Multiple tumor-specific Dark Antigen peptide-HLA complexes (Dark Antigen pHLA)

Tumor-specific Dark Antigen peptide-HLA (pHLA) complexes represent a novel class of cancer targets derived from the genomic "dark matter," which includes non-coding regions, introns, and alternative open reading frames (alt-ORFs) that are typically silenced in healthy cells. In various cancers, epigenetic and translational dysregulation causes these regions to be transcribed and translated into unique peptides, which are then presented on the cell surface by Human Leukocyte Antigen (HLA) molecules. Unlike traditional neoantigens that are often patient-specific, many Dark Antigens are shared across multiple patients and tumor types, making them ideal for "off-the-shelf" immunotherapies. These complexes are primarily targeted by T-cell receptor (TCR)-based therapies and bispecific T-cell engagers (TCEs) that recognize the specific peptide-HLA interface. For instance, the lead candidate ENA101 targets the DARKFOX peptide presented by HLA-A*03:01, a complex found in several solid tumors including lung and gastrointestinal cancers. By targeting antigens outside the conventional protein-coding exome, these therapies aim to overcome the limitations of current treatments and provide new options for patients with low mutational burden or resistance to checkpoint inhibitors.

Other names

Dark AntigensGenomic Dark Matter-derived antigensNon-canonical tumor antigensCryptic antigensNon-canonical MHC-associated peptides (ncMAPs)Dark Antigen-HLA complexes

T-cell redirection and activation via recognition of specific peptide-HLA complexes by T-cell receptors (TCRs) or TCR-mimic antibodies, leading to cytotoxic killing of tumor cells.