natalizumab + methotrexate

Natalizumab + methotrexate is a combination therapeutic regimen involving a humanized monoclonal antibody and a small molecule folate analogue. Natalizumab (Tysabri) binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, effectively blocking their interaction with vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). This inhibition prevents leukocyte transmigration into inflamed parenchymal tissues, such as the central nervous system and the intestinal mucosa. Methotrexate acts as a competitive inhibitor of the enzyme dihydrofolate reductase (DHFR), leading to the depletion of tetrahydrofolates required for purine and thymidylate synthesis, thereby inhibiting DNA synthesis and cell proliferation, particularly in rapidly dividing immune cells. While this combination has been evaluated for the treatment of refractory Crohn's disease and rheumatoid arthritis, its clinical utility is severely limited by safety concerns. Specifically, the co-administration of natalizumab with immunosuppressants like methotrexate is associated with a significantly increased risk of developing progressive multifocal leukoencephalopathy (PML), a severe viral infection of the brain.

Other names

natalizumabmethotrexateMTX