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. An author video to accompany this article is available online.
Pemphigus is a rare but potentially life-threatening disease. It causes blisters to form on the skin, mouth and genitals. It can lead to the loss of body fluids and proteins. It is also associated with severe infections. Blisters are caused by ‘autoantibodies’ (misguided defence proteins in the immune system) that bind to a component of the skin called Dsg3. The autoantibodies are produced by specialized immune cells known as ‘B cells’ with the help of another group of immune cells called ‘T cells’. These cells play an important role in starting autoimmune responses. In this study, we tried to block the effects of T cells in pemphigus. We did this using ‘nanoparticles’ to deliver pieces of Dsg3 to the liver. These nanoparticles have the potential to inhibit (or stop) the misdirected immune response. We carried out a study in Germany, Italy and the UK and gave increasing doses of Dsg3-loaded nanoparticles to a group of 17 patients with the disease. We found that the treatment was well-tolerated by the patients. They did not experience any severe side effects. We also found changes in the patients’ blood. This provided the first hints that T cells and activated B cells that promote inflammation could be blocked, leading to a decrease in pemphigus autoantibodies. Our study findings suggest that Dsg3-loaded nanoparticles should be further developed. The aim would be to treat pemphigus, and maybe even other autoimmune diseases, in a safe and specific way.
© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists.