دورية
TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers
| العنوان: | TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers |
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| المؤلفون: | 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 |
| المصدر: | Nature; April 2024, Vol. 628 Issue: 8007 p416-423, 8p |
| مستخلص: | Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1–9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11and 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00280836 14764687 |
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| DOI: | 10.1038/s41586-024-07233-2 |