Immunomodulation in Type 1 Diabetes by NBI‐6024, an Altered Peptide Ligand of the Insulin B(9−23) Epitope

Neurocrine Biosciences, Inc., San Diego, CA 92130, USA.
Scandinavian Journal of Immunology (Impact Factor: 1.74). 02/2006; 63(1):59-69. DOI: 10.1111/j.1365-3083.2005.01705.x
Source: PubMed

ABSTRACT NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B(9-23)), an epitope recognized by inflammatory interferon-gamma-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9-23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9-23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.

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Available from: Rich A Maki, Oct 16, 2014
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    • "Different approaches have been used, including, theoretically, favoring presentation of auto-antigens by tolerogenic APCs, altering the TCR recognition of its cognate antigen in autoreactive cells and/or the skewing of the T-cell response from pathogenic Th1 cells to protective Th2 cells. So far, some phase I and II clinical trials have shown efficacy in maintaining C-peptide levels and inducing favorable immune parameters such as decreased Th1/Th2 ratio and increased Tregs and TGF-b (Agardh et al. 2005; Alleva et al. 2006; Ludvigsson 2009; Orban et al. 2010; Ludvigsson et al. 2011). Currently available data on the outcome on disease progression have shown either no effect or encouraging results such as improved C-peptide and HbA1C levels and decreased insulin need, and the clinical benefits were but short-lived. "
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    ABSTRACT: Type 1 Diabetes (T1D), also called juvenile diabetes because of its classically early onset, is considered an autoimmune disease targeting the insulin-producing β cells in the pancreatic islets of Langerhans. T1D reflects a loss of tolerance to tissue self-antigens caused by defects in both central tolerance, which aims at eliminating potentially autoreactive lymphocytes developing in the thymus, and peripheral tolerance, which normally controls autoreactive T cells that escaped the thymus. Like in other autoimmune diseases, the mechanisms leading to T1D are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in the breakdown of peripheral tolerance. In this article, we discuss the contribution of these factors in the development of the autoimmune response targeting pancreatic islets in T1D and the therapeutic strategies currently being explored to correct these defects.
    Cold Spring Harbor Perspectives in Medicine 03/2012; 2(3):a007807. DOI:10.1101/cshperspect.a007807 · 9.47 Impact Factor
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    • "This B9–23 APL showed promising results in NOD mice [75]. Results of a Phase I clinical study on recent-onset T1D patients suggested that NBI-6024 treatment shifted Th1 responses to a Th2 phenotype [76]. However, a subsequent Phase II, dose-ranging trial testing repeated NBI-6024 subcutaneous treatment at 0.1, 0.5, or 1 mg did not preserve β-cell function [77]. "
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    ABSTRACT: The ideal drug of modern medicine is the one that achieves its therapeutic target with minimal adverse effects. Immune therapy of Type 1 diabetes (T1D) is no exception, and knowledge of the antigens targeted by pathogenic T cells offers a unique opportunity towards this goal. Different antigen formulations are being considered, such as proteins or peptides, either in their native form or modified ad hoc, DNA plasmids, and cell-based agents. Translation from mouse to human should take into account important differences, particularly in the time scale of autoimmune progression, and intervention. Critical parameters such as administration route, dosing and interval remain largely empirical and need to be further dissected. T1D staging through immune surrogate markers before and after treatment will be key in understanding therapeutic actions and to finally turn ordinary blanks into magic bullets.
    Clinical and Developmental Immunology 05/2011; 2011(1740-2522):286248. DOI:10.1155/2011/286248 · 2.93 Impact Factor
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    ABSTRACT: Type 1 diabetes mellitus results from a loss of insulin-producing beta-cells in the pancreatic islets caused by an immune-mediated chronic destructive process. It is generally believed that immune tolerance to beta-cells is broken by environmental factors in genetically susceptible individuals, leading to beta-cell destruction that is mediated by T lymphocytes. A key assumption in the current pathogenic concept of type 1 diabetes is a defective immunoregulation affecting both central and peripheral mechanisms of tolerance induction against beta-cell antigens. In animal models of type 1 diabetes, disease-protective modulation of the islet autoimmune response can be effected by various strategies including administration of islet antigens. In human type 1 diabetes, therefore, new strategies are currently being developed with the aim of actively suppressing the autoimmune process and inducing a lasting tolerance against islet antigens. In this context, inducing regulatory T cells in vivo (i.e. CD4(+)CD25(+) T cells or type 1 regulatory T cells) is currently becoming more widespread. The following report highlights some of the recent studies on immunotherapy of type 1 diabetes, presented at the 64(th) Scientific Sessions, held in June 2004, in Orlando, Florida.
    The Review of Diabetic Studies 02/2004; 1(3):137-40. DOI:10.1900/RDS.2004.1.137
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