Type 1 diabetes (T1DM) is a chronic autoimmune disease that leads to destruction of insulin producing beta cells, which leaves the patient dependent on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in T1DM, but interventions to prevent clinical progression before T1DM onset are not yet available.

© 2015 by the American Diabetes Association.Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying

DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Supplement 1, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.1510 ORIGINAL ARTICLE Immune Intervention for Type 1 Diabetes, 2012–2013 Jay S. Skyler Introduction Results T Teplizumab (14-day full dose) reduced the loss of C-peptide mean area under curve (AUC; a prespecified secondary end- point) at 2 years versus placebo. In analyses of subsets at entry, U.S. residents, patients with C-peptide mean AUC > 0.2 nmol/L, those randomized < 6 weeks after diagnosis, HbA1c < 7.5% (58 mmol/mol), insulin use < 0.4 U/kg/day, and ages 8–17, each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be re- duced versus placebo. Antidrug antibodies developed in some patients without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. his chapter of the ATTD 2013 Yearbook reviews the key articles that have appeared between July 2012 and August 2013 in the area of immune intervention in type 1 diabetes. Also included are two studies dealing with beta-cell regen- eration or replacement. The first three studies discussed deal with anti-CD3 monoclonal antibody therapy. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial Hagopian W 1 , Ferry RJ Jr 2 , Sherry N 3 , Carlin D 4 , Bonvini E 4 , Johnson S 4 , Stein KE 4 , Koenig S 4 , Daifotis AG 4 , Herold KC 5 , Ludvigsson J 6 ; for the Prote´ge´ Trial Investigators Pacific Northwest Diabetes Research Institute, Seattle, WA; 2 Divi- sion of Pediatric Endocrinology and Metabolism, Le Bonheur Chil- dren’s Hospital and University of Tennessee Health Science Center, Memphis, TN; 3 Massachusetts General Hospital, Boston, MA; MacroGenics, Rockville, MD; 5 Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; and 6 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden Conclusion Anti-CD3 therapy reduced C-peptide loss and thus pre- served b-cell function for 2 years. Diabetes 2013 Jun 25: [Epub ahead of print]; DOI: 10/2337/db13-0236 Background Two years ago we discussed the 1-year results of the Prote´ge´ phase 3 study using teplizumab. The primary outcome measure—a composite of the percentage of patients with in- sulin use of < 0.5 U/kg per day and HbA1c of < 6.5% at 1 year— was not met. However, exploratory analyses suggested that teplizumab could help preserve b-cell function—as measured by C-peptide—at 1 year, particularly in subgroups such as children. This report describes the 2-year results from this study. Methods Of the 516 subjects randomized, 462 completed 2 years of follow-up. Treatment was given both at study entry and 6 months later. Comment Previous reports have shown that a short course of hu- manized anti-CD3 monoclonal antibody—either with teplizumab or otelixizumab—preserved b-cell function as measured by C-peptide. The Prote´ge´ study selected a different primary outcome measure—a composite of the percentage of patients with insulin use of < 0.5 U/kg/ day plus HbA1c of < 6.5% at 1 year. That outcome was not met, and thus many have labeled the Prote´ge´ study a failure. Yet, in the original report, teplizumab was found to preserve b-cell function at 1 year. The current article demonstrates that this effect was maintained at 2 years. As noted in our earlier discussion of the 1-year results, there was no prior basis for the outcome measure se- lected. Moreover, taking two continuous variables (in- sulin use and HbA1c) and converting them to a single combined dichotomous variable reduces the statistical power of assessment of continuous variables. The C- peptide results, both at 1 year and at 2 years, highlight the problem. Thus, although the original primary outcome was not met, we are still learning from the Prote´ge´ study. Division of Endocrinology, Diabetes, & Metabolism, and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL. S-85

Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3 gamma 1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 9.6% of response at study entry in drug-treated patients vs. 53 +/- 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA(1c), and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8(+) T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3 gamma 1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.

BACKGROUND:Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.METHODS:We studied the effects of a nonactivating humanized monoclonal antibody against CD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease.RESULTS:Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment.CONCLUSIONS:Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.