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

Nature Cancer volume 6, pages 2011–2024 (2025) Cite this article

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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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Fig. 1: TRBC2-specific antibody generation by phage display.
The alternative text for this image may have been generated using AI.
Fig. 2: Anti-TRBC2 antibody shows specific binding to TRBC2+ cells.
The alternative text for this image may have been generated using AI.
Fig. 3: Anti-TRBC2 antibody is internalized into lysosomes.
The alternative text for this image may have been generated using AI.
Fig. 4: Anti-TRBC2 ADC specifically kills TRBC2+ cells.
The alternative text for this image may have been generated using AI.
Fig. 5: Anti-TRBC2 ADC kills patient-derived cancer cells.
The alternative text for this image may have been generated using AI.
Fig. 6: JX1.1 anti-TRBC2 ADC performance in vivo.
The alternative text for this image may have been generated using AI.

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Data availability

The new anti-TRBC2 antibody sequences described in this work are provided in Supplementary Table 3. The remaining data are available within the article, Supplementary Information and from the corresponding author on request. Source data are provided with this paper.

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Acknowledgements

We thank A. Dbouk (Johns Hopkins), A. Tam (Johns Hopkins), K. Judge (Johns Hopkins), P. Tiwari (Georgetown University) and A. Uren (Georgetown University) for their scientific and technical support. We thank the patients for contributing samples to the biorepository at Johns Hopkins and the Biacore Molecular Interaction Shared Resource (BMISR) facility at Georgetown University. This work was supported by grants from the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research, Commonwealth Fund, Bloomberg–Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies and National Institutes of Health (NIH) Cancer Center Support Grant (no. P30 CA006973). S.P. was supported by the National Cancer Institute (NCI, grant no. K08CA270403), Blood Cancer United, formerly the Leukemia & Lymphoma Society, Translation Research Program award, the American Society of Hematology Scholar award and the Swim Across America Translational Cancer Research award. B.J.M., S.R.D. and A.H.P. were supported by the NIH (grant no. T32 GM136577). T.D.N. was supported by the NCI (grant no. T32 CA153952). M.F.K. was supported by an NIH and/or National Institute of Allergy and Infectious Diseases grant (no. 1R21AI176764-01), the Jerome Greene Foundation and the Cupid Foundation. C.B. was supported by the NCI (grant no. R37 CA230400). C.B. and N.P. were supported by NCI (grant no. U01CA230691). N.M. was supported by the NIGMS (grant no. T32 GM148383). The BMISR is supported by the NIH (grant no. P30CA51008). X.L. was supported by the NIH and National Institute of General Medical Sciences (grant no. T32GM007057-47). C.G.M. was supported by a P30 Cancer Center Support Grant that facilitates the infrastructure (grant nos. CA021765 and R35 CA197695) and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The illustrations were generated using BioRender, ChemDraw and Adobe Illustrator.

Author information

Author notes

  1. Jiaxin Ge

    Present address: Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA

Authors and Affiliations

  1. Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jiaxin Ge, Joshua Urban, Sarah R. DiNapoli, Bum Seok Lee, Taha Ahmedna, Tushar D. Nichakawade, Brian J. Mog, Steve Lu, Xuyang Li, Nikita Marcou, Stephanie Glavaris, Jacqueline Douglass, Jin Liu, Maximilian F. Konig, Evangeline Watson, Maria Popoli, Nickolas Papadopoulos, Chetan Bettegowda, Shibin Zhou, Surojit Sur, Kenneth W. Kinzler, Bert Vogelstein & Suman Paul

  2. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Jiaxin Ge, Joshua Urban, Sarah R. DiNapoli, Bum Seok Lee, Taha Ahmedna, Tushar D. Nichakawade, Brian J. Mog, Steve Lu, Xuyang Li, Nikita Marcou, Stephanie Glavaris, Jacqueline Douglass, Jin Liu, Maximilian F. Konig, Evangeline Watson, Maria Popoli, Surojit Sur & Bert Vogelstein

  3. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA

    Tushar D. Nichakawade

  4. Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA

    Tushar D. Nichakawade & Maximilian F. Konig

  5. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Brian J. Mog & Xuyang Li

  6. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Jacqueline Douglass, Kathy Gabrielson, Nickolas Papadopoulos, Drew M. Pardoll, Shibin Zhou, Surojit Sur, Kenneth W. Kinzler & Bert Vogelstein

  7. Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Maximilian F. Konig

  8. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    J. David Peske, Kathy Gabrielson, Nickolas Papadopoulos & Bert Vogelstein

  9. Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Sima Rozati

  10. Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Cole H. Sterling, Nina Wagner-Johnston, Richard F. Ambinder & Suman Paul

  11. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Charles G. Mullighan

  12. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Chetan Bettegowda

  13. Bloomberg–Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Drew M. Pardoll, Shibin Zhou, Kenneth W. Kinzler & Bert Vogelstein

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  1. Jiaxin Ge
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  2. Joshua Urban
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  31. Suman Paul
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Contributions

