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

  • Nature. 2024 Mar 27. doi: 10.1038/s41586-024-07233-2.
Tushar D Nichakawade  1  2  3  4 ,  Jiaxin Ge  1  2 ,  Brian J Mog  1  2  5 ,  Bum Seok Lee  1  2 ,  Alexander H Pearlman  1  2 ,  Michael S Hwang  1  2  6 ,  Sarah R DiNapoli  1  2 ,  Nicolas Wyhs  1  2 ,  Nikita Marcou  1  2 ,  Stephanie Glavaris  1  2 ,  Maximilian F Konig  1  2  4  7 ,  Sandra B Gabelli  8  9  10 ,  Evangeline Watson  1  2 ,  Cole Sterling  11 ,  Nina Wagner-Johnston  11 ,  Sima Rozati  12 ,  Lode Swinnen  11 ,  Ephraim Fuchs  11 ,  Drew M Pardoll  8  9 ,  Kathy Gabrielson  9  13 ,  Nickolas Papadopoulos  1  9  13 ,  Chetan Bettegowda  1  14 ,  Kenneth W Kinzler  1  8  9 ,  Shibin Zhou  1  8  9 ,  Surojit Sur  1  2  9 ,  Bert Vogelstein  1  2  8  9  13 ,  Suman Paul  15  16
Affiliations
  • 1. Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2. Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • 3. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • 4. Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • 5. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • 6. Genentech, San Francisco, CA, USA.
  • 7. Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8. Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
  • 9. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 10. Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA.
  • 11. Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 12. Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 13. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 14. Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 15. Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 16. Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. [email protected].
PMID: 38538786 DOI: 10.1038/s41586-024-07233-2
Abstract

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.

Products