T细胞淋巴瘤（TCL）具有异质性，侵袭性，并且只有少数针对性治疗药物可供选择。在本研究中，我们确定了CD6，这是一个已知的T细胞标志物，在几乎所有检查的TCL患者标本中表达水平较高，暗示CD6可能是一种新的针对这种危及生命的血液癌症的治疗靶点。我们通过将一种FDA批准的有丝分裂毒素单甲基芦丝环素E（MMAE）与高亲和力的抗人CD6单克隆抗体（mAb）偶联制备了一种CD6靶向抗体药物复合物（CD6-ADC）。与未偶联的抗CD6 mAb和非结合的对照ADC相比，CD6-ADC以时间和浓度依赖方式在体外强有力地选择性杀死TCL细胞。它还在TCL的临床模型中预防了肿瘤的发展。更重要的是，全身或局部给药的CD6-ADC或其人源化版本，而不是对照组，显著缩小了TCL的临床小鼠模型中已建立的肿瘤。这些结果表明，CD6是TCL的一种新的治疗靶点，并为进一步开发CD6-ADC作为治疗这些潜在致命淋巴系肿瘤患者的有希望的疗法提供了强有力的理论基础。© 2023。本作者（们），在Springer Nature Limited独家许可下。

T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.