S.P., J.G., K.W.K., B.V. and S.Z. conceived the study. S.P., J.G., B.S.L., T.A., S.L., S.R.D., X.L., J.D., M.P., T.D.N., S.S., B.J.M., K.W.K. and B.V. developed the methods. J.G., J.U., X.L. and M.P. performed the phage display. J.G., T.A. and B.S.L. generated ADCs and conducted in vitro assays. J.G., E.W., S.P. and K.G. conducted in vivo studies. J.G., T.D.N., B.J.M., S.R.D., N.W., N.M., S.G., J.L., M.F.K., C.S., N.W.J., S.R., D.M.P., N.P., C.B., K.W.K., S.Z., S.S., B.V. and S.P. assisted with the analysis and interpretation of data. S.R., J.D.P., R.F.A., C.S. and N.W.J. provided patient samples. C.G.M. provided PDX samples. S.P., J.G. and B.V. wrote the original draft. All authors reviewed and edited the final manuscript. S.P., K.W.K. and B.V. supervised the study.

Corresponding author

Correspondence to Suman Paul.

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The Johns Hopkins University has filed patent applications related to technologies described in this paper, including patent WO 2025/007013, on which S.P., T.D.N., J.G., B.V., K.W.K., N.P. and S.Z. are listed as inventors. S.P. is a consultant to Merck, owns equity in Gilead and received payments from IQVIA and Curio Science. S.P., M.F.K., B.V., K.W.K. and S.Z. are founders and hold equity in TBD Pharma. C.B. and N.P. hold equity in TBD Pharma. B.V., K.W.K. and N.P. are founders of Thrive Earlier Detection, an Exact Sciences Company and hold equity in Haystack Oncology and CAGE Pharma. K.W.K. and N.P. are consultants to Exact Sciences. B.V., K.W.K., N.P. and S.Z. hold equity in Exact Sciences, and are founders of or consultants to and own equity in CLASP. N.P., B.V. and K.W.K. hold equity in NeoPhore; B.V. and K.W.K. are consultants to NeoPhore. M.F.K. received personal fees from Argenx, Revel Pharmaceuticals, Sanofi and Doximity, all unrelated to this work. M.F.K. is a consultant to Alexion Pharmaceuticals, Allogene, Amgen, Argenx, Atara Biotherapeutics, Bristol Myers Squibb, Legend Biotech, Mucommune, Revel Pharmaceuticals, Sana Biotechnology and Sanofi. M.F.K. received research support from Blackbird Labs, NorthStar Medical Radioisotope and TBD Pharmaceuticals, Inc. B.V. is a consultant for and holds equity in Catalio Capital Management. S.Z. has a research agreement with BioMed Valley Discoveries, Inc. C.B. is a consultant to Depuy-Synthes, Bionaut Labs, Haystack Oncology and Privo Technologies and is a co-founder of OrisDx and Belay Diagnostics. C.H.S. is a consultant to Kyowa Kirin, and has served on advisory boards for Acrotech Biopharma and received honoraria from Medical Logix and Haymarket Medical Education. D.M.P. reports grant and patent royalties through institutions from BMS, a grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals and founder equity from Potenza; is a consultant for Aduro Biotech, Amgen, AstraZeneca (Medimmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona and ImmunomicTherapeutics; and is on the scientific advisory board of Five Prime Therapeutics, Camden Nexus II and WindMil and on the board of directors for Dracen Pharmaceuticals. C.G.M. serves on the advisory board of Illumina, reports speaking fees from Amgen and has received funding from Pfizer and royalties from Cyrus. J.D. is a consultant to Clasp Therapeutics and Hemogenyx. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. S.P., T.D.N., J.G., B.V., K.W.K., N.P. and S.Z. are inventors of some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. Patent applications on the work described in this paper may be filed by Johns Hopkins University. The terms of all these arrangements are being managed by Johns Hopkins University following its conflict-of-interest policies. The remaining authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Anti-TRBC2 antibody production.

a, SDS PAGE and Coomassie Blue stain of the indicated anti-TRBC2 antibodies under reducing and non-reducing conditions. Number of independent repeats = 1 b, Size exclusion chromatography (SEC) of the SEC standards and the indicated anti-TRBC2 antibodies. Data from one experiment.

Extended Data Fig. 2 SPR measurements and explanation of SLISY ratios.

a, Antibody binding to TRBC1 and TRBC2 proteins was measured with multiple-cycle kinetics by SPR. Antibodies were captured on CM5 chips, followed by injection of TRBC2 or TRBC1 proteins at the indicated concentrations. The affinities of each antibody to TRBC1 and TRBC2 proteins are indicated on the graph. NB = no binding. Data representative of one experiment. b, Example of calculation of binding ratio and enrichment ratio of the phage display illustrated in Fig. 1b.

