Natalizumab and PML in MS

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By Anthony T Reder MD

Natalizumab is the generic name for Tysabri®. -ed.

Natalizumab is an effective therapy for multiple sclerosis. In rare cases, it may be too potent in its ability to block ingress of T cells into the central nervous system. Natalizumab changes the ecology of the cell entry into the brain. This suggests new principles about multiple sclerosis therapy, T cell/endothelial cell interactions, central nervous system viral infections, and central nervous system immunology.

Questions addressed include:

  1. The role of VLA-4 in adhesion of immune cells to endothelial cells in periphery and brain
  2. The role of VLA-4 in adhesion to the bone marrow stroma
  3. Regulation of the number of white blood cells in the blood and CSF
  4. VLA-4 expression and whether anti-VLA-4 blockade affects immune regulation specific to multiple sclerosis
  5. VLA-4 in immune activation, costimulation, and central nervous system-specific adhesion
  6. Migration through the blood-brain barrier
  7. How immunity differs between blood and brain
  8. Anti-adhesion molecule therapy is effective in multiple sclerosis.
  9. Adverse effects of natalizumab and unexpected benefits
  10. Does the combination of natalizumab and interferon, rather than natalizumab alone, induce progressive multifocal leukoencephalopathy (PML)?
  11. Could anti-VLA-4 therapy and other treatments induce PML in other diseases?
  12. Why does JC virus-induced PML, but not other virus infections, appear with natalizumab treatment? Pathogenesis, target cells, JC virus interaction with other viruses, and why PML develops with natalizumab therapy.
  13. Can JC virus be detected?
  14. PML in multiple sclerosis and calculation of risk of PML based on prior treatments and antibodies to JC virus.
  15. Can PML and immune reconstitution inflammatory syndrome be treated effectively in multiple sclerosis patients?
  16. Can PML be predicted, and can it be prevented by natalizumab washout in multiple sclerosis patients?

Natalizumab is a human IgG4k monoclonal antibody with short murine segments at the antigen recognition site. Natalizumab is derived by grafting short portions of low immunogenicity from the complementarity determining region of a potent murine anti-VLA-4 Ab to a human IgG4 chain. This immunoglobulin isotype does not bind complement and persists for a long time in the circulation. Natalizumab binds to the alpha-chain of VLA-4 glycoprotein (alpha4beta1 integrin) found on immune cell membranes. The antibody blocks VLA-4 interaction with VCAM-1 on endothelial cells. Related anti-VLA-4 antibodies also affect immune cell activation. After an impressively short trip from lab bench to bedside, natalizumab was approved by the FDA in 2004 for treatment of relapsing-remitting forms of multiple sclerosis. It is also effective in Crohn disease and possibly in rheumatoid arthritis.