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


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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    • "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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