Natalizumab: overview of its pharmacology and safety.

Abstract

Natalizumab is a humanized monoclonal antibody that is produced in murine myeloma cells. It functions in the body as an antagonist of integrin heterodimers that contain the a4 integrin subunit. These heterodimers include a4b1 integrin and a4b7 integrin, which are expressed on the surface of most leukocytes. When natalizumab binds to the a4-subunit of the integrin, it prevents the a4-mediated adhesion of the leukocytes to their counter-receptor(s) (eg, vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1), thus preventing transmigration of the leukocytes across the endothelium and into the inflamed parenchymal tissue. Clinical trials with natalizumab for the treatment of the relapsing forms of multiple sclerosis have found the drug is capable of delaying the accumulation of physical disability and reducing the frequency of clinical exacerbations. Clinical trials of natalizumab for the treatment of Crohn's disease have found the drug, alone or in combination with infliximab, is effective in improving clinical response and remission rates as well as health-related quality of life in patients with Crohn's disease who have not been able to achieve remission with infliximab therapy alone. Like all drugs, natalizumab is not without risks. The drug was temporarily withdrawn from the market because of 3 reported cases of progressive multifocal leukoencephalopathy. Subsequent evaluations determined that the risk of this severe, but rare, adverse reaction did not justify keeping the drug off the market. When natalizumab was reintroduced, however, a closed prescribing and distribution program (Tysabri Outreach Unified Commitment to Health [TOUCH]) was also introduced. This program requires all patients prescribed natalizumab to be enrolled in and to receive their medication through the TOUCH system. Any serious adverse reactions must be reported to the TOUCH and MedWatch systems.