Pharmacological mechanism of Natalizumab

Natalizumab binds to the α4 subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils and inhibits α4-mediated adhesion of leukocytes to their counterreceptors. Receptors of the integrin α4 family include vascular cell adhesion molecule-1 (VCAM-1) expressed on activated vascular endothelial cells and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells in the gastrointestinal tract. Disruption of these molecular interactions prevents leukocyte migration across the endothelium into inflamed parenchymal tissue.

In vitro, anti-α4 integrin antibodies also block α4-mediated cell binding to ligands such as osteopontin and the alternatively spliced domain linker fragment-1 (CS-1) of fibronectin. In vivo, natalizumab can further inhibit the interaction of α4-expressing leukocytes with their ligands on the extracellular matrix and parenchymal cells, thereby inhibiting further recruitment of activated immune cells and inflammatory activity. The specific mechanisms by which natalizumab works in multiple sclerosis and Crohn's disease have not been fully determined.

In multiple sclerosis, lesions occur when activated inflammatory cells, includingT lymphocytes, cross the blood-brain barrier (BBB). The migration of leukocytes across the blood-brain barrier involves interactions between adhesion molecules on inflammatory cells and corresponding receptors on endothelial cells in the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blocking the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and CS-1 and/or osteopontin expressed by brain parenchymal cells. Data from an animal model of experimental autoimmune encephalitis in multiple sclerosis showed that after repeated administration of natalizumab, reduced leukocyte migration into the brain parenchyma and reduced plaque formation were detected by magnetic resonance imaging (MRI). The clinical significance of these animal data is unclear.

In Crohn's disease, The interaction of α4β7 integrin with the endothelial receptor MAdCAM-1 is thought to be an important factor in the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is primarily expressed on intestinal endothelial cells and plays a key role in the homing of T lymphocytes to intestinal lymphoid tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at sites of inflammatory activity in patients with CD, suggesting that it may play a role in leukocyte recruitment to the mucosa and contribute to the inflammatory response characteristic of CD. Therefore, the clinical effect of natalizumab in the treatment of CD may be secondary to blocking the molecular interaction of α4-7 integrin receptors with MAdCAM-1 expressed on venular endothelial cells in inflammatory lesions. Upregulation of VCAM-1 expression in colonic endothelial cells was found in mouse models of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. However, the role of VCAM-1 in CD is unclear.

Natalizumab's original patent drug is not marketed in the country and cannot be included in medical insurance. Currently, the generic drug natalizumab on the market overseas may cost more than 8,000 US dollars per box (the price may fluctuate due to exchange rates), which is very expensive. For more drug information and specific prices, please consult Yaode Medical Consultant.