T 细胞衍生的癌症具有异质性、侵袭性和不良临床结果的特点。由于缺乏能够区分恶性 T 细胞和健康 T 细胞的靶抗原，可用的靶向治疗受到严重限制。在此，我们报告了一种治疗 T 细胞疾病的新方法，该方法基于靶向癌性 T 细胞群展示的克隆重排 T 细胞受体。作为概念证明，我们鉴定了一种对不同 T 细胞受体 (TCR) 具有独特特异性的抗体，并开发了抗体-药物缀合物，精确识别和消除目标 T 细胞，同时保持整体 T 细胞库的完整性和细胞免疫。我们的抗 TCR 抗体-药物偶联物表现出有效的受体介导的细胞内化，与诱导癌细胞死亡和强烈的细胞凋亡迹象相关。此外，在靶标阴性细胞上观察到的细胞增殖抑制旁观者效应可能有助于该分子的抗肿瘤特性，排除潜在的肿瘤逃逸机制。据我们所知，这代表了第一个抗 TCR 抗体药物偶联物，旨在为 T 细胞驱动的病理学定制免疫疗法。© 2024 作者。

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.© 2024 The Author(s).