Anti-CD3 treatment in type 1 diabetes

Bart Keymeulen Academisch Ziekenhuis and Diabetes Research Center -Brussels Free University-VUB, Brussels, Belgium

Abstract Type 1 diabetes is caused by an immune mediated destruction of the insulin-secreting beta cells in the pancreas. The disease can become clinically apparent at any age. At diagnosis, there is invariably some residual beta cell function and more so in adults than in children. Recent studies - including one mainly conducted in Belgium - have provided proof of principle that short-term anti-T-cell antibody treatment is able to preserve residual beta cell function for at least 18 months. The resultant stabilizing effect on metabolic control is expected to delay or limit chronic complications in these patients. The ultimate goal is prevention of clinical disease. Studies by the Belgian Diabetes Registry and others in first degree family members of type 1 diabetic patients have refined identification of individuals at very high risk of hyperglycemia so that new immunological treatments can be tested in the prediabetic phase. Tertiary prevention of type 1 diabetes in C-peptide positive patients at clinical onset During the last decade, encouraging outcomes in terms of beta cell function have been reported when experimental treatment is given at clinical onset of the disease This .prevention strategy aims to safeguard the patient from chronic complications of the disease. A substudy of the DCCT provided strong evidence that preservation of beta cell function not only results in improved glucose control, and consequently fewer chronic complications such as retinopathy and incipient nephropathy but also leads to a lower incidence of severe hypoglycaemic events (1). Following the hypothesis that Type 1 diabetes is an autoimmune disorder that involves the killing of beta cells by cytotoxic T-lymphocytes, a wide range of immunosuppressive or immunomodulating agents have been tested at clinical onset in small, poorly controlled pilot trials. Demonstration of both the feasibility and effectiveness of this approach was first provided by the usage of cyclosporine. This calcineurin-inhibitor was the first immunosuppressive agent that was used in placebo-controlled, double-blind clinical trials (2;3). Beta-cell function was preserved by daily intake of cyclosporine during the first 12 months. However, the benefit was lost after withdrawal from the drug, implying a need for the indefinite administration of cyclosporine, with attendant risks of chronic immunosuppression and calcineurin nephrotoxicity. An alternative approach consists of short-term intravenous administration of monoclonal antibodies directed at the CD3-complex that is present on all T-lymphocytes. The first on the market, OKT3, was a mouse IgG2a that was successfully used to treat and prevent renal allograft rejection (4). However, the associated major cytokine-release syndrome excluded its use in recent onset type 1 diabetic patients (5). Because of its high antigenic nature, OKT3 also stimulates the production of neutralizing antibodies that may decrease the efficiency of OKT3 after a few injections. L. Chatenoud et al administered during 6 consecutive days monoclonal antibodies against mouse CD3 to NOD mice with recent overt hyperglycemia and was thereby able to obtain long-term remission in 80 percent of the animals. These studies provided the basis for development of monoclonal anti-CD3 antibodies with a better safety profile (6). Human engineered anti-CD3 antibodies that do not produce a full cytokine-release syndrome and that are less antigenic are now available. To achieve this, two mutations were introduced into the Fc portion of the humanised version of OKT3, giving rise to OKT3?1 Ala-Ala (7). Another antibody, ChAglyCD3, derived from the rat YTH 12.5 antibody, contains a single mutation that prevents glycosylation of its ?1 Fc portion (8). With OKT3?1 Ala-Ala, a phase 1 study in children and adults was performed in the United States with promising results, although some concern was expressed since the study was not blinded (7). Because glycemic control was not standardized and HbA1c concentrations were higher in the control group, residual beta cell function could have been underestimated in this group due to presumed glucotoxicity (7).. The Belgian Diabetes Registry together with Schwabing Hospital in Munich (A. Ziegler) therefore performed a multicenter placebo-controlled phase 2 trial including 80 patients randomly assigned to receive placebo or ChAglyCD3 for 6 consecutive days (9). Only autoantibody positive patients between the ages of 12 and 39 years who had been undergoing insulin treatment for less than 4 weeks, and