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Natalizumab

Natalizumab is an experimental drug for Multiple Sclerosis and Crohn's Disease entering phase III human trials for MS as of September 2001. It is being marketed under the brand name Antegren by Elan and Biogen.

Natalizumab is a potential disease modifying treatment and is not a cure for multiple sclerosis. Results of double-blind, placebo-controlled Phase II trials of 213 MS patients at 26 sites in the United States, Canada and the United Kingdom were published on 17th September 2001.

Early indications based on the results of these trials indicate that Natalizumab may reduce the number of new enhancing lesions by around 85-95% and the relapse rate by around 45-75%. Dosages used in the trials were 3 mg/kg and 6 mg/kg by intravenous infusion every four weeks.

Natalizumab works by interfering with the process that pulls white blood cells (leukocytes) into the central nervous system (CNS) from the blood - i.e. gets them across the blood-brain barrier. It is the white blood cells that are believed mediate the damage in multiple sclerosis.

A sub-group of white blood cells are called lymphocytes, one type of lymphocyte is called a T-cell and one type of T-cell is called a helper T-cell (you may also see it called a CD4+ cell). It is this type of cell that is thought to be the orcestrator of the damage in MS and some other autoimmune diseases including Crohn's disease.

The blood-brain barrier consists of two layers, the outer of which is called the endothelium. This is a single layer of cells that line the blood vessels that supply the central nervous system. The endothelium layer in blood vessles supplying the brain is not dissimilar to the endothelium layer on blood vessels elsewhere in the body.

In response to chemical signals (cytokines) sent by T-cells already inside the CNS, the cells in the endothelium (endothelial cells) express special molecules called adhesion molecules. These are sticky molecules that attach to lymphocytes passing through the blood. One of these adhesion molecules is called VLA-4 (Very Late Antigen 4) and sticks to another adhesion molecule expressed on the surface of lymphocytes called alpha-4-integrin.

Natalizumab attaches to alpha-4-integrin and renders it unable to stick to VLA-4. This inteferes with the process by which lymphocytes are able to enter the central nervous system and thus reduces the damage that they wreak in MS and Crohn's.

Natalizumab is what is called a monoclonal antibody.

Antibodies are Y-shaped molecules released the other sort of lymphocyte, the B-cell. Each B-cell has thousands of receptors which recognise specific molecules called antigens and allow the B-cell to identify specific viruses and bacteria (pathogens). However, for each B-cell, all the receptors are identical (monoclonal). When a B-Cell's receptor is activated by the molecule which it recognises, it sheds thousands of identical receptors in a soluable form called antibodies.

Each antibody goes off around the body sticking to any other instance of that same antigen that it finds. By sticking to the antigen, it can interupt how the cell carrying the antigen behaves and also signal to other white blood cells to kill it.

Natalizumab, as a monoclonal antibody, copies how the body's immune system deals with pathogens, but instead, it is attaching to alpha-4-integrin on the body's lymphocytes rather than to a pathogen.

Because Crohn's disease operates in a similar way to MS, interrupting chemotaxis in the endothelium layer around the gut to prevent lymphocytes getting in also has a disease modifying effect.

Natalizumab links:
Antegren(Natalizumab)
Antegren/Promising Phase II Results
Elan to Develop Antegren


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