Dendritic-cell/T-cell co-cultures and drug-specific clones revealed separate responses to mitiperstat and four metabolites. Most clone activation was consistent with direct pharmacological interaction.
Researchers investigated whether mitiperstat and metabolites M7, M9, M10 and M12 activate human T cells in vitro. The irreversible myeloperoxidase (MPO) inhibitor, described as being in clinical development, had been associated with delayed maculopapular rash.
A healthy-donor dendritic-cell/T-cell co-culture assay assessed de novo responses. The team characterized 29 predominantly CD4+ clones specific to mitiperstat and 47 CD4+ or CD8+ clones responsive to its metabolites. Tritiated-thymidine incorporation measured proliferation, while enzyme-linked immunospot (ELISpot) measured IFN-γ, IL-5, IL-13 and granzyme B. Proliferation was dose-dependent, with heterogeneous secretion profiles.
Major histocompatibility complex (MHC) class II or class I blockade attenuated CD4+ or CD8+ activation, respectively. Despite mitiperstat’s irreversible target pharmacology, nearly all responsive clones could be activated with the compound present alongside fixed antigen-presenting cells, supporting direct pharmacological interactions. One clone instead responded to drug-pulsed antigen-presenting cells.
Clones were highly specific to their cognate compounds, with no observed cross-reactivity. The results support testing the parent and individual metabolites when examining this candidate’s immune reactivity. The authors propose these assays as a framework for comparing T-cell responses to future MPO-targeting therapies.
A four-platform comparison combined lipid imaging, liver-function measurements, expression profiling and CYP assays. Lipid accumulation did not uniformly reduce drug metabolism, and differences depended on the model and donor.
Cardiomyocytes derived from one CAV3 p.Ala46Thr carrier showed altered protein localization and irregular calcium transients. Fenoterol increased transient frequency, but the pattern remained less regular than in a relative's control cells.
