Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years

Abstract

Anti-CD3 mAbs may prolong beta cell function up to 2 years in patients with new onset Type 1 diabetes (T1DM). A randomized open label trial of anti-CD3 mAb, Teplizumab, in T1DM was stopped after 10 subjects because of increased adverse events than in a previous trial related with higher dosing of drug. Teplizumab caused transient reduction in circulating T cells, but the recovered cells were not new thymic emigrants because T cell receptor excision circles were not increased. There was a trend for reduced loss of C-peptide over 2 years with drug treatment (p=0.1), and insulin use was lower (p<0.001). In 4 drug-treated subjects followed up to 60 months, C-peptide responses were maintained. We conclude that increased doses of Teplizumab are associated with greater adverse events without improved efficacy. The drug may marginate rather than deplete T cells. C-peptide levels may remain detectable up to 5 years after treatment.

Figure 1. Effects of teplizumab on circulating T cells

A: Changes in the absolute lymphocyte count in the peripheral blood during treatment with teplizumab. The number of circulating lymphocytes was calculated from the CBC and differential in subjects in the drug treatment group. The nadir lymphocyte count on Day 2 was 24.4± 8.4 % of the baseline count. Note that the scale on the X axis is logarithmic. The absolute lymphocyte counts in the control subjects were 94% of the baseline value at month 6 (not shown). B: Changes in the absolute number of CD4+ and CD8+ T cells during and after treatment with anti-CD3 mAb. The absolute CD4+ and CD8+ T cell counts (percentage of each subset*absolute lymphocyte count) are expressed as the percentage of the baseline value. The nadir CD4+ T cell count was lower than the nadir CD8+ T cell count (p<0.01). C and D: Copy number of TRECs in CD4+ (C) and CD8+ (D) T cells. The Y axis represents TREC copy number per million cells corrected for actin, as described in Materials and Methods. The symbols used for each subject are consistent in panels A, C, and D.

Figure 2. Effects of teplizumab treatment on clinical measures

A: C-peptide AUC to a mixed meal tolerance test: Data from individuals in the drug treated(open symbols, n=6) and control group (closed symbols, n=4). B: Extended follow up of subjects in the drug treated group (n=4). The average C-peptide responses of the drug treated (open symbol±SEM) and control (solid symbol±SEM) group at 24 months are shown for comparison. C: Insulin use by the study groups: The average (±SEM) insulin use by subjects enrolled in the study (drug treated, n=6, open symbols, and n=4 control, closed symbols, n=4) are shown. There was a significant reduction in the use of insulin in the drug treated group in a mixed effects model (p<0.001, *p<0.05 drug treated vs control). D: Hemoglobin A1c levels in the study groups: The average (±SEM) are shown for the drug treated (open symbol) and control (closed symbol) groups.

Figure 3. Relationship between C-peptide AUC and insulin use

Data from all of the time points from all of the 10 enrolled subjects are shown (open squares = drug treated) closed squares = controls) are plotted (R=-.53, p<0.0001).