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

Cutaneous T cell lymphomas (CTCL) are heterogeneous non-Hodgkin hematolymphoid malignancies characterized by clonal T cell receptors (TCR), 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 - which, however, all express the same clonal TCR. Antibodies against the TCR constant β-chain region (TRBC) 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 few (1-10%) percent of normal T-cells, making it an attractive clone-restricted target. Analysis of TCR sequencing from 104 CTCL patients showed TCRVβ2 (TRBV20-1) is the most common form of TCRVβ. Here, we show that anti-TCRVβ2 antibody is efficiently internalized and traffics to lysosomes, fulfilling key requirements for antibody-drug conjugate (ADC) development. A TCRVβ2-directed ADC selectively kills the TCRVβ2⁺ malignant MOLT-16 T-cell line and primary TCRVβ2⁺ cancer T-cells from leukemic CTCL patients (n=6; 4 TCRVβ2⁺ and 2 TCRVβ2- patients), whereas the unconjugated antibody has little effect. In a MOLT-16 tumor mouse model, TCRVβ2-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.