2. Academic Validation
  3. TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers

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

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. spaul19@jhmi.edu.
  • 16 Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. spaul19@jhmi.edu.
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.

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