Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies^{1,2,3,4,5,6,7,8,9}. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival^10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity¹², making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells^13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody–drug conjugate that could kill TRBC1⁺ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody–drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

抗体和嵌合抗原受体 (CAR) T 细胞介导的靶向治疗改善了实体瘤和血液恶性肿瘤患者的生存率^{1,2,3,4,5,6,7,8,9}。患有 T 细胞白血病和淋巴瘤（统称为 T 细胞癌）的成年人的生存期很短^10,11并且缺乏此类靶向治疗。因此，T 细胞癌症特别需要开发 CAR T 细胞和抗体来改善患者的治疗效果。临床前研究表明，靶向 T 细胞受体 β 链恒定区 1 (TRBC1) 可以杀死癌性 T 细胞，同时保留足够的健康 T 细胞以维持免疫力¹²，使 TRBC1 成为治疗 T 细胞癌症的有吸引力的靶点。然而，抗TRBC1 CAR T细胞的首次人体临床试验报告了低反应率和不明原因的抗TRBC1 CAR T细胞损失^13,14。在这里，我们证明 CAR T 细胞由于被患者正常 T 细胞杀死而丢失，从而降低了其功效。为了解决这个问题，我们开发了一种抗体-药物偶联物，可以在体外杀死 TRBC1 ⁺癌细胞，并在小鼠模型中治愈人类 T 细胞癌症。抗TRBC1抗体-药物偶联物可以为TRBC1靶向提供最佳形式，并在T细胞癌症患者中产生优异的反应。