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Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab

Key Points

  • Lymphocytes flowing in the blood vessels are induced to slow, roll along the blood vessel walls and finally arrest their movement and attach to the endothelium through a complex sequence of events. Investigators had long searched for molecules that would allow the specific attachment of lymphocytes to the site of inflammation. Immunologists had proposed that specific molecular 'zip codes' were crucial for the entry of lymphocytes to specific tissues. A different zip code might exist for brain, synovium and gut, for example.

  • α4β1integrin is key for binding of lymphocytes to the walls of blood vessels in the inflamed brain.

  • α4β1integrin is also crucial for entry to the β-cells in the pancreas, the gut and the synovium, rendering the zip-code hypothesis problematic.

  • Preclinical development of a drug to block lymphocyte homing was focused on the animal model of multiple sclerosis, known as experimental autoimmune encephalomyelitis (EAE). In ongoing EAE, where disease has already been established with evidence of clinical paralysis of the hind limbs, anti-α4β1 integrin antibodies reversed the paralysis and cleared the brain of ongoing lymphocytic infiltration

  • A humanized monoclonal antibody to α4β1integrin, known as natalizumab, was taken into the clinic for patients with relapsing remitting multiple sclerosis. Phase II clinical trial results with natalizumab showed a reduction in lesions on magnetic resonace imaging and a reduction in the relapse rate in patients with multiple sclerosis.

  • Phase III clinical trials demonstrated a 66% reduction in the rate of relapse after 1 year, leading to approval of the drug for treatment of relapsing remitting multiple sclerosis. Promising clinical trial results in Phase II were reported for Crohn's disease and rheumatoid arthritis as well.

  • Three months after the FDA approval the drug was voluntarily withdrawn from the market, after two cases of the deadly disease progressive multifocal leukoencephalopathy (PML) were reported in patients who took the drug in clinical trials for multiple sclerosis. A third patient in a trial for Crohn's disease died of PML. At present natalizumab is off the market for all its indications, and whether it will return to the market is uncertain.

Abstract

Immunologists have long hypothesized that particular 'molecular addresses' govern lymphocyte entry to a given organ. In 1992, α4β1 integrin was identified as the key molecule involved in homing to inflamed regions of the brain. An antibody to α4β1integrin blocked paralysis in an animal model of multiple sclerosis, and the humanized monoclonal antibody natalizumab, which binds α4β1 integrin, reduced relapses 66% in clinical trials in multiple sclerosis. Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.

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Figure 1: Macrophages and lymphocytes in a perivascular distribution.
Figure 2: Physiological steps in lymphocyte flow and adhesion.
Figure 3: Blockade of lymphocyte binding to inflamed brain.
Figure 4: The pathophysiology of multiple sclerosis showing some key checkpoints.

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Acknowledgements

I would like to thank K. Gijbels for the figure in Box 1.

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Competing interests

L.W. founded Neurocrine Biosciences and Bayhill Therapeutics. These companies are testing new therapies for multiple sclerosis. L.W. is a consultant to Neurocrine Biosciences and Bayhill Therapeutics.

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DATABASES

Entrez Gene

CD44

ICAM1

L-selectin

MBP

VCAM1

OMIM

Multiple sclerosis

rheumatoid arthritis

Glossary

NATALIZUMAB (TYSABRI)

The generic and trade name, respectively, for the humanized antibody to α4β1 integrin, approved in November 2004 for the treatment of multiple sclerosis.

INTEGRIN

Proteins involved with the cytoskeleton that have extracellular domains comprising elements of α- and β-chains. The α4β1 integrin is involved in lymphocyte homing to the brain and to other organs.

MULTIPLE SCLEROSIS

A demyelinating autoimmune disease of the brain and spinal cord affecting 400,000 individuals in the United States.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE)

An animal model of multiple sclerosis that was discovered 75 years ago.

LYMPHOCYTE HOMING

Lymphocytes are mobile elements of the immune system that have the capacity to home from lymph nodes via the blood circulation to particular target sites.

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Steinman, L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 4, 510–518 (2005). https://doi.org/10.1038/nrd1752

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