DARKFOX peptide presented in HLA-A*03:01 (DARKFOX-A3)

DARKFOX is a novel cancer-specific "Dark Antigen" discovered by Enara Bio, derived from an alternative open reading frame (alt-ORF) within the FOXM1 gene transcript [2, 4]. Unlike canonical antigens, it originates from genomic regions previously considered non-coding or "dark matter" [7]. The DARKFOX-A3 peptide is specifically presented on the cell surface by the HLA-A*03:01 allele and is highly prevalent across various solid tumors, including lung, esophageal, and colorectal cancers [3, 5]. It is characterized by homogeneous intratumoral expression and minimal presence in normal tissues, suggesting a wide therapeutic window [4, 6]. This high tumor specificity and broad prevalence make it an attractive target for immunotherapy, particularly in patient populations where traditional targets are lacking [2, 8]. The lead therapeutic candidate targeting this complex is ENA101, a bispecific T-cell engager (TCE) designed to redirect T-cell cytotoxicity specifically toward DARKFOX-presenting tumor cells [3, 6]. ENA101 utilizes a TCR-mimic antibody with picomolar affinity for the DARKFOX-A3 peptide-HLA complex [6]. Preclinical studies have demonstrated potent anti-tumor activity, including deep tumor regression in xenograft models [3]. The target's expression in B-cell rich tissues is low, which may minimize off-target toxicity [4, 5]. Overall, DARKFOX represents a breakthrough in validating the dark genome as a source of actionable, shared tumor antigens for solid tumor immunotherapy [2, 7].

Other names

DARKFOX-A3FOXM1 alternative open reading frame peptideDark Antigen FOXM1FOXM1 alt-ORF peptide

Bispecific T-cell engager (TCE) that binds to the DARKFOX-A3 peptide-HLA complex on tumor cells and CD3 on T cells to induce T-cell mediated tumor cell lysis [3, 6].