Anti-Integrin Therapy

ANTI-INTEGRIN THERAPY

Integrins are a family of adhesion molecules on the surface of leu-kocytes that may interact with another class of adhesion molecules on the surface of the vascular endothelium known as selectins,

allowing circulating leukocytes to adhere to the vascular endothe-lium and subsequently move through the vessel wall into the tis-sue. Integrins consist of heterodimers that contain two subunits, alpha and beta. Natalizumab is a humanized IgG 4 monoclonal antibody targeted against the α4 subunit, and thereby blocks sev-eral integrins on circulating inflammatory cells and thus prevents binding to the vascular adhesion molecules and subsequent migra-tion into surrounding tissues.

Natalizumab has shown significant efficacy for a subset of patients with moderate to severe Crohn’s disease. Unfortunately, in initial clinical trials of patients with Crohn’s disease and multi-ple sclerosis, 3 of 3100 patients treated with natalizumab devel-oped progressive multifocal leukoencephalopathy due to reactivation of a human polyomavirus (JC virus), which is present in latent form in over 80% of adults. All three patients were receiving concomitant therapy with other immunomodulators. After voluntary withdrawal and review of the drug by the manu-facturer in 2005, it was approved by the FDA in 2008 for patients with moderate to severe Crohn’s disease who have failed other therapies through a carefully restricted program. The approved dosage is 300 mg every 4 weeks by intravenous infusion, and patients should not be on other immune suppressant agents. Approximately 50% of patients respond to initial therapy with natalizumab. Of patients with an initial response, long-term response is maintained in 60% and remission in over 40%. Other adverse effects include acute infusion reactions and a small risk of opportunistic infections.