Cathepsin G peptide (CG1)-HLA complex

Class

TCR-mimetic bispecific T-cell engager (CD3 x peptide-HLA)

Pathway

T-cell-mediated cytotoxicity against leukemic cells presenting the CG1 peptide-MHC complex, including bystander killing

This target is not a conventional cell-surface protein but a peptide-HLA (human leukocyte antigen) complex: a short fragment of cathepsin G, a serine protease normally stored in myeloid cell granules, displayed on the cell surface bound to an HLA class I molecule. All cells continuously degrade internal proteins and present resulting peptides on HLA for surveillance by the immune system. When a protein like cathepsin G is overexpressed in leukemic myeloid cells, its peptide-HLA complex becomes a marker that distinguishes malignant from most normal cells, even though cathepsin G itself sits inside the cell and is inaccessible to conventional antibodies. TCR-mimetic antibodies solve this by binding the peptide-HLA complex the way a T-cell receptor would, in effect using antibody engineering to reach targets normally restricted to the T-cell system. Fusing such a binder to a second arm recognizing CD3 on T cells creates a bispecific engager that physically bridges T cells to leukemic cells, triggering targeted cytotoxicity along with secondary killing of nearby tumor cells through released cytotoxic mediators. This approach broadens the druggable target space in leukemia beyond surface antigens, offering a strategy relevant to hematologic malignancies where few tumor-restricted surface markers exist.