who had basal C-peptide levels greater than 0.60 ng/ml, were included. These entry criteria ensured that patients with type 1 diabetes who had already experienced a major loss of beta cell function when diagnosed did not participate. Beta cell function was assessed with a hyperglycemic clamp every 6 months. Results showed that up to 18 months post-treatment residual beta?cell function was better maintained in antibody-treated patients than in those who were given placebo. Importantly, both treatment groups had comparable HbA1c concentrations of less than 7% during the whole treatment period. To maintain this level of glucose control, ChAglyCD3 treated patients needed less insulin than placebo-treated patients. Follow-up of this study, which has been extended to 48 months, will reveal whether the ChAglyCD3 treatment effect is maintained. Another interesting aspect of this study is the finding that ChAglyCD3 was particularly effective in those among the 80 patients who initially had the highest residual beta-cell function (9). The fact that ChAglyCD3 appears predominantly effective when substantial residual beta cell function is present may limit its routine clinical use, as injecting the CD3 monoclonal antibody with potential side-effects may be ineffective if the beta cell function is too low. Adverse events caused by anti-CD3 treatment will be better assessed in phase 3 trials that are underway. In the phase 2 study, 6 consecutive doses of 8 mg of ChAglyCD3 treatment resulted in a limited cytokine related flu syndrome in virtually all patients, especially after the first two infusions, but these side-effects never necessitated stopping or delay of treatment (9). Future studies should assess whether similarly effective anti-CD3 treatment can be obtained with lower doses in adults and in children. In the phase 2 study, which included only subjects with a history of Epstein Barr virus (EBV) infection, confirmed by their EBV IgG positive status, a reactivation of EBV was observed 10-20 days after the first injection. An increase in EBV copies in peripheral blood mononuclear cells was measured and 75 percent of patients had symptoms of infectious mononucleosis. Within 1-3 weeks all patients were asymptomatic and the number of EBV copies returned to normal baseline pre-treatment levels. Concomitantly, a cellular and humoral immune response specific to EBV was measured, comparable to that observed in normal subjects who develop acute infectious mononucleosis (9). At the present time, no lymphoma, PTLD like disease or other serious adverse events related to treatment, have been reported. It is unclear whether the EBV related disease resulting from anti-CD3 treatment is triggered by the cytokines released during the first days of treatment or by other mechanisms. The question of whether the induction of virus-antigen-specific CD8+ T cells is implicated in the maintenance of residual beta cell function must also be answered. The mechanisms of action of human anti-CD3 antibodies remain unclear. From experiments in NOD mice, it can be speculated that induction of so-called regulatory CD4+CD25+ T cells play a decisive role and may help to restore self-tolerance to ?beta ?cell autoantigens without triggering generalized immune suppression (10). Perspectives Provided that anti-CD3 treatment is also safe in children, it may be reasonable to attempt this therapy in children and adults with a very high risk of developing clinical disease (11-13). The promising results of experimental interventions at clinical onset in insulin-requiring type 1 diabetes may also be of interest for a subgroup of diabetic patients that is frequently misdiagnosed as suffering from type 2 diabetes. These individuals have no insulinopenic symptoms at clinical diagnosis, are frequently older than 40 years of age and show evidence of autoantibodies (14;15) GADA is the most frequently occurring autoantibody, followed by ICA. The disease of these autoantibody-positive type 2 diabetics is often termed latent autoimmune diabetes in adults (LADA). This group of patients comprises approximately 10-15% of Caucasian "type 2" diabetes patients (16). In the United Kingdom Prospective Diabetes Study (UKPDS), the LADA patients entering this study were estimated to have approximately 50% of the residual beta cell secretory capacity. The natural course of these patients shows that C peptide will decrease with time in these patients in parallel with the curve for C peptide in classical type 1 diabetic patients. Most of the LADA patients will require insulin injections for appropriate glucose control within 6 years after clinical diagnosis (17). 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