Combined inhibition of human plasmacytoid dendritic cell activity during systemic lupus erythematosus (SLE)

Plasmacytoid dendritic cells (pDC) are immune cells which reside in blood and lymphoid organs, but during inflammation enter tissues where they serve as a major source of type I interferons (IFN). They play roles in both protective immune responses and disease related immune responses to viral infections, and are implicated in inflammatory and autoimmune diseases like systemic lupus erythematosus (SLE). B-cell targeting therapies are the current standard treatment of SLE patients with severe disease progressions and who are irresponsive to global immunosuppressive drugs. However, these strategies fail to target plasma cells and do not reduce circulating levels of autoantibodies and immune complexes. Inhibitors against important therapeutic targets (JAK2, STAT5, SLC7A11 the subunit of antiporter xc-) are available, but doses of inhibiting compounds were only suboptimal to efficiently block cytokine production in activated pDCs or lead to dose-specific toxicity as in the case of JAK inhibitors.

Scientists from the Max-Planck-Institute of Immunobiology and Epigenetics have identified the System L amino acid transporter SLC7A5:SLC3A2 and the ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as additional therapeutic targets for autoimmune diseases in which pDCs are implicated. A combination of an inhibitor targeting xc- with an inhibitor of the JAK2-STAT5 pathway required to induce SLC7A5:SLC3A2 expression, resulted in an additive effect that essentially prevented cytokine production at the suboptimal doses of each drug alone. This is of particular importance as it allows for fewer possible toxic effects. Further dose reduction can be achieved when inhibitors for ENPP2 are included. Therefore, a combinatorial treatment significantly reduced IFNa and TNF production compared to single doses and as such represents a novel strategy for targeted inhibition of pDCs at sites of inflammation to treat autoimmune diseases like SLE.

We are now looking for either a licensing partner, or a collaboration partner to further develop this project.

Grzes et al., 2021. Immunity. DOI: 10.1016/j.immuni.2021.10.009

A PCT application was filed on December, 6th 2021: WO2022122668A1.