Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis

Abstract

Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drugtreated responders showed an increased frequency of 'partially exhausted' CD8 + T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA 1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA 1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8 + T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).

A future for CD3 antibodies in immunotherapy of type 1 diabetes

“…The TrialNet group has recruited 76 children to a placebo-controlled study designed to test the ability of teplizumab to delay onset of insulin therapy in at-risk individuals presenting with at least two autoantibodies and an abnormal OGTT but no hyperglycaemia. Importantly, it would not have been possible to allow such a large number of patients to have undergone this therapy had it not been for the favourable safety profile of teplizumab, a major feature that is confirmed by the results of the 7 year follow-up study described here [27].…”

“…<7.5% difference between the two values, as used previously in some clinical studies. The authors found that, overall, C-peptide levels were not significantly different between drug-treated patients and control participants during the MMTT; however, C-peptide levels were higher in drug-treated responders (identified at 1 year) than in control participants and drug-treated non-responders [27]. The question of the real clinical meaning of this difference in C-peptide is important given that it was not associated with better glycaemic control or a decrease in insulin requirements.…”

“…In this issue of Diabetologia, an article by Perdigoto et al provides further insight into the use of teplizumab for the treatment of type 1 diabetes, presenting the longterm follow-up (7 years on average, range up to 9 years) results of the AbATE trial [27]. This new study was designed at the conclusion of AbATE (2 years post-treatment) and data were available on 43 (56%) of the 77 participants in AbATE (31 in the treatment group and 12 in the control group).…”

miR-409-3p is reduced in plasma and islet immune infiltrates of NOD diabetic mice and is differentially expressed in people with type 1 diabetes

“…In conclusion, circulating plasma-borne miR-409-3p may represent a candidate biomarker of islet inflammation in both type 1 diabetic mice and humans and could be potentially useful for serial tracking of islet inflammation or response to immune therapies, such as teplizumab aCD3 therapy, in intervention and prevention trials [50,51].…”

New era of therapy for endocrine autoimmune disorders

“…Teplizumab (mAbs against CD3 with mutated Fc-chain) has recently been shown to slow down progression of T1D in high-risk groups. [97][98][99][100][101][102] The long-term effects were due to Teff depletion and enhanced Treg activity. The drug is now in phase 3 trials for T1D in the PROTECT study (NCT03875729; https://www.type1 diabe tesre search.org.uk/curre nt-trial s/ prote ct-study/).…”