Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function

Sharyn Thomas, Fiyaz Mohammed, Rogier Reijmers, Annemarie Woolston, Theresa Stauss, Alan Kennedy, David Stirling, Angelika Holler, Louisa Green, David Jones, Kathaerine K Matthews, David A Price, Benjamin Chain, Mirjam HM Heemskerk, Emma Morris, Benjamin Willcox, Hans J Stauss

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
507 Downloads (Pure)

Abstract

TCR-gene-transfer is an efficient strategy to produce therapeutic T cells of defined antigen specificity. However, there are substantial variations in the cell surface expression levels of human TCRs, which can impair the function of engineered T cells. Here we demonstrate that substitutions of 3 amino acid residues in the framework of the TCR variable domains consistently increase the expression of human TCRs on the surface of engineered T cells.The modified TCRs mediate enhanced T cell proliferation, cytokine production and cytotoxicity, while reducing the peptide concentration required for triggering effector function up to 3000-fold. Adoptive transfer experiments in mice show that modified TCRs control tumor growth more efficiently than wild-type TCRs. Our data indicate that simple variable domain modifications at a distance from the antigen-binding loops lead to increased TCR expression and improved effector function. This finding provides a generic platform to optimize the efficacy of TCR gene therapy in humans.

Original languageEnglish
Article number4451
Number of pages15
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Oct 2019

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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