Two recent reports in the New England Journal of Medicine support the idea that blocking the entry of aggressive leukocytes into inflamed tissues could be an effective strategy for the treatment of autoimmune disorders. A 'humanized' monoclonal antibody specific for α4 integrin — known as natalizumab — was tested in Phase II clinical trials, in patients with Crohn disease and multiple sclerosis.
α4 integrin pairs with β1 integrin or β7 integrin to form dimers that are expressed by activated lymphocytes and monocytes and that are involved in the migration of these cells from the circulation into tissues. α4β1 integrin, also known as very late antigen 4 (VLA4), recognizes vascular cell-adhesion molecule 1 (VCAM1), an adhesion molecule that is upregulated on inflamed endothelium. α4β7 integrin binds mucosal vascular addressin cell-adhesion molecule 1 (MADCAM1) and facilitates the entry of leukocytes into the intestines.
Previous studies in humans with Crohn disease or ulcerative colitis, which are forms of inflammatory bowel disease, had shown that monoclonal antibodies specific for α4 integrin had beneficial effects. In this placebo-controlled double-blind trial, 248 patients with moderate to severe Crohn disease received two antibody infusions, four weeks apart, of placebo or natalizumab, and were assessed over a 12-week period. The groups that received the drug had a significantly higher (by approximately twofold) clinical response and rate of remission than the placebo groups.
The anti-inflammatory effects of natalizumab were only partial, but the authors concluded that for the treatment of Crohn disease, natalizumab seems to be at least as effective as the approved drug infliximab, which is a tumour-necrosis factor inhibitor.
Multiple sclerosis is characterized by the appearance of inflammatory and demyelinating lesions in the central nervous system, in which expression of VCAM1 is upregulated. In the multiple sclerosis trial, 213 patients with relapsing multiple sclerosis received either placebo or natalizumab once a month for six months. Whereas the placebo groups had an average of 9.6 new lesions per patient during the treatment period (as assessed by magnetic resonance imaging), groups that received natalizumab had approximately ten times fewer lesions. Moreover, significantly fewer relapses were reported in the groups that received the drug. The downside is that the effect is lost when the treatment stops.
In both trials, no adverse effects were associated with natalizumab and only a small percentage of patients developed antibody responses to the drug. However, in the multiple sclerosis trial, there was a trend towards increased susceptibility to infections. Further studies will be required to determine the consequences of long-term treatment with natalizumab on immunity to infection.
Together, these studies show that blocking the access of leukocytes to inflammatory regions produces beneficial effects, in at least two inflammatory disorders. However, larger Phase III trials (which are now underway) will be necessary to establish longer-term safety and efficacy compared with existing treatments.
ORIGINAL RESEARCH PAPERS
Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003)
Ghosh, S. et al. Natalizumab for active Crohn's disease. N. Engl. J. Med. 348, 24–32 (2003)
von Andrian, U. H. & Engelhardt, B. α4 integrins as therapeutic targets in autoimmune disease. N. Engl. J. Med. 348, 68–72 (2003)