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

Abstract

BACKGROUNDType 1 diabetes is a chronic autoimmune disease that leads to destruction of insulinproducing 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. METHODSWe 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. RESULTSA 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. TIGIT+KLRG1+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONSTeplizumab delayed progression to clinical type 1 diabetes in high-risk participants.

Antibodies to watch in 2020

“…A single 14-day course of teplizumab significantly delayed the onset and diagnosis of clinical T1D, as compared to placebo, with median times to the diagnosis of type 1 diabetes of 48.4 months in the teplizumab group and 24.4 months in the placebo group. 89 Provention Bio is currently evaluating teplizumab in the Phase 3 PROTECT study (NCT03875729) to determine whether teplizumab slows the loss of β cells and preserves β cell function in children and adolescents 8-17 years old who have been diagnosed with T1D in the previous 6 weeks. Estimated enrollment for the PROTECT study is 300 patients, and the estimated primary completion date is May 2022.…”

Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type1 diabetes therapeutic reversal in preclinical models

“…Our data suggests that contrast-enhanced ultrasound measurement of pancreas blood flow dynamics could be a viable approach to predict successful prevention of diabetes when treated during the asymptomatic phase of T1D. This is critically important, given heterogeneous or incomplete responses to therapeutic reversal [3] or prevention [2] of T1D in human trials and the lack of any approach presently that can predict the therapeutic reversal of T1D [20]. While autoantibodies can be used to predict onset of diabetes [4], it is unclear whether they can be used to predict therapeutic prevention.…”

“…Detecting T1D remission achieved by antiCD3 therapy-While we could predict disease progression upon CD4+ T cell depletion, antiCD4 is not a viable therapy for T1D. We next tested whether we could predict prevention or delay of T1D upon an immunotherapy, antiCD3, that has been demonstrated to successfully delay β-cell decline at onset and prevent T1D prior to onset in clinical studies [2,12,13]. AT mice were treated at 2 weeks of age with 5 daily doses antiCD3 (clone 145-2C11).…”

“…This asymptomatic phase presents a window in which preventative therapeutic intervention can be made, while significant β-cell mass remains [1]. Indeed, recent clinical trials have demonstrated successful delay of diabetes when applied during this asymptomatic phase [2]. However, responses to therapeutic treatments are often heterogeneous, with only a subset of subjects showing a significant delay in β-cell decline (responders) [3].…”

Islet–immune interactions in type 1 diabetes: the nexus of beta cell destruction

“…Indeed, therapies targeting effector T cells for depletion [25] and those inhibiting T cell co-stimulation [26] successfully prevented immune cell infiltration of the pancreatic islets and symptomatic diabetes in NOD mice hundreds [27] of times and reversed in a handful of studies [28][29][30]. In contrast, clinical trials of anti-CD3 [31,32], anti-thymocyte globulin (ATG) [33][34][35], abatacept (CTLA4-Ig) [36], and alefacept (LFA-3/IgG1) [37] have, at best, provided only temporary preservation of baseline C-peptide production in subgroups of T1D patients while anti-CD3 was recently reported to delay T1D onset in at-risk individuals [38]. Though an indepth analysis of the contributions of animal models is beyond the scope of this review, Table 1 summarizes a selection of key findings relevant to human disease made possible by in vivo models.…”