TRBC2-targeting antibody-drug conjugates for the treatment of T cell cancers PMID: 41429932

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
15. Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. [email protected].

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.