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

Nature. 2024 Apr;628(8007):416-423. doi: 10.1038/s41586-024-07233-2. Epub 2024 Mar 27.


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 survival10,11 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.

MeSH terms

  • Animals
  • Female
  • Humans
  • Immunoconjugates* / immunology
  • Immunoconjugates* / therapeutic use
  • Immunotherapy, Adoptive
  • Leukemia, T-Cell* / drug therapy
  • Leukemia, T-Cell* / immunology
  • Lymphoma, T-Cell* / drug therapy
  • Lymphoma, T-Cell* / immunology
  • Mice
  • Receptors, Antigen, T-Cell, alpha-beta* / immunology
  • Receptors, Chimeric Antigen / immunology
  • T-Lymphocytes* / immunology
  • Xenograft Model Antitumor Assays


  • Immunoconjugates
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Chimeric Antigen
  • TRBC1 protein, human