A Single Course of Anti-CD3 Monoclonal Antibody hOKT3 1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

Associate Professor of Medicine, Columbia University, PH10-105, 630 W. 168th St., New York, NY 10032, USA.
Diabetes (Impact Factor: 8.1). 07/2005; 54(6):1763-9. DOI: 10.2337/diabetes.54.6.1763
Source: PubMed


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 hOKT3gamma1(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 hOKT3gamma1(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.

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Available from: Brygida Bisikirska, Jan 23, 2015
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    • "Pre-clinical [29], [38] and clinical [1], [2], [4], [5] studies point towards anti-CD3 monoclonal antibodies as the most promising intervention in newly-diagnosed mice and humans with type 1 diabetes. Particularly interesting are the pre-clinical studies indicating that when anti-CD3 is combined with antigen-specific interventions, an antigen-specific restoration of tolerance is observed [29], [30], [39]. "
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    • "In humans, clinical improvement of type 1 diabetic patients was observed after treatment with an anti-CD3 monoclonal antibody (hOKT3γ1(Ala-Ala); Teplizumab) and did not require use of any other immunosuppressive treatment during a 2-year follow-up [77]. Likewise, psoriatic arthritis patients treated with a similar anti-CD3 antibody showed better clinical outcome after a two-week treatment [78]. "
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    • "This understanding has led to interventional trials with biologic agents aimed at preserving insulin-secreting β-cells early in the course of the disease (Bluestone et al., 2010). Treatment of T1D with teplizumab or otelixizumab – monoclonal antibodies to CD3, which is present on T cells – transiently preserved insulinsecreting function in some subjects (Herold et al., 2005; Keymeulen "
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