HLA-A*02/NY-ESO-1 peptide-MHC complex (tumor) x CD3 (T cells)

Class

HLA-A*02/NY-ESO-1-directed bispecific T-cell engager (TCR-mimetic bispecific antibody)

Pathway

Effectorless-Fc bispecific antibody binds the HLA-A*02-restricted NY-ESO-1 cancer/testis antigen peptide-MHC complex on tumor cells and engages T cells, redirecting T-cell-mediated cytotoxicity toward NY-ESO-1-positive tumors

This mechanism targets a highly specific molecular signature: a fragment of the NY-ESO-1 protein, a cancer-testis antigen normally restricted to germ cells and re-expressed in various tumors, displayed on the cell surface bound to a particular HLA-A*02 major histocompatibility complex (MHC) molecule. Because NY-ESO-1 is an intracellular protein, it cannot be reached by antibodies that recognize only surface proteins; presentation via peptide-MHC is the only way it becomes visible on the tumor cell exterior. A TCR-mimetic bispecific antibody is engineered with one arm that recognizes this specific peptide-MHC combination, much like a T-cell receptor would, and a second arm that binds CD3, a signaling component of the T-cell receptor complex on essentially all T cells. By physically bridging tumor cell and T cell, the antibody forces an immune synapse and redirects cytotoxic T-cell killing toward the tumor, independent of the T cell's own native specificity. This approach broadens the druggable antigen space beyond conventional surface targets and is relevant to solid tumors and hematologic malignancies that express NY-ESO-1, particularly in patient populations carrying the HLA-A*02 allele required for this specific presentation.