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

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Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. / Thomas, Sharyn; Mohammed, Fiyaz; Reijmers, Rogier; Woolston, Annemarie; Stauss, Theresa; Kennedy, Alan; Stirling, David; Holler, Angelika; Green, Louisa ; Jones, David; Matthews, Kathaerine K; Price, David A; Chain, Benjamin E; Heemskerk, Mirjam HM; Morris, Emma; Willcox, Benjamin; Stauss, Hans J.

In: Nature Communications, Vol. 10, No. 1, 4451, 01.10.2019.

Research output: Contribution to journalArticle

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Thomas, S, Mohammed, F, Reijmers, R, Woolston, A, Stauss, T, Kennedy, A, Stirling, D, Holler, A, Green, L, Jones, D, Matthews, KK, Price, DA, Chain, BE, Heemskerk, MHM, Morris, E, Willcox, B & Stauss, HJ 2019, 'Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function', Nature Communications, vol. 10, no. 1, 4451. https://doi.org/10.1038/s41467-019-12441-w

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Thomas, Sharyn ; Mohammed, Fiyaz ; Reijmers, Rogier ; Woolston, Annemarie ; Stauss, Theresa ; Kennedy, Alan ; Stirling, David ; Holler, Angelika ; Green, Louisa ; Jones, David ; Matthews, Kathaerine K ; Price, David A ; Chain, Benjamin E ; Heemskerk, Mirjam HM ; Morris, Emma ; Willcox, Benjamin ; Stauss, Hans J. / Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. In: Nature Communications. 2019 ; Vol. 10, No. 1.

Bibtex

@article{ceab959b280444f6aa53869892cf6435,
title = "Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function",
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.",
author = "Sharyn Thomas and Fiyaz Mohammed and Rogier Reijmers and Annemarie Woolston and Theresa Stauss and Alan Kennedy and David Stirling and Angelika Holler and Louisa Green and David Jones and Matthews, {Kathaerine K} and Price, {David A} and Chain, {Benjamin E} and Heemskerk, {Mirjam HM} and Emma Morris and Benjamin Willcox and Stauss, {Hans J}",
year = "2019",
month = "10",
day = "1",
doi = "10.1038/s41467-019-12441-w",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

T1 - Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function

AU - Thomas, Sharyn

AU - Mohammed, Fiyaz

AU - Reijmers, Rogier

AU - Woolston, Annemarie

AU - Stauss, Theresa

AU - Kennedy, Alan

AU - Stirling, David

AU - Holler, Angelika

AU - Green, Louisa

AU - Jones, David

AU - Matthews, Kathaerine K

AU - Price, David A

AU - Chain, Benjamin E

AU - Heemskerk, Mirjam HM

AU - Morris, Emma

AU - Willcox, Benjamin

AU - Stauss, Hans J

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85072848099&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-12441-w

DO - 10.1038/s41467-019-12441-w

M3 - Article

C2 - 31575864

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4451

ER -