Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.
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 (< or =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.
Academic Hospital and Diabetes Research Center, Brussels Free University-VUB, Brussels. bart.keymeulen@az.vub.ac.be
Bart
B
Keymeulen
Evy
E
Vandemeulebroucke
Anette G
AG
Ziegler
Chantal
C
Mathieu
Leonard
L
Kaufman
Geoff
G
Hale
Frans
F
Gorus
Michel
M
Goldman
Markus
M
Walter
Sophie
S
Candon
Liliane
L
Schandene
Laurent
L
Crenier
Christophe
C
De Block
Jean-Marie
JM
Seigneurin
Pieter
P
De Pauw
Denis
D
Pierard
Ilse
I
Weets
Peppy
P
Rebello
Pru
P
Bird
Eleanor
E
Berrie
Mark
M
Frewin
Herman
H
Waldmann
Jean-François
JF
Bach
Daniel
D
Pipeleers
Lucienne
L
Chatenoud
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000096:biosynthesis; D017252:CD3 Complex / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D015309:Glucose Clamp Technique; D006564:Herpesviridae / Q000302:isolation & purification; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D008297:Male
D001323:Autoantibodies; D001786:Blood Glucose; D002096:C-Peptide; D017252:CD3 Complex; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007328:Insulin