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

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

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  • Medientyp: E-Artikel
  • Titel: Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
  • Beteiligte: Lucero, Olivia M.; Lee, Ji-Ann; Bowman, Jenna; Johnson, Kara; Sapparapu, Gopal; Thomas, John K.; Fan, Guang; Chang, Bill H.; Thiel-Klare, Karina; Eide, Christopher A.; Okada, Craig; Palazzolo, Mike; Lind, Evan; Kosaka, Yoko; Druker, Brian J.; Lydon, Nicholas; Bowers, Peter M.
  • Erschienen: American Association for Cancer Research (AACR), 2023
  • Erschienen in: Clinical Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-22-0906
  • ISSN: 1557-3265; 1078-0432
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> <jats:p>See related commentary by Varma and Diefenbach, p. 4024</jats:p> </jats:sec>