Inside and Out: Antigen Type Shapes T-Cell Engager Performance Across Intracellular and Extracellular Targets
Bi-specific T-cell engagers (BiTEs) are engineered antibodies that redirect a patient’s own T cells to attack tumors, providing an “off-the-shelf” immunotherapy option alongside cell-based therapies like CAR T cells. Most BiTEs focus on surface proteins, yet many of the most clinically relevant tumor antigens reside inside the cell and are displayed only as peptide–MHC complexes. In this work, we directly compared BiTEs targeting a conventional melanoma surface antigen (MCSP) with BiTEs recognizing an intracellular peptide presented by HLA. Through analysis of T-cell activation, cytokine release, and tumor cell killing across a range of antigen densities, we demonstrate that the route of antigen presentation decisively shapes therapeutic potency and functional outcomes.
