NATALIZUMAB IS AN ALPHA-4 INTEGRIN-SPECIFIC HUMANISED MONOCLONAL ANTIBODY THAT IS USED AS MONOTHERAPY TO REDUCE THE FREQUENCY OF CLINICAL EXACERBATIONS, AND DELAY THE ACCUMULATION OF PHYSICAL DISABILITY, IN PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS .
NATALIZUMAB BINDS TO THE A4-SUBUNIT OF A4B1 AND A4B7 INTEGRINS EXPRESSED ON THE SURFACE OF ALL LEUKOCYTES EXCEPT NEUTROPHILS, AND INHIBITS THE A4-MEDIATED ADHESION OF LEUKOCYTES TO THEIR COUNTER-RECEPTOR(S). THE RECEPTORS FOR THE A4 FAMILY OF INTEGRINS INCLUDE VASCULAR CELL ADHESION MOLECULE-1 (VCAM-1), WHICH IS EXPRESSED ON ACTIVATED VASCULAR ENDOTHELIUM, AND MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1 (MADCAM-1) PRESENT ON VASCULAR ENDOTHELIAL CELLS OF THE GASTROINTESTINAL TRACT. DISRUPTION OF THESE MOLECULAR INTERACTIONS PREVENTS TRANSMIGRATION OF LEUKOCYTES ACROSS THE ENDOTHELIUM INTO INFLAMED PARENCHYMAL TISSUE. IN VITRO, ANTI-A4-INTEGRIN ANTIBODIES ALSO BLOCK A4-MEDIATED CELL BINDING TO LIGANDS SUCH AS OSTEOPONTIN AND AN ALTERNATIVELY SPLICED DOMAIN OF FIBRONECTIN, CONNECTING SEGMENT-1 (CS-1). IN VIVO, NATALIZUMAB MAY FURTHER ACT TO INHIBIT THE INTERACTION OF A4-EXPRESSING LEUKOCYTES WITH THEIR LIGAND(S) IN THE EXTRACELLULAR MATRIX AND ON PARENCHYMAL CELLS, THEREBY INHIBITING FURTHER RECRUITMENT AND INFLAMMATORY ACTIVITY OF ACTIVATED IMMUNE CELLS.
THE SPECIFIC MECHANISM(S) BY WHICH NATALIZUMAB EXERTS ITS EFFECTS IN MULTIPLE SCLEROSIS HAVE NOT BEEN FULLY DEFINED. IN MULTIPLE SCLEROSIS, LESIONS ARE BELIEVED TO OCCUR WHEN ACTIVATED INFLAMMATORY CELLS, INCLUDING T-LYMPHOCYTES, CROSS THE BLOOD-BRAIN BARRIER (BBB). LEUKOCYTE MIGRATION ACROSS THE BBB INVOLVES INTERACTION BETWEEN ADHESION MOLECULES ON INFLAMMATORY CELLS AND THEIR COUNTER-RECEPTORS PRESENT ON ENDOTHELIAL CELLS OF THE VESSEL WALL. THE CLINICAL EFFECT OF NATALIZUMAB IN MULTIPLE SCLEROSIS MAY BE SECONDARY TO BLOCKADE OF THE MOLECULAR INTERACTION OF A4B1-INTEGRIN EXPRESSED BY INFLAMMATORY CELLS WITH VCAM-1 ON VASCULAR ENDOTHELIAL CELLS, AND WITH CS-1 AND/OR OSTEOPONTIN EXPRESSED BY PARENCHYMAL CELLS IN THE BRAIN. DATA FROM AN EXPERIMENTAL AUTOIMMUNE ENCEPHALITIS ANIMAL MODEL OF MULTIPLE SCLEROSIS DEMONSTRATE REDUCTION OF LEUKOCYTE MIGRATION INTO BRAIN PARENCHYMA AND REDUCTION OF PLAQUE FORMATION DETECTED BY MAGNETIC RESONANCE IMAGING (MRI) FOLLOWING REPEATED ADMINISTRATION OF NATALIZUMAB. THE CLINICAL SIGNIFICANCE OF THESE ANIMAL DATA IS UNKNOWN.