Integrin alpha 4 (ITGA4) (ITGA4)

Integrin alpha 4 (ITGA4), also known as CD49d, is a critical transmembrane protein that serves as the alpha subunit for the heterodimeric integrin receptors alpha 4 beta 1 (VLA-4) and alpha 4 beta 7 [11, 14]. It is predominantly expressed on the surface of most leukocytes, including lymphocytes, monocytes, and eosinophils, where it mediates essential cell-cell and cell-matrix adhesion processes required for immune cell trafficking and extravasation [6, 12]. By interacting with ligands such as vascular cell adhesion molecule-1 (VCAM-1) and mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), ITGA4 facilitates the recruitment of immune cells into inflamed tissues, such as the central nervous system and the gastrointestinal tract [1, 5]. In pathological conditions like multiple sclerosis and Crohn's disease, the overactive infiltration of leukocytes mediated by ITGA4 leads to chronic inflammation and tissue damage [9, 17]. Natalizumab is a humanized monoclonal antibody that specifically targets the alpha 4 subunit, effectively blocking both alpha 4 beta 1 and alpha 4 beta 7 mediated adhesion to prevent leukocyte entry into target organs [3, 16]. While highly effective in reducing disease relapses, therapeutic blockade of ITGA4 is associated with a significant risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection caused by the reactivation of the JC virus due to impaired local immune surveillance [5, 8, 17].

Other names

CD49dVLA-4 alpha subunitAntigen CD49DIA4Integrin subunit alpha 4

Natalizumab acts as a humanized monoclonal antibody that binds to the alpha 4 subunit of both alpha 4 beta 1 (VLA-4) and alpha 4 beta 7 integrins. This binding sterically hinders the interaction between these integrins and their endothelial ligands, specifically Vascular Cell Adhesion Molecule-1 (VCAM-1) and Mucosal Vascular Addressin Cell Adhesion Molecule-1 (MAdCAM-1). By blocking these interactions, the drug inhibits the adhesion and subsequent transmigration of leukocytes across the blood-brain barrier into the central nervous system and into the intestinal mucosa, thereby reducing localized inflammation in diseases like multiple sclerosis and Crohn's disease [1, 3, 5, 16].