Selective Adhesion Molecule Inhibitors

Natalizumab is a humanized monoclonal antibody to a4 integrin that was approved by the US FDA in 2004 for the treatment of relapsing forms of MS.23-25 The integrins are a large family of adhesion molecules mediating cell-cell and cell-ECM interactions. Expression of a4 integrin is predominantly on lymphocytes, monocytes, eosinophils, and basophils, but is usually undetectable on neutrophils. It forms heterodimers with either p or P7. One ligand for a4p integrin is VCAM-1 (vascular cell adhesion molecule), which is expressed on vascular endothelial cells and, perhaps, glial cells. Other ligands of a4pi integrin include the ECM proteins, osteopontin, thrombospondin, and fibronectin. Osteopontin has adhesion and cytokine activity, and its expression is increased in MS lesions and spinal cord of EAE rats; mice deficient in osteopontin are relatively resistant to EAE.

Leukocytes are concentrated in lymphatic tissues, and present in other tissues, including brain, in low numbers. In MS, and other inflammatory diseases, their migration across endothelium into tissues (in the case of MS, across the blood-brain barrier to sites of new or active brain lesions) is enhanced. Binding of a4pl integrin, in the case of lymphocytes, leads to phenotypic transformation to promote migration, activation, and proliferation. Indeed, translocation of CD4 + T cells to brain parenchyma is dependent on the expression of a4pl integrin.

In Crohn's disease, an organ-specific autoimmune disease in which the immune system attacks the intestinal mucosa, the therapeutic target of natalizumab is a4^7 integrin, which, like a4pl integrin, is recognized by a4 integrin-specific antibodies. This integrin has multiple functions, including mediating migration of gut-homing T cells via its counter-receptor in the gut, MadCAM.

Early in 2005, all dosing of natalizumab was voluntarily suspended by the sponsor after learning of two cases of progressive multifocal leukoencephalopathy (PML) in MS patients receiving natalizumab and IFN-P combination therapy; a third case of PML was subsequently discovered in a patient with Crohn's disease receiving natalizumab following extensive therapy with various immunosuppressive medications. One of the two MS patients recovered; however, the other two cases proved fatal. Following an exhaustive safety review, the US FDA approved the use of natalizumab in open-label monotherapy clinical trials. The FDA subsequently granted approval for reintroduction based on the review of natalizumab clinical trial data; revised labeling with enhanced safety warnings; and a risk management plan (TOUCH Prescribing Program) designed to inform physicians and patients of the benefits and risks of natalizumab treatment and minimize potential risk of progressive multifocal leukoencephalopathy (PML). Because of the increased risk of PML, natalizumab monotherapy is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies.

In a monotherapy clinical trial, natalizumab seemed to significantly reduce the progression of disability, the occurrence of relapse, and the formation of lesions visualized by MRI in patients with relapsing MS.26 A second trial suggested that natalizumab-IFN-b combination therapy was significantly more effective than IFN-b alone in a population of RRMS patients who experienced breakthrough disease during IFN-b monotherapy.27 Prior to the PML reports, side effects were modest, and there were no reports of adverse effects, suggesting the most promising risk:benefit ratio for an MS therapy to date. However, no head-to-head studies with IFN-b or glatiramer acetate therapies have been completed.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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