2003, doi:10.1164/rccm.200304-543OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 1, January 2004, 97-104

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Submitted on May 13, 2003
Accepted on October 16, 2003

A Monoclonal Antibody to {alpha}1{beta}1 Blocks Antigen-Induced Airway Responses in Sheep

William M Abraham1*, Ashfaq Ahmed1, Irakli Serebriakov1, Amie N Carmillo2, Janine Ferrant2, Antonin R de Fougerolles2, Ellen A Garber2, Philip J Gotwals2, Victor E Koteliansky2, Fred Taylor2, and Roy R Lobb2

1 Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, FL, USA, 2 Biogen, Inc., Cambridge, MA, USA

* To whom correspondence should be addressed. E-mail: abraham{at}msmc.com.

The integrin {alpha}1{beta}1 (very late antigen-1; VLA-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 auto-immune pathologies. However, the role of {alpha}1{beta}1 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 {alpha}1 chain of human and sheep VLA-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 mAb 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 {alpha}1 integrins may be useful in preventing these events.
Key words: Asthma; Inflammation; Integrin; Animal Model; CD49a




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