Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial

Abstract

Aims/hypothesis Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. Methods In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4–12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. Results Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p=0.03), when corrected for baseline imbalances in HbA1c levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p=0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p=0.03). The teplizumab group required less exogenous insulin (p<0.001) but treatment differences in HbA1c levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HgbA1c <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders. Conclusions/interpretations This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. Trial registration ClinicalTrials.gov NCT00378508 Funding This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes

“…With the exception of the anti-CD3 mAb teplizumab, which demonstrated preservation of C-peptide in patients with T1D 4 to 12 months after diagnosis (22), low-dose ATG/G-CSF remains the only other approach known to preserve C-peptide in patients with established T1D and, importantly, it extends the observation to patients with durations of T1D of nearly 2 years. In addition, the effect of ATG/G-CSF was the same when comparing patients with disease duration of less than or greater than 1 year.…”

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

“…Therefore, monotherapies have proven not to be particularly successful (23,(38)(39)(40) even with the most promising antibodies, anti-CD3 in humans and mice and in analogy anti-TCR in rats (25,27,28,(41)(42)(43)(44). We report here a successful combination therapy for T1D in the IDDM rat, an animal model of human T1D (25), using two antibodies with different target profiles.…”

Microbiota control immune regulation in humanized mice

“…In patients with type 1 diabetes treated with teplizumab, an increase in CD8CM T cells is a biomarker of responses to the drug (20,22). CD8CM T cells were increased in the mesenteric lymph nodes of the humanized mice treated with teplizumab ( Figure 5B, P = 0.049) but not when they received antibiotics (Supplemental Figure 3, P = 0.03).…”