Article

A single course of anti-CD3 monoclonal antibody hOKT3 gamma 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: 8.47). 07/2005; 54(6):1763-9. DOI: 10.2337/diabetes.54.6.1763
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
74 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m2; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. FUNDING. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.
    Journal of Clinical Investigation 12/2014; 125(1). DOI:10.1172/JCI78492 · 13.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with type 1 diabetes (T1D) rapidly lose β cell function and/or mass, leading to a life-long dependence on insulin therapy. β Cell destruction is mediated by aberrant immune responses; therefore, immune modulation has potential to ameliorate disease. While immune intervention in animal models of diabetes has shown promising results, treatment of patients with T1D with the same agents has not been as successful. In this issue of the JCI, Haller and colleagues present data from a small clinical trial that tested the efficacy of a combination of immunomodulatory agents, anti-thymocyte globulin and pegylated granulocyte CSF, neither of which have shown benefit for T1D as single treatment agents. Many patients that received combination therapy maintained β cell function at baseline levels up to a year after treatment. The results from this study challenge current trial design paradigm that for combined therapy to be successful individual agents should show benefit.
    Journal of Clinical Investigation 12/2014; 125(1):1-3. DOI:10.1172/JCI79190 · 13.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Complement is recognized as a key player in a wide range of normal as well as disease-related immune, developmental and homeostatic processes. Knowledge of complement components, structures, interactions, and cross-talk with other biological systems continues to grow and this leads to novel treatments for cancer, infectious, autoimmune- or age-related diseases as well as for preventing transplantation rejection. Antibodies are superbly suited to be developed into therapeutics with appropriate complement stimulatory or inhibitory activity. Here we review the design, development and future of antibody-based drugs that enhance or dampen the complement system. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Full-text

Download
11 Downloads
Available from
Jan 23, 2015