De-risking clinical trial failure through mechanistic simulation.

Drug development typically comprises a combination of pre-clinical experimentation, clinical trials, and statistical data-driven analyses. Therapeutic failure in late-stage clinical development costs the pharmaceutical industry billions of USD per year. Clinical trial simulation represents a key derisking strategy and combining them with mechanistic models allows one to test hypotheses for mechanisms of failure and to improve trial designs. This is illustrated with a T-cell activation model, used to simulate the clinical trials of IMA901, a short-peptide cancer vaccine. Simulation results were consistent with observed outcomes and predicted that responses are limited by peptide off-rates, peptide competition for dendritic cell (DC) binding, and DC migration times. These insights were used to hypothesise alternate trial designs predicted to improve efficacy outcomes. This framework illustrates how mechanistic models can complement clinical, experimental, and data-driven studies to understand, test, and improve trial designs, and how results may differ between humans and mice.

Kinetics of Abacavir-Induced Remodelling of the Major Histocompatibility Complex Class I Peptide Repertoire.

Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life-threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLA-B*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.

Characterization of the Class I MHC Peptidome Resulting From DNCB Exposure of HaCaT Cells.

Skin sensitization following the covalent modification of proteins by low molecular weight chemicals (haptenation) is mediated by cytotoxic T lymphocyte (CTL) recognition of human leukocyte antigen (HLA) molecules presented on the surface of almost all nucleated cells. There exist 3 nonmutually exclusive hypotheses for how haptens mediate CTL recognition: direct stimulation by haptenated peptides, hapten modification of HLA leading to an altered HLA-peptide repertoire, or a hapten altered proteome leading to an altered HLA-peptide repertoire. To shed light on the mechanism underpinning skin sensitization, we set out to utilize proteomic analysis of keratinocyte presented antigens following exposure to 2,4-dinitrochlorobenzene (DNCB). We show that the following DNCB exposure, cultured keratinocytes present cysteine haptenated (dinitrophenylated) peptides in multiple HLA molecules. In addition, we find that one of the DNCB modified peptides derives from the active site of cytosolic glutathione-S transferase-ω. These results support the current view that a key mechanism of skin sensitization is stimulation of CTLs by haptenated peptides. Data are available via ProteomeXchange with identifier PXD021373.