Phosphatidylinositol-3-kinase (PI3K) delta-dependent pathways are essential for immune cell activation. Targeting PI3K-delta has beneficial effect in several preclinical models of inflammatory disorders. PI3K-delta contributes to T and B cell development, survival, and antigen recognition as well as various neutrophil functions. Here, we investigated the effect of INCB050465, a novel PI3K-delta inhibitor, on disease-driving pathways in the pemphigoid diseases (PD) namely bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA), which are autoantibody (aAb)- induced and neutrophil-dependent. INCB050465 suppressed release of reactive oxygen species (ROS) from immune complex (IC)-activated polymorphonuclear cells (PMNs) in a dose-dependent manner. The effects were achieved at non-toxic concentrations, and the compound has no ROS-scavenging activity, as evidenced by a cell-free ROS assay. When cryosections of human skin were incubated with BP or EBA IgG and subsequently with PMNs, INCB050465 dose-dependently hindered the extent of dermal-epidermal separation. In a final set of experiments, INCB050465 was used in the immunization-induced mouse model of EBA. In this model, EBA-typical skin lesions were induced by immunization of mice with recombinant type VII collagen. When in an individual mouse 2% or more of the body surface area was affected by skin lesions, randomization to twice daily INCB050465 or vehicle was performed. After 4-week treatment, the INCB050465 group showed significantly less skin lesions compared with the vehicle-treated mice. In summary, we demonstrated that INCB050465 ameliorates tissue destruction in PD by inhibition of neutrophil functions and thus INCB050465 has emerged as a potential drug candidate for PD.

Inhibition of phosphatidylinositol-3-kinase δ improves tissue destruction in pemphigoid diseases by impairing neutrophil function