Abstract

Background Pemphigus vulgaris (PV) is a CD4+ T-cell-dependent autoantibody-mediated blistering disease associated with human leucocyte antigen (HLA) class II molecules. IgG autoantibodies against the primary autoantigen desmoglein 3 (Dsg3), a desmosomal adhesion protein on epidermal keratinocytes, cause loss of epidermal cell adhesion. Objectives To assess the clinical applicability of an innovative nanoparticle platform for the induction of immune tolerance exploiting the natural tolerance potential of liver sinusoidal endothelial cells. An open-label first-in-human study was conducted with TPM203, a mixture of four nanoparticle-coupled immunodominant Dsg3 T-cell peptides. Methods The efficacy and mechanism of action of TPM203 were first tested in a humanized HLA-DRB1*0402-transgenic PV mouse model. In the clinical phase I trial, TPM203 was administered intravenously in patients with PV with no-to-moderate disease activity in single ascending and multiple doses (three doses of TPM203 two weeks apart). Primary endpoints included safety and tolerability. As a secondary endpoint, pharmacokinetics were assessed. Exploratory endpoints comprised changes in Dsg3-specific and bulk T- and B-cell frequencies, anti-Dsg3 IgG levels and autoantibody-induced keratinocyte dissociation. The trial was registered with EudraCT (2019-001727-12). Results In the PV mouse model, two administrations of TPM203 significantly reduced anti-Dsg3 IgG. On the cellular level, TPM203 led to a significant decrease in CD4+ T cells in the spleen, accompanied by increased frequencies of regulatory T (Treg) cells. In the clinical trial, the 17 patients with PV enrolled across single- and multiple-dose groups did not experience any serious or severe adverse events, or treatment-related PV worsening. Pharmacokinetics confirmed rapid TPM203 clearance from the circulation. Significant TPM203-induced modulations in bulk lymphocyte subsets included an increase in Treg cells, and reductions in T helper 17.1 and CD27+ memory B cells, when dose groups were combined for analysis. Dsg3-specific T cells were found to be significantly reduced at week 8 following single administration of TPM203. Anti-Dsg3 IgG levels trended downward in the three lower single ascending dose groups, while IgG-induced keratinocyte-dissociating capacity was significantly reduced after multiple doses. Conclusions Administered for the first time in humans, TPM203 was shown to be a safe and well-tolerated nanoparticle-based therapeutic approach with the potential to promote tolerance induction in PV, justifying further clinical development in this and other autoimmune diseases.