Extended Data Fig. 3 Anti-TRBC2 antibody binding and internalization.

a, PBMCs isolated from three different normal human donors and stained with the JX1.1 anti-TRBC2 antibody (with C-terminus 6x histidine tag) followed by secondary staining with an anti-histidine DyLight 650 antibody. PBMCs were also stained with the indicated antibodies to identify B cells, NK cells and monocytes. Numbers beside plots indicate the percentage of cells in a representative experiment. b, Quantification of red fluorescence over time after the addition of the indicated pHrodo-tagged anti-TRBC2 antibodies. Data represent mean ± standard error of the mean. p-values obtained by one-way ANOVA with Sidak’s multiple comparison test. Data representative of one experiment.

Source Data

Extended Data Fig. 4 Synthesis and characterization of anti-TRBC2 ADCs.

a, Schematic of the anti-TRBC2 antibody conjugation to SG3249. b, Hydrophobic interaction chromatography of the indicated anti-TRBC2 antibodies and the anti-TRBC2-SG3249 ADCs. c, The calculated drug antibody ratio (DAR) for the indicated anti-TRBC1-SG3249 ADCs. Data representative of one (SAM.2, YR3-A5, KFN) or two (JX1.1) independent experiments. d, e, Flow cytometry histogram depicting binding of JX1.1 antibody and JX1.1 ADC (1 µg/mL) to the three TRBC2-expressing T-cell lines (b) with aggregate median fluorescent intensity from three experiments plotted in (e). Data represent mean ± standard error of the mean. The JX1.1 antibody and JX1.1 ADC harbors a C-terminal 6x histidine tag, and were detected using secondary staining with an anti-his Alexa Fluor 647 antibody. Only the anti-his Alexa Flour 647 antibody was used in the no primary antibody condition.

Source Data

Extended Data Fig. 5 JX1.1 anti-TRBC2 ADC efficacy.

a, b, normal T cells were activated with CD3/CD28 Dynabeads at a bead:cell ratio of 1:1 for 3 days. Following bead removal, the ‘bead-activated’ normal T cells were incubated with IgG2a control ADC (as negative control) or JX1.1 ADC at the indicated concentrations. After 5 days, flow cytometry was used to detect TRBC2+ and TRBC1+ cells. Numbers beside plots indicate the percentage of surviving cells (a), with data from three human T cell donors shown in (b). Bar graphs represent mean ± standard error of mean. p-values obtained by one-way ANOVA with Sidak’s multiple comparison test. c, Timeline of in vivo experiment using NSG mice injected with Jurkat TRBC2+ cells that express luciferase and GFP. On day 3, mice were intravenously injected with YR3-A5 ADC (5 mice) or JX1.1 ADC (5 mice). d, e, BLI was performed on the indicated days with individual mouse data shown in blue (mean value in dark blue) for YR3-A5 ADC, or pink (mean value in red) for JX1.1 ADC (e). Panel c was created using BioRender.com.

Source Data

Extended Data Fig. 6 JX1.1 anti-TRBC2 ADC kills patient-derived xenografts.

a, T cell cancer PDX samples were stained with control antibodies linked with BV711 or AL647 fluorophores or with anti-CD3-BV711 and JX1.1-AL647 antibodies. b, Timeline of in vivo experiment using NSG mice injected with PDX cells (8 mice for each PDX). On day 7, mice were intravenously injected with ADCs (control in 4 mice, JX1.1-ADC in 4 mice). c, d, Flow cytometry on day 7 and day 13 to assess circulating PDX cells, and aggregate data from 4 mice are shown in (d). In (d) p-value obtained by one-tailed t-test with Welch’s correction. e, f, Body weight and Kaplan-Meier survival of PDX bearing mice with 4 mice in each group. PDX SJTALL056671, median survival 20.5 days in control condition vs. median survival undefined (not reached) in JX1.1 ADC condition. p = 0.0084 by Log-rank Mantel-Cox test. PDX SJTALL055668, median survival 35.5 days in control condition vs. median survival undefined (not reached) in JX1.1 ADC condition. p = 0.0067 by Log-rank Mantel-Cox test. In (e, f) individual mouse data are shown in gray (mean value in black) for control, or pink (mean value in red) for JX1.1 ADC. Panel b was created using BioRender.com.

Source Data

Extended Data Fig. 7 SPR analysis of anti-TRBC2 antibodies.

SPR analysis of anti-TRBC2 antibodies binding to the indicated TRBC peptides, with overlaid fitted data shown in black. Data representative of one (KFNM, 28K30K32R, 30K32R113R, 30K32R56G) or two (YR3-A5) or three (KFN, SAM.2, JX1.1) independent experiments.

Supplementary information

Source data

Source Data (download XLSX )

Excel file containing source data used to generate Figs. 1–6 and Extended Data Figs. 3–6.

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Ge, J., Urban, J., DiNapoli, S.R. et al. TRBC2-targeting antibody–drug conjugates for the treatment of T cell cancers. Nat Cancer 6, 2011–2024 (2025). https://doi.org/10.1038/s43018-025-01069-z

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