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Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab.

Lawrence Steinman¹

¹Stanford University, Stanford, California 94305, USA. steinman@stanford.edu

Nature Reviews. Drug Discovery

|June 3, 2005

Summary

Alpha4beta1 integrin facilitates lymphocyte homing to the brain. Natalizumab, an antibody targeting this molecule, effectively reduced multiple sclerosis relapses but was later withdrawn due to rare, fatal side effects.

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Area of Science:

Immunology
Neurology

Background:

Lymphocyte homing to organs is regulated by specific molecular interactions.
Alpha4beta1 integrin was identified as a crucial mediator for lymphocyte entry into inflamed brain tissue.

Purpose of the Study:

To investigate the role of alpha4beta1 integrin in lymphocyte trafficking to the central nervous system.
To evaluate the therapeutic potential of targeting alpha4beta1 integrin for multiple sclerosis treatment.

Main Methods:

Utilized an animal model of multiple sclerosis to assess the efficacy of an alpha4beta1 integrin antibody.
Reviewed clinical trial data for natalizumab, a humanized monoclonal antibody targeting alpha4beta1 integrin, in multiple sclerosis patients.

Main Results:

Related Experiment Videos

Antibody blockade of alpha4beta1 integrin demonstrated efficacy in preventing paralysis in an animal model.

Natalizumab significantly reduced multiple sclerosis relapses by 66% in clinical trials.

Post-market surveillance identified two fatal cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab.

Conclusions:

Alpha4beta1 integrin is a key determinant of lymphocyte homing to the brain, relevant to multiple sclerosis pathogenesis.
While effective in reducing relapses, natalizumab carries a risk of rare but severe neurological side effects, necessitating careful risk-benefit assessment.