Phase I Clinical Trial of Islet Antigen-Specific Plasmid Coexpressing Tolerogenic Proteins Demonstrates Safety in Adults With Type 1 Diabetes.

Abstract

There is significant interest in antigen-specific approaches to delaying type 1 diabetes in preclinical stages and supporting tolerance after diagnosis. We conducted a phase I trial of a nonintegrating DNA plasmid constructed to secrete the type 1 diabetes antigen preproinsulin (PPI) and the immune modulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. In this placebo-controlled, double-masked study of 47 adults with stage 3 type 1 diabetes, we showed that the drug is safe and well tolerated, with most reported adverse events (AEs) categorized as grade 1 and with no clinically significant difference in AEs among treatment groups. There were no untoward metabolic or immune effects. We found pharmacodynamic evidence of treatment, as demonstrated by a dose-dependent type 1 interferon (IFN) signature. Plasmid DNA, representing a pharmocokinetic measure, was detected in the two highest dosing groups. We did not find global or antigen-specific immune cell changes following treatment with a DNA plasmid expressing PPI, IL-2, IL-10, and TGF-β1, and we did not detect immune changes driven by IL-2, IL-10, or TGF-β1. Our results support further trials of this novel tolerizing antigen construct. Antigen-specific therapy is needed to induce tolerance in type 1 diabetes at early disease stages or in combination with immunotherapy. We conducted a phase I trial in type 1 diabetes of a novel plasmid construct expressing the islet antigen preproinsulin (PPI) and immunomodulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. The therapy was safe and well tolerated. Dose-dependent changes in DNA plasmid levels and type 1 interferon signatures were detected; however, global and antigen-specific immune changes to PPI, IL-2, IL-10, or TGF-β1 were not observed. Further trials are needed to assess efficacy.