An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.

Document Type

Article

Publication Date

8-15-2019

Identifier

DOI: 10.1056/NEJMoa1902226; PMCID: PMC6776880

Abstract

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.

RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.

CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

Journal Title

The New England journal of medicine

Volume

381

Issue

7

First Page

603

Last Page

613

MeSH Keywords

Adolescent; Adult; Antibodies, Monoclonal, Humanized; CD3 Complex; Child; Diabetes Mellitus, Type 1; Disease Progression; Double-Blind Method; Exanthema; Female; Glucose Tolerance Test; HLA-DR3 Antigen; HLA-DR4 Antigen; Humans; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Proportional Hazards Models; T-Lymphocytes; Young Adult

Keywords

Adolescent; Adult; Antibodies, Monoclonal, Humanized; CD3 Complex; Child; Diabetes Mellitus, Type 1; Disease Progression; Double-Blind Method; Exanthema; Female; Glucose Tolerance Test; HLA-DR3 Antigen; HLA-DR4 Antigen; Humans; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Proportional Hazards Models; T-Lymphocytes; Young Adult

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