MLN-02. A letter to the editor of NEJM.
[Just to sort things out a little bit. We still don't know if MLN-02 will be of much use for anything. Genentech was not interested to pursue this further and handed the lot back to Millennium].
To the editor: The a4b7 integrin plays a crucial role in the physiological homing of T cells and monocytes by mediating specific binding of these cells to mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) and vascular-cell adhesion molecule 1 (VCAM-1) on the intestinal microvasculature. 1 Feagan et al. (June 16 issue) report efficacy in the treatment of ulcerative colitis with MLN02, a humanized antibody that blocks the a4b7 integrin. However, a similar drug that interrupted leukocyte homing through blockade of the a4b1 integrin (natalizumab) has recently caught the attention of clinical investigators in inflammatory bowel disease. Natalizumab reduced immune surveillance in the brain — an effect that was associated with fatal reactivation of JC virus. This adverse effect led to progressive multifocal leukoencephalopathy, and as a result, natalizumab has been withheld from the market.
Both natalizumab and MLN02 target the shared a4 integrin, whose ligands (MAdCAM-1 and VCAM-1) are expressed on endothelial cells in the brain and on microvessels in the inflamed central nervoussystem.
Long-term safety data are, therefore, essential to allow an assessment of the real risks of JC virus reactivation and the development of progressive multifocal leukoencephalopathy in patients who have been administered MLN02.
Silvio Danese, M.D.
Catholic University of Rome
00168 Rome, Italy
sdanese@hotmail.com
Sarah A. De La Rue, M.D.
University of Virginia Health System
Charlottesville, VA 22908
Antonio Gasbarrini, M.D.
Catholic University of Rome
00168 Rome, Italy
the authors and a colleague reply:
We wish to emphasize that important differences exist between
natalizumab and MLN02. MLN02 specifically binds the a4b7 heterodimer and blocks its interaction with MAdCAM-1. In contrast, natalizumab binds the shared a4 subunit of both a4b1 and a4b7 integrins. Thus, both the a4b1–VCAM-1 interaction and the a4b7–MAdCAM-1 interaction are blocked.
This broad activity results in a peripheral-blood lymphocytosis that is not observed with the more selective agent MLN02. We speculate that such widespread interference with lymphocyte trafficking may be a risk factor in reactivation of JC virus.
Although a single study suggested that blocking b7 integrins has an immunosuppressive effect in murine autoimmune encephalomyelitis, this result has not been replicated by others.
No central nervous system infections have been observed in 300 patients exposed to MLN02. In summary, the existing basic and clinical data suggest that MLN02 has minimal effects on immunity in the central nervous system. Ultimately, the definitive safety and efficacy profile of MLN02 will be established in long-term studies.
Brian G. Feagan, M.D.
Robarts Research Institute
London, ON N6A 5K8, Canada
bfeagan@robarts.ca
Irving H. Fox, M.D., C.M.
Kei Kishimoto, Ph.D.
Millennium Pharmaceuticals
Cambridge, MA 02139 |
