Antibody to 47 Integrin for Ulcerative Colitis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The 47 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)2 report efficacy in the treatment of ulcerative colitis with MLN02, a humanized antibody that blocks the 47 integrin. However, a similar drug that interrupted leukocyte homing through blockade of the 41 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,3,4 and as a result, natalizumab has been withheld from the market.
Both natalizumab and MLN02 target the shared 4 integrin, whose ligands (MAdCAM-1 and VCAM-1) are expressed on endothelial cells in the brain and on microvessels in the inflamed central nervous system.5 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
References
Danese S, Semeraro S, Marini M, et al. Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation. Dig Liv Dis (in press).
Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the 47 integrin. N Engl J Med 2005;352:2499-2507.
Adelman B, Sandrock A, Panzara MA. Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med 2005;353:432-433.
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368.
Kanwar JR, Harrison JE, Wang D, et al. Beta7 integrins contribute to demyelinating disease of the central nervous system. J Neuroimmunol 2000;103:146-152.
The Authors and a Colleague Reply: We wish to emphasize that important differences exist between natalizumab and MLN02. MLN02 specifically binds the 47 heterodimer and blocks its interaction with MAdCAM-1. In contrast, natalizumab binds the shared 4 subunit of both 41 and 47 integrins. Thus, both the 41–VCAM-1 interaction and the 47–MAdCAM-1 interaction are blocked.1 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.2
Although a single study3 suggested that blocking 7 integrins has an immunosuppressive effect in murine autoimmune encephalomyelitis, this result has not been replicated by others.4 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
References
von Andrian UH, Engelhardt B. 4 Integrins as therapeutic targets in autoimmune disease. N Engl J Med 2003;348:68-72.
Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab -- unforeseen consequences. N Engl J Med 2005;353:414-416.
Kanwar JR, Harrison JE, Wang D, et al. Beta7 integrins contribute to demyelinating disease of the central nervous system. J Neuroimmunol 2000;103:146-152.
Engelhardt B, Laschinger M, Schulz M, Samulowitz U, Vestweber D, Hoch G. The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin. J Clin Invest 1998;102:2096-2105.
Both natalizumab and MLN02 target the shared 4 integrin, whose ligands (MAdCAM-1 and VCAM-1) are expressed on endothelial cells in the brain and on microvessels in the inflamed central nervous system.5 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
References
Danese S, Semeraro S, Marini M, et al. Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation. Dig Liv Dis (in press).
Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the 47 integrin. N Engl J Med 2005;352:2499-2507.
Adelman B, Sandrock A, Panzara MA. Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med 2005;353:432-433.
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368.
Kanwar JR, Harrison JE, Wang D, et al. Beta7 integrins contribute to demyelinating disease of the central nervous system. J Neuroimmunol 2000;103:146-152.
The Authors and a Colleague Reply: We wish to emphasize that important differences exist between natalizumab and MLN02. MLN02 specifically binds the 47 heterodimer and blocks its interaction with MAdCAM-1. In contrast, natalizumab binds the shared 4 subunit of both 41 and 47 integrins. Thus, both the 41–VCAM-1 interaction and the 47–MAdCAM-1 interaction are blocked.1 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.2
Although a single study3 suggested that blocking 7 integrins has an immunosuppressive effect in murine autoimmune encephalomyelitis, this result has not been replicated by others.4 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
References
von Andrian UH, Engelhardt B. 4 Integrins as therapeutic targets in autoimmune disease. N Engl J Med 2003;348:68-72.
Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab -- unforeseen consequences. N Engl J Med 2005;353:414-416.
Kanwar JR, Harrison JE, Wang D, et al. Beta7 integrins contribute to demyelinating disease of the central nervous system. J Neuroimmunol 2000;103:146-152.
Engelhardt B, Laschinger M, Schulz M, Samulowitz U, Vestweber D, Hoch G. The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin. J Clin Invest 1998;102:2096-2105.