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

Abstract

NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B (9À23) ), an epitope recognized by inflammatory interferon-g-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recentonset 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 (9À23) 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 (9À23) 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 dosedependently 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.

Immunotherapy of type 1 diabetes — How to rationally prioritize combination therapies in T1D

“…While those strategies have been shown to mediate a powerful effect in mice [22][23][24], the clinical trials that have been completed did not observe such effects in humans [25,26]. However, several trials are still ongoing and might bring more promising results (NCT00057499 and NCT00453375).…”

Inverse vaccination with islet autoantigens to halt progression of autoimmune diabetes

“…Furthermore, using an IFN-g directed ELISpot assay, the authors were able to estimate the frequency of B-(9-23)-specific T cells in freshly isolated peripheral lymphocytes, finding that these cells were more prevalent in both recentonset T1D and prediabetic first degree relatives than controls [Alleva et al, 2001]. These results were pursued with a Phase I clinical trial examining safety and tolerability of a subcutaneous regimen of the altered peptide ligand insulin [A16,19]B-(9-23) (NBI-6024) in a multicenter, placebo-controlled, doubleblind trial in recent-onset T1D patients [Alleva et al, 2006]. The study examined 32 T1D patients, stratified into adolescent and adult cohorts, subcutaneously injected 5 times biweekly with 0.1, 1 or 5 mg NBI-6024 (or placebo), and used ELISpot assays to examine stimulatory effects of B-(9-23) or NBI-6024 on Th1 (IFN-g) and Th2 (IL-5) cytokine responses of peripheral blood mononuclear cells.…”

“…The study examined 32 T1D patients, stratified into adolescent and adult cohorts, subcutaneously injected 5 times biweekly with 0.1, 1 or 5 mg NBI-6024 (or placebo), and used ELISpot assays to examine stimulatory effects of B-(9-23) or NBI-6024 on Th1 (IFN-g) and Th2 (IL-5) cytokine responses of peripheral blood mononuclear cells. Longitudinal analysis of cytokine responses over 26 weeks showed a great degree of variability in both IFN-g and IL-5 responses, but significant effects of treatment over placebo were observed at certain sampling time points, with the authors concluding ''analysis strongly suggests that [altered peptide ligand] administration induced, predominantly, Th2 responses to both the endogenous B-(9-23) epitope and NBI-6024'' [Alleva et al, 2006]. In general, there was a trend toward a dose-dependent conversion of Th1 to Th2 phenotypes in [A16,19]B-(9-23) treated T1D patients, and no treatment-related adverse effects.…”

Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes

“…Additional trials to test the safety and efficacy of insulin peptides are ongoing. A Phase I trial in which a modified insulin B9-23 peptide (altered peptide ligand) was administered subcutaneously to normal individuals and new onset patients has shown no major safety concerns [103]. It also appears that the altered peptide induced a Th2 bias, which may inhibit T-cell responses, while data on overall efficacy are not presently available.…”