Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases

Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vβ) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vβ would eliminate the malignant clone while having minimal effects on healthy T cells.

We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vβ13.3. We developed a panel of anti-Vβ13.3 antibodies to test for binding and elimination of the malignant T-cell clone.

Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vβ13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vβ13.3 were also killed by antibody administration in an in vivo murine model.

This approach serves as an outline for development of therapeutics that can treat clonal T-cell-based malignancies and potentially other T-cell-mediated diseases. See related commentary by Varma and Diefenbach, p. 4024.