A fully human pan VL9 HLA-E TCRm antibody enables functional dissection of HLA-E biology and checkpoint signaling

HLA-E's function as an immune checkpoint in cancer depends on its display of the canonical peptide (VL9), yet direct profiling of these complexes has been stymied by lack of specific reagents. We now introduce ABX002, a fully human TCR-mimic antibody capable of recognizing all tested VL9/HLA-E complexes with high affinity and specificity in situ. Using ABX002, we reveal that canonical VL9/HLA-E surface expression is tightly controlled by inflammatory cues, remarkably infrequent on tumors without stimulation, and almost absent from immune cells except myeloid-lineage cells. ABX002 unlocks cell-type and context-specific quantification of HLA-E antigen presentation, providing unprecedented insight into immune evasion and regulation. It additionally disrupts the NKG2A checkpoint, restoring cytotoxic lymphocyte function and enabling mechanistic and therapeutic mapping of HLA-E restricted peptide presentation. Together, these findings position ABX002 as a transformative tool for dissecting the landscape and biology of canonical peptide restriction in cancer immunity.