Background Type 1 diabetes mellitus is a T-cell–mediatedautoimmune disease that leads to a major loss of insulin-secretingbeta cells. The further decline of beta-cell function afterclinical onset might be prevented by treatment with CD3 monoclonalantibodies, as suggested by the results of a phase 1 study.To provide proof of this therapeutic principle at the metaboliclevel, we initiated a phase 2 placebo-controlled trial witha humanized antibody, an aglycosylated human IgG1 antibody directedagainst CD3 (ChAglyCD3).
Methods In a multicenter study, 80 patients with new-onset type1 diabetes were randomly assigned to receive placebo or ChAglyCD3for six consecutive days. Patients were followed for 18 months,during which their daily insulin needs and residual beta-cellfunction were assessed according to glucose-clamp–inducedC-peptide release before and after the administration of glucagon.
Results At 6, 12, and 18 months, residual beta-cell functionwas better maintained with ChAglyCD3 than with placebo. Theinsulin dose increased in the placebo group but not in the ChAglyCD3group. This effect of ChAglyCD3 was most pronounced among patientswith initial residual beta-cell function at or above the 50thpercentile of the 80 patients. In this subgroup, the mean insulindose at 18 months was 0.22 IU per kilogram of body weight perday with ChAglyCD3, as compared with 0.61 IU per kilogram withplacebo (P<0.001). In this subgroup, 12 of 16 patients whoreceived ChAglyCD3 (75 percent) received minimal doses of insulin(0.25 IU per kilogram per day) as compared with none of the21 patients who received placebo. Administration of ChAglyCD3was associated with a moderate "flu-like" syndrome and transientsymptoms of Epstein–Barr viral mononucleosis.
Conclusions Short-term treatment with CD3 antibody preservesresidual beta-cell function for at least 18 months in patientswith 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.
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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. 
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