Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes

Carolina Digital Repository (University of North Carolina at Chapel Hill)

Abstract

In type 1 diabetes (T1D) an intense inflammatory response destroys β cells in the pancreas, where insulin is produced and released. A therapy for T1D that reduces the specific autoimmune response in this disease while leaving the remainder of the immune system intact has long been sought. Proinsulin is a major target of adaptive immunity in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve β cell function in T1D patients through reduction of insulin-specific T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide served as an exploratory measure of efficacy and safety. Islet-specific CD8+ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides containing pancreatic or unrelated antigens. No serious adverse events related to BHT-3021 occurred. C-peptide levels improved relative to placebo at all doses, most notably at 1 mg at 15 weeks (+19.5% BHT-3021 versus −8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8+ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8+ T cells reactive to proinsulin while preserving C-peptide over the course of dosing.

Authors 17

1. Lawrence Steinman Aachen

   Leiden University

   Affiliation as printed

   Leiden University

2. Josephine Quan

   Foothill College

   Affiliation as printed

   Foothill College

3. Paul J. Utz

   University of Colorado Denver

   Affiliation as printed

   University of Colorado Denver

4. William H. Robinson Aachen

   Leiden University

   Affiliation as printed

   Leiden University

5. William Hagopian

   Walter and Eliza Hall Institute of Medical Research

   Affiliation as printed

   Walter and Eliza Hall Institute of Medical Research,

6. Joaquim Abreu

   University of Colorado Denver

   Affiliation as printed

   University of Colorado Denver

7. Matthias von Herrath

   University of Colorado Denver

   Affiliation as printed

   University of Colorado Denver

8. Peter A. Gottlieb
   Affiliation as printed

   Bayhill Therapeutics

9. Michael W. Leviten
   Affiliation as printed

   Pacific Northwest Research Institute

10. Hideki Garren
    Affiliation as printed

    University of North Carolina

11. Nanette W. Solvason

    La Jolla Institute for Immunology

    Affiliation as printed

    La Jolla Inst. for Allergy and Immunology

12. Liping Yu
    Affiliation as printed

    Bayhill Therapeutics

13. Bart O. Roep
    Affiliation as printed

    Bayhill Therapeutics

14. Richard S. King

    Stanford University

    Affiliation as printed

    Stanford University

15. Leonard Charles Harrison

    Stanford University

    Affiliation as printed

    Stanford University

16. John Buse J.B. Buse
    Affiliation as printed

    Bayhill Therapeutics

17. George S. Eisenbarth

    Stanford University

    Affiliation as printed

    Stanford University