Enhanced peptide immunotherapy – interim report of first-in-man delivery of proinsulin peptide attached to gold nanoparticles

Background. Peptide immunotherapy aims to induce the tolerance to beta-cell antigens and stop beta-cell destruction in Type 1 diabetes (T1D). Proinsulin peptide C19-A3 is safe and potentially effective in modulating autoreactive CD4+ T-cells and preserving beta-cell function. Methods. Our aim is to facilitate this effect by attaching C19-A3 onto gold nanoparticles (GNPs) (Midatech Pharma, Midacore®), which are delivered into the skin using hollow microneedles (Nanopass MJ600). We hypothesise that minimally-invasive delivery of the construct will enhance C19-A3 uptake into skin antigen-presenting cells and promote tolerance. This open-label uncontrolled single group Phase-1A safety study involves participants with long-standing T1D aged 18-40 who will have 3 doses of C19-A3 GNP (10μg peptide) administered into the upper arm every 28 days. Results. The first participant was a 33 year old male with a 10 months history of T1D. The participant maintained good glycaemic control (Hb1Ac 40 vs 44 mmol/l) and low insulin requirements (0.37 vs 0.45 Units/kg) with a reduction in Mixed Meal stimulated AUC C-peptide (0.68 vs 0.21 nM/min) before and after treatment. No systemic reactions nor blood test abnormalities were evident. In all five recruited participants thus far (1 completed, 1 withdrew for non-study related reasons and 3 still in the study), initial local skin reaction developed approximately 3 weeks post injection. The reaction consisted of a small central area of GNP-derived pigmentation surrounded by an asymptomatic erythematous induration (1cm), which partially faded during the several months long observation. Histopathology showed T-cell infiltrate (equal distribution of CD4+ and CD8+) with some B-cells and histiocytes. This suggests potential prolonged skin retention of the GNP construct, possibly attracting antigen specific T-cells, which could have implications for tolerance induction. Recruitment continues.