Lobb R R, Pepinsky B, Leone D R, Abraham W M
Biogen Inc., Cambridge Center, MA 02142, USA.
Eur Respir J Suppl. 1996 Aug;22:104s-108s.
The alpha 4 integrins are heterodimeric leucocyte cell surface molecules central to their cell and matrix adhesive interactions. The integrin alpha 4 beta 1 interacts with the immunoglobulin superfamily member vascular cell adhesion molecule-1 (VCAM-1), and with an alternatively spliced form of fibronectin. The integrin alpha 4 beta 7 binds not only VCAM-1 and fibronectin, but also the mucosal addressin cell adhesion molecule (MAdCAM). Certain monoclonal antibodies (MoAbs) to the alpha 4 chain of alpha 4 beta 1 and alpha 4 beta 7 can block their in vitro adhesive function. In vivo studies with these MoAbs in lung antigen challenge models in several species demonstrate that alpha 4 integrins play a key role in eosinophil and T-cell recruitment, in the late phase response, and in airways hyperresponsiveness. In particular, MoAb HP1/2 is efficacious in a sheep model of allergic airways challenge, whether given intravenously or as aerosol. To evaluate the mechanism of action of this MoAb, Fab fragments were generated and shown to be equipotent in vitro and as efficacious in vivo as the intact immunoglobulin G (IgG). These data demonstrate that the in vivo efficacy of monoclonal antibody HP1/2 is not due to indirect effects, such as antigen cross-linking, but rather to blockade of alpha 4 integrin adhesive function. Humanized monoclonal antibody or other alpha 4 integrin antagonists may provide novel therapeutics for asthma.
α4整合素是异二聚体白细胞细胞表面分子，在其细胞与基质的黏附相互作用中起核心作用。整合素α4β1与免疫球蛋白超家族成员血管细胞黏附分子-1（VCAM-1）以及纤连蛋白的一种可变剪接形式相互作用。整合素α4β7不仅结合VCAM-1和纤连蛋白，还结合黏膜地址素细胞黏附分子（MAdCAM）。某些针对α4β1和α4β7的α4链的单克隆抗体（MoAb）可阻断其体外黏附功能。在多个物种的肺部抗原激发模型中对这些MoAb进行的体内研究表明，α4整合素在嗜酸性粒细胞和T细胞募集、晚期反应以及气道高反应性中起关键作用。特别是，MoAb HP1/２在绵羊过敏性气道激发模型中有效，无论是静脉注射还是雾化给药。为了评估该MoAb的作用机制，制备了Fab片段，结果表明其在体外具有同等效力，并且在体内与完整的免疫球蛋白G（IgG）一样有效。这些数据表明，单克隆抗体HP1/２的体内疗效不是由于间接作用，如抗原交联，而是由于阻断了α4整合素的黏附功能。人源化单克隆抗体或其他α4整合素拮抗剂可能为哮喘提供新的治疗方法。
