Adhesion molecule blocker for ulcerative colitis

This report in the NEJM shows that treatment with an antibody designed to block T cell migration into the gut is effective in treating ulcerative colitis. The antibody block a molecule on lymphocytes (white blood cells) called alpha-4 beta-7 integrin (integrins are adhesion molecules that bind to other molecules, in this case allowing lymphocytes to home to the appropriate tissue; integrins consist of two chains an alpha chain and a beta and are named based on the identity of these chains. alpha-4 beta-7 is important for homing to the gut. Binding to this integrin and blocking its interaction with other adhesion molecules on the wall of blood vessels block the lymphocytes that are destined for the gut. Since UC is a disease of inflammation this presumably decreases inflammation and therefore disease

About 2/3 of patients with ulcerative colitis achieved remission, versus only 1/3 of controls. There were two possible downsides. First about 1/4 of patients treated with the antibody, cleverly named MLN02, made antibodies against it (that is antibodies to the antibodies), which prevented it from having full effect. Patients in this trial only got 2 doses, so this could be an increasing problem with longer use. Second there were 3 serious infections in the MLN02 groups (two doses were used) versus none in the placebo group. This didn’t reach statistical significance, but bears watching in larger trials.

Recall that natalizumab (tysrabi), an antibody against just the alpha-4 component (which is part of other integrins beside alpha-4 beta-7) apparently caused several cases of progressive multifocal leukoencephalopathy (PML), which is caused by an unusual virus. The idea being that preventing lymphocytes entering the brain allows the JC virus that causes PML to evade an effective immune reaction.

Natalizumab was also trialed for Crohn’s disease, which shares some similarities to UC, but caused a case of PML in a patient in that trial as well, although it apparently wasn’t recognized until later.

Because MLN02 is specific for the alpha-4 beta-7 pair, which is not involved in migration of white blood cells into the central nervous system (that is thought to be alpha-4 beta-1 integrin) it shouldn’t cause PML, but it bears watching.