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Previous Volume 352:2598-2608 June 23, 2005 Number 25 Next

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ABSTRACT

Background 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<0.001). In this subgroup, 12 of 16 patients who received ChAglyCD3 (75 percent) received minimal doses of insulin (0.25 IU per kilogram per day) as compared with none of the 21 patients who received placebo. Administration of ChAglyCD3 was associated with a moderate "flu-like" syndrome and transient symptoms of Epstein–Barr viral mononucleosis.

Conclusions Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.

Source Information

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 bart.keymeulen{at}az.vub.ac.be.

Full Text of this Article

Related Letters:

CD3-Antibody Therapy in New-Onset Type 1 Diabetes Mellitus
Haller M. J., Schatz D. A., Schwartz I. D., Keymeulen B., Pipeleers D., Chatenoud L.
Extract | Full Text | PDF  
N Engl J Med 2005; 353:2086-2087, Nov 10, 2005. Correspondence

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