Abstract
T cell-derived cancers are hallmarked by heterogeneity, aggressiveness, and poor clinical outcomes. Available targeted therapies are severely limited due to a lack of target antigens that allow discrimination of malignant from healthy T cells. Here, we report a novel approach for the treatment of T cell diseases based on targeting the clonally rearranged T cell receptor displayed by the cancerous T cell population. As a proof of concept, we identified an antibody with unique specificity toward a distinct T cell receptor (TCR) and developed antibody-drug conjugates, precisely recognizing and eliminating target T cells while preserving overall T cell repertoire integrity and cellular immunity. Our anti-TCR antibody-drug conjugates demonstrated effective receptor-mediated cell internalization, associated with induction of cancer cell death with strong signs of apoptosis. Furthermore, cell proliferation-inhibiting bystander effects observed on target-negative cells may contribute to the molecules' anti-tumor properties precluding potential tumor escape mechanisms. To our knowledge, this represents the first anti-TCR antibody-drug conjugate designed as custom-tailored immunotherapy for T cell-driven pathologies.