Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals

Abstract

We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml; P = 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1+TIGIT+CD8+ T cells (r = 0.44, P = 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8+ T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy.

Timing of Immunotherapy in Type 1 Diabetes: The Earlier, the Better?

“…Extended follow-up of this trial examined the metabolic and immune implications of teplizumab treatment and found that, in addition to modulating pathogenic T cell signatures, treatment with teplizumab improved b cell function as measured by C-peptide responses and insulin secretion rates (26). Improvements in b cell function were accompanied by increased frequencies of TIGIT 1 KLRG1 1 memory CD8 1 T cells and decreased secretion of inflammatory cytokines, supporting CD8 1 T cell functional exhaustion as a mechanism of action.…”

“…Median time to T1D diagnosis in the teplizumab-treated group was 5 y, compared with 2 y in the placebo group. Of the 44 participants randomized to the teplizumab group, eight remained disease free (18%) over 5 y after treatment compared with only two of the initial 32 participants randomized to the placebo group (6%) (26).…”

“…The results of the teplizumab trial call to question the prioritizing of immunomodulatory agents that show efficacy at disease onset for prevention trials (10,27). In follow-up analysis of responders compared with nonresponders, teplizumab was most effective in individuals whose responses to the oral glucose tolerance test at baseline were below the median, suggesting that teplizumab works best in individuals with more advanced disease and that efficacy is not improved with earlier intervention in individuals with stage 2 T1D (26). Teplizumab selectively targets CD8 1 effector T cells; therefore, it may not be efficacious at an earlier stage when CD8 1 T cells are playing a lesser role in disease pathogenesis (Fig.…”

Inflammasomes and Type 1 Diabetes

“…However, a study combining anti-CD3 treatment with either Anakinra or an anti-IL-1β antibody resulted in reversal of diabetes in recent-onset T1D NOD mice ( 142 ), suggesting that combined therapy may also improve clinical efficacy in humans. Given the success of Teplizumab (anti-CD3) in delaying the development of T1D in relatives at risk ( 143 , 144 ), a combined study evaluating the role of Teplizumab with IL-1 blockade may further enhance clinical efficacy. It is intriguing that NLRP3-deficient NOD mice were protected from T1D, while IL-1 receptor-, Caspase-1/11-, IL-1β- and IL-18-deficient NOD mice were not.…”

Historical and new insights into pathogenesis of type 1 diabetes (2)

“…While several biologicals have been trialled in human type 1 diabetes, recently discussed by Ke and colleagues [7], there have been few immunological interventions that have had a lasting effect when administered after diabetes onset. Most recently, anti‐CD3 (teplizumab) presents exciting promise – when administered in autoantibody‐positive individuals, the onset of overt type 1 diabetes has been delayed [8]. Thus, an ability to predict who will develop disease will be critical [9] and appreciating the largest context, including the multiple players in this process, will be vital for the development of future therapeutics.…”