Results from the Anti-CD3 mAb (teplizumab) prevention trial
Kevan Herold, MD
Department of Internal Medicine, Yale University, New Haven, CT, USA
Peter S. Linsley, PhD
Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
Immune interventions such as the anti-CD3 monoclonal antibody teplizumab are considered promising in delaying decline in beta-cell function.
A single two-week course of treatment with teplizumab delayed progression to clinical type 1 diabetes in relatives of patients with type 1 diabetes who were at high-risk for development of disease by a median of 2 years.
This is the first trial to demonstrate that immune therapy can delay the onset of type 1 diabetes.
Several immune interventions in patients with recent-onset clinical type 1 diabetes have been reported to delay the decline in beta-cell function. Fc receptor–nonbinding anti-CD3 monoclonal antibodies, such as teplizumab, appear to show promise, and studies in patients with type 1 diabetes have suggested that teplizumab reduces loss of beta-cell function, although it is unclear if interventions at stage 1 or 2 can alter progression to clinical type 1 diabetes.
Eligible participants were nondiabetic relatives of patients with type 1 diabetes and at least 8 years of age at the time of randomisation and at high risk for development of clinical diabetes.
Participants had to have had two or more diabetes-related autoantibodies detected in two samples obtained within 6 months before randomisation.
Participants had to have had evidence of dysglycaemia by oral glucose-tolerance test (fasting glucose 110-125 mg/dL), 2-hour postprandial plasma glucose 140-200 mg/dL, or an intervening postprandial glucose level at 30, 60, or 90 minutes >200 mg/dL on two occasions, within 52 days before enrolment.
Total patients randomised: 76.
Patients were randomly assigned to a single 14-day course of teplizumab or placebo.
Teplizumab (n = 44).
Placebo (n = 32).
Primary outcome measure
Elapsed time from randomisation to clinical diagnosis of type 1 diabetes with American Diabetes Association criteria.
Median time to diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group.
Type 1 diabetes was diagnosed in 19 (43%) of participants who received teplizumab and in 23 (72%) of those who received placebo.
The hazard ratio for diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% CI, 0.22-0.78; P = 0.006).
Annualised rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group.
As expected, rash and transient lymphopenia were observed.
TIGIT+KLRG1+ CD8+ T cells were more common with teplizumab vs placebo.
Among 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.