Natalizumab (Tysabri)

SUMMARY: Natalizumab is a humanized IgG4κ monoclonal antibody that is a selective adhesion molecule inhibitor, which prevents adhesion of leukocytes to endothelial cells. It is the first monoclonal antibody approved by the FDA for the treatment of relapsing-remitting MS. This article will review the mechanism of action and clinical role of this agent.

N atalizumab (Tysabri; Biogen Idec, Cambridge, Massachusetts and Elan Pharmaceuticals, Dublin, Ireland) was the first FDA-approved monoclonal antibody for the treatment of MS. Natalizumab received FDA approval in 2004 for treatment of relapsing-remitting MS based on the AFFIRM and SENTINEL phase 3 clinical trials. 1,2 More recently, the indications for natalizumab were expanded to include Crohn disease. [3][4][5] In 2005, natalizumab was removed from the market following cases of PML but was reintroduced by the FDA with a mandatory surveillance program in 2006 called TOUCH (Biogen). 6

Proposed Mechanism of Action
Natalizumab is a humanized monoclonal IgG4 antibody that selectively binds to the ␣4-integrin component of adhesion molecules found on lymphocytes, monocytes, and eosinophils. 7 ␣4-integrin is a subunit of the leukocyte adhesion molecules ␣4␤1 and ␣4␤7. In 1991, Yednock et al 8 showed that targeting ␣4-integrin could prevent the development of demyelinating lesions in a mouse model of MS, elucidating the therapeutic potential for this medication. 9 Natalizumab inhibits the interaction of ␣4␤1 with VCAM-1 and of ␣4␤7 with MAdCAM-1. 10 VCAM-1 and MAdCAM-1 are found on endothelial cells and interact with ␣4␤1 and ␣4␤7 on leukocytes for firm adherence of leukocytes to endothelial cells, a requisite step for their extravasation into inflamed tissue (Fig 1). 11 Natalizumab prevents migration of autoreactive leukocytes out of blood vessels into target organs by blocking the adhesion to endothelial cells of the ␣4-integrin component of adhesion molecules on leukocytes, inhibiting inflammation ( Fig  2). Because VCAM-1 is expressed on inflamed cerebrovascular endothelial cells, ␣4␤1 is believed to be the critical target of natalizumab in preventing leukocyte migration into the central nervous system in MS. In contrast, both VCAM-1 and MAdCAM-1 are upregulated on intestinal endothelium in Crohn disease. The efficacy of natalizumab in Crohn disease very likely is due to blockade of leukocyte adhesion factors ␣4␤1 and ␣4␤7 in tandem. 4,7,10 Clinical Indications Natalizumab is approved for treatment of relapsing-remitting MS and Crohn disease. It is generally reserved for patients who fail first-line therapies (Figs 3 and 4). 12 It must be given in conjunction with the TOUCH program, which is a national risk-minimization program designed to "minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions regarding Natalizumab use." 6 This drug is being investigated for use in ulcerative colitis.

Administration
Natalizumab is administered at specialized infusion centers enrolled in the TOUCH program for 1 hour with 1-hour monitoring. The TOUCH program also mandates regular appointments and follow-ups to monitor for signs of PML. The halflife is 11 days after 6 months of therapy. 13

Side Effects
Reported serious side effects include the following: • Neutralizing antibody development: occurs in Յ10% of patients. 1,4,5,14 • Transfusion reaction/hypersensitivity: transfusion reactions ranging in severity from minor to anaphylaxis have been reported. 1,2,12 These reactions are more common in patients with neutralizing antibodies. 5 • PML: a serious central nervous system infection due to JC virus, cases have been reported in patients with MS and Crohn disease. 15 Natalizumab is recommended for use as a monotherapy in MS 12 and Crohn disease to minimize risk. • Hepatotoxicity: clinically significant liver injury has been reported in 6 individuals without long-term liver failure. 16

Economic Issues
Natalizumab is given at 300 mg intravenously every 4 weeks for Crohn disease and MS. The cost is roughly $2800 per vial (300 mg) with an annual cost of $34,000. This is covered by most insurance companies.