TCRVβ-targeting antibody-drug conjugates as a novel strategy to eliminate malignant T cells in T cell cancers

Sep 22, 2026

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin malignancy where malignant clones share a clonal T-cell receptor, yet current therapies fail and targeted options are uneven across subclones. Anti-TCR constant β-chain antibodies can kill cancer T cells but may also deplete about half of benign T cells. Targeting the clone-restricted TCR variable β-chain (TCRVβ) can spare most healthy T cells. Using CTCL TCR sequencing, the most common TCRVβ2 form was identified and evaluated. An anti-TCRVβ2 antibody-drug conjugate (ADC) was internalized to lysosomes, selectively killed TCRVβ2+ cancer cells, and inhibited tumor growth in a mouse model.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages9

Reading Time23 min

AccessFree to download

Key Points

Introduction

Methods

PBMC isolation and cell culture

REGULAR ARTICLE TCRVβ-targeting antibody-drug conjugates as a novel strategy to eliminate malignant T cells in T cell cancers Chella Krishna Vadivel,1 Kirstine Sandal Nørregaard,2, 3 Alba Martínez Perlado,2, 3 Lara P. Sorrosal, 1 Ziao Zeng,1 Lang Yan,1 Martin R.J. Namini, 1 Maria Gluud,1 Terkild B. Buus, 1 Lars H. Engelholm,2, 3 Niels Behrendt,2, 3 and Niels Ødum 1 1 LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; 2The Finsen Laboratory, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; and 3 Biotech Research & Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Key Points • TCRVβ2-targeting antibody-drug conjugates kills malignant cells. • Anti-TCRVβ2 ADC– induced malignant cell death is significantly greater compared to unconjugated antibody treatment. Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin hematolymphoid malignancy characterized by clonal T-cell receptors (TCRs), which serve as diagnostic hallmarks and potential therapeutic targets. Advanced CTCL remains difficult to treat, with poor prognosis and heterogeneous expression of actionable treatment targets across cancer subclones; however, all express the same clonal TCR. Antibodies against the TCR constant β-chain region can eliminate cancer T cells but may also deplete approximately half of benign T cells. In contrast, each TCR variable β-chain (TRBV or TCRVβ) family is expressed by only a small percentage (1%-10%) of normal T cells, making it an attractive clone-restricted target. Analysis of TCR sequencing from 104 patients with CTCL showed TCRVβ2 (TRBV20-1) is the most common form ofTCRVβ . Here, we demonstrate that an antiTCR Vβ2 antibody is efficiently internalized and traffics to lysosomes, fulfilling key requirements for antibody-drug conjugate (ADC) development. A TCR Vβ2-directed ADC selectively kills the TCR Vβ2+ malignant MOLT-16 T-cell line and primary TCRVβ2+ cancer T cells from patients with leukemic CTCL (n = 6; 4 with TCRVβ2+ and 2 with TCR Vβ2 − ), whereas the unconjugated antibody has little effect. In a MOLT-16 tumor mouse model, TCR Vβ2 ADC significantly inhibits tumor growth. In conclusion, TCRVβ-specific ADC is a novel, clone-targeted strategy to eliminate cancer T cells by exploiting their clonal TCR while minimizing collateral damage to the healthy T-cell repertoire. Introduction Patients with advanced cutaneous T-cell lymphoma (CTCL) have a poor prognosis, largely due to treatment failure and infection.1-3 Cancer T cells exhibit heterogeneous expression of actionable surface targets across subclones, complicating therapy and promoting resistance to chemotherapy and biologics.4-6 In contrast, all malignant subclones in any given patient share an identical, clonally rearranged T-cell receptor (TCR), which serves as both a diagnostic hallmark and a unique therapeutic target.7,8 Several strategies have sought to exploit this feature.9-13 Chimeric antigen receptor (CAR) T cells and monoclonal antibodies (mAbs) directed against the TCR β-chain constant region (TRBC) can potentially Submitted 2 March 2026; accepted 22 April 2026; prepublished online on Blood Advances First Edition 29 April 2026. [https://doi.org/10.1182/](https://doi.org/10.1182/)[ ](https://doi.org/10.1182/)[bloodadvances.2026020282](bloodadvances.2026020282.)[.](bloodadvances.2026020282.) All data needed to evaluate the conclusions in the study are present in the manuscript and the supplemental Materials. Publicly available single-cell RNA and T-cell receptor sequencing data sets were used to analyze TRBV gene usage frequencies. These data sets are accessible via the original publications, which are cited in the Methods and the reference list provided in the article. The full-text version of this article contains a data supplement. © 2026 American Society of Hematology. Published

FAQs

Why are TCRVβ variable β-chain targets considered more selective than targeting the β-chain constant region?

TCR constant β-chain targeting can deplete roughly half of benign T cells, whereas each TCRVβ family is expressed by only about 1%–10% of normal T cells, enabling clone-restricted killing of malignant T cells while sparing most healthy repertoire.

What did TCR sequencing of CTCL patients show in this study?

Analysis of TCR sequencing from 104 CTCL patients indicated that TCRVβ2 (TRBV20-1) is the most common form of TCRVβ.

How does the TCRVβ2-directed ADC affect malignant cells compared with the unconjugated antibody?

The TCRVβ2 ADC is efficiently internalized and traffics to lysosomes, selectively killing TCRVβ2+ malignant T-cell lines and primary cancer T cells, while the unconjugated antibody shows little effect. The ADC also significantly inhibits tumor growth in a MOLT-16 tumor mouse model.

Sep 22, 2026

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