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

Olivia M. Lucero, Ji Ann Lee, Jenna Bowman, Kara Johnson, Gopal Sapparapu, John K. Thomas, Guang Fan, Bill H. Chang, Karina Thiel-Klare, Christopher A. Eide, Craig Okada, Mike Palazzolo, Evan Lind, Yoko Kosaka, Brian J. Druker, Nicholas Lydon, Peter M. Bowers

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Purpose: 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 (Vb) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vb would eliminate the malignant clone while having minimal effects on healthy T cells. Experimental Design: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vb13.3. We developed a panel of antiVb13.3 antibodies to test for binding and elimination of the malignant T-cell clone. Results: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vb13.3 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 Vb13.3 were also killed by antibody administration in an in vivo murine model. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)4230-4241
Number of pages12
JournalClinical Cancer Research
Volume29
Issue number20
DOIs
StatePublished - Oct 15 2023

ASJC Scopus subject areas

  • General Medicine

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