new england journal
Insulin Needs after CD3-Antibody Therapy in New-Onset Type 1 Diabetes Bart Keymeulen, M.D., Ph.D., Evy Vandemeulebroucke, M.D., Anette G. Ziegler, M.D., Ph.D., Chantal Mathieu, M.D., Ph.D., Leonard Kaufman, Ph.D., Geoff Hale, Ph.D., Frans Gorus, M.D., Ph.D., Michel Goldman, M.D., Ph.D., Markus Walter, M.D., Sophie Candon, M.D., Ph.D., Liliane Schandene, Ph.D., Laurent Crenier, M.D., Christophe De Block, M.D., Ph.D., Jean-Marie Seigneurin, Ph.D., Pieter De Pauw, Ph.D., Denis Pierard, M.D., Ph.D., Ilse Weets, M.D., Ph.D., Peppy Rebello, B.Sc., Pru Bird, Ph.D., Eleanor Berrie, Ph.D., Mark Frewin, Herman Waldmann, M.D., Ph.D., Jean-François Bach, M.D., Ph.D., Daniel Pipeleers, M.D., Ph.D., and Lucienne Chatenoud, M.D., Ph.D.
abstract background From the Academic Hospital and Diabetes Research Center (B.K., E.V., F.G., P.D.P., D. Pierard, I.W., D. Pipeleers) and the Department of Biostatistics and Medical Informatics (L.K.), Brussels Free University–VUB, Brussels; Hospital München-Schwabing, Munich, Germany (A.G.Z., M.W.); the Department of Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium (C.M.); the Sir William Dunn School of Pathology, Oxford, United Kingdom (G.H., P.R., P.B., E.B., M.F., H.W.); the Université Libre de Bruxelles, Hôpital Erasme, Brussels (M.G., L.S., L. Crenier); INSERM U580-IRNEM, Hôpital Necker, Paris (S.C., J.-F.B., L. Chatenoud); the Department of Diabetology, University Hospital Antwerp, Edegem, Belgium (C.D.B.); and Centre Hospitalier Universitaire Michallon, Laboratory of Virology, Grenoble, France (J.-M.S.). Address reprint requests to Dr. Keymeulen of the JDRF Center for Beta Cell Therapy at the Medical Campus of Brussels Free University–VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium, or at [email protected]
vub.ac.be. N Engl J Med 2005;352:2598-608. Copyright © 2005 Massachusetts Medical Society.
Type 1 diabetes mellitus is a T-cell–mediated autoimmune disease that leads to a major loss of insulin-secreting beta cells. The further decline of beta-cell function after clinical onset might be prevented by treatment with CD3 monoclonal antibodies, as suggested by the results of a phase 1 study. To provide proof of this therapeutic principle at the metabolic level, we initiated a phase 2 placebo-controlled trial with a humanized antibody, an aglycosylated human IgG1 antibody directed against CD3 (ChAglyCD3). methods
In a multicenter study, 80 patients with new-onset type 1 diabetes were randomly assigned to receive placebo or ChAglyCD3 for six consecutive days. Patients were followed for 18 months, during which their daily insulin needs and residual beta-cell function were assessed according to glucose-clamp–induced C-peptide release before and after the administration of glucagon. results
At 6, 12, and 18 months, residual beta-cell function was better maintained with ChAglyCD3 than with placebo. The insulin dose increased in the placebo group but not in the ChAglyCD3 group. This effect of ChAglyCD3 was most pronounced among patients with initial residual beta-cell function at or above the 50th percentile of the 80 patients. In this subgroup, the mean insulin dose at 18 months was 0.22 IU per kilogram of body weight per day with ChAglyCD3, as compared with 0.61 IU per kilogram with placebo (P