美国约翰霍普金斯大学Suman Paul研究组研开发出用于治疗T细胞癌症的TRBC1靶向抗体-药物偶联物。相关论文于2024年3月27日在线发表于国际学术期刊《自然》。

研究人员表示，抗体和嵌合抗原受体（CAR）T细胞介导的靶向疗法提高了实体瘤和血液恶性肿瘤患者的生存率。成人T细胞白血病和淋巴瘤（统称为T细胞癌）患者的生存期较短，且缺乏此类靶向疗法。因此，T细胞癌症尤其需要开发CAR T细胞和抗体，以改善患者的预后。

临床前研究表明，靶向T细胞受体β链恒定区1（TRBC1）可以杀死癌变T细胞，同时保留足够的健康T细胞以维持免疫力，这使得TRBC1成为治疗T细胞癌的一个有吸引力的靶点。然而，抗TRBC1 CAR T细胞的首次人体临床试验报告显示，抗TRBC1 CAR T细胞的应答率很低，而且抗TRBC1 CAR T细胞的丢失原因不明。

研究人员证明，CAR T细胞会因患者正常T细胞的杀伤而丢失，从而降低其疗效。为了避免这一问题，研究人员开发了一种抗体-药物偶联物，它可以在体外杀死TRBC1⁺癌细胞，并在小鼠模型中治愈人类T细胞癌症。抗TRBC1抗体-药物偶联物可为TRBC1靶向提供最佳形式，并对T细胞癌患者产生卓越的反应。

附：英文原文

Title: TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers

Author: Nichakawade, Tushar D., Ge, Jiaxin, Mog, Brian J., Lee, Bum Seok, Pearlman, Alexander H., Hwang, Michael S., DiNapoli, Sarah R., Wyhs, Nicolas, Marcou, Nikita, Glavaris, Stephanie, Konig, Maximilian F., Gabelli, Sandra B., Watson, Evangeline, Sterling, Cole, Wagner-Johnston, Nina, Rozati, Sima, Swinnen, Lode, Fuchs, Ephraim, Pardoll, Drew M., Gabrielson, Kathy, Papadopoulos, Nickolas, Bettegowda, Chetan, Kinzler, Kenneth W., Zhou, Shibin, Sur, Surojit, Vogelstein, Bert, Paul, Suman

Issue&Volume: 2024-03-27

Abstract: Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1,2,3,4,5,6,7,8,9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 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 cells13,14. 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.

DOI: 10.1038/s41586-024-07233-2

Source: https://www.nature.com/articles/s41586-024-07233-2