2. Academic Validation
  3. TRBC2-targeting antibody-drug conjugates for the treatment of T cell cancers

TRBC2-targeting antibody-drug conjugates for the treatment of T cell cancers

  • Nat Cancer. 2025 Dec;6(12):2011-2024. doi: 10.1038/s43018-025-01069-z.
Jiaxin Ge 1 2 3,  Joshua Urban 1 2,  Sarah R DiNapoli 1 2,  Bum Seok Lee 1 2,  Taha Ahmedna 1 2,  Tushar D Nichakawade 1 2 4 5,  Brian J Mog 1 2 6,  Steve Lu 1 2,  Xuyang Li 1 2 6,  Nikita Marcou 1 2,  Stephanie Glavaris 1 2,  Jacqueline Douglass 1 2 7,  Jin Liu 1 2,  Maximilian F Konig 1 2 5 8,  Evangeline Watson 1 2,  Maria Popoli 1 2,  J David Peske 9,  Sima Rozati 10,  Cole H Sterling 3,  Nina Wagner-Johnston 3,  Richard F Ambinder 3,  Kathy Gabrielson 7 9,  Charles G Mullighan 11,  Nickolas Papadopoulos 1 7 9,  Chetan Bettegowda 1 12,  Drew M Pardoll 7 13,  Shibin Zhou 1 7 13,  Surojit Sur 1 2 7,  Kenneth W Kinzler 1 7 13,  Bert Vogelstein 1 2 7 9 13,  Suman Paul 14 15
Affiliations

Affiliations

  • 1 Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • 3 Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 4 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • 5 Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • 6 Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • 7 Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 8 Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 9 Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 10 Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 11 Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 12 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 13 Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
  • 14 Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. spaul19@jhmi.edu.
  • 15 Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. spaul19@jhmi.edu.
PMID: 41429932 DOI: 10.1038/s43018-025-01069-z
Abstract

Antibody-drug conjugates (ADCs) have been remarkably successful in treating solid and hematological malignancies. Generation of ADCs for T cell cancers is challenging because the ADCs must selectively target cancerous T cells while sparing some normal T cells necessary for immune function. T cells express one of two TRBC alleles: TRBC1 or TRBC2. Normal T cells are composed of about 40% TRBC1-expressing and 60% TRBC2-expressing cells. In contrast, T cell malignancies are characterized by the clonal expression of either TRBC1 or TRBC2. Selective targeting of TRBC1 or TRBC2 enables the killing of Cancer cells but preserves about 60-40% of the normal T cells. To enable such a therapy for cancers expressing TRBC2, here we developed a high-affinity anti-TRBC2 antibody. An ADC generated with this antibody and a pyrrolobenzodiazepine dimer payload showed specific killing of TRBC2+ cancers in vitro and in mouse models. The anti-TRBC2 ADC provides a promising, off-the-shelf therapy for patients with T cell cancers.

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