-transparent.png){kind=logo}
Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen. 2022
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
Immunocore Ltd., 92 Park Drive, Milton Park, Abingdon, OX14 4RY, USA.
Neoantigens derived from somatic mutations are specific to cancer cells and are ideal targets for cancer immunotherapy. KRAS is the most frequently mutated oncogene and drives the pathogenesis of several cancers. Here we show the identification and development of an affinity-enhanced T cell receptor (TCR) that recognizes a peptide derived from the most common KRAS mutant, KRASG12D, presented in the context of HLA-A*11:01. The affinity of the engineered TCR is increased by over one million-fold yet fully able to distinguish KRASG12D over KRASWT. While crystal structures reveal few discernible differences in TCR interactions with KRASWT versus KRASG12D, thermodynamic analysis and molecular dynamics simulations reveal that TCR specificity is driven by differences in indirect electrostatic interactions. The affinity enhanced TCR, fused to a humanized anti-CD3 scFv, enables selective killing of cancer cells expressing KRASG12D. Our work thus reveals a molecular mechanism that drives TCR selectivity and describes a soluble bispecific molecule with therapeutic potential against cancers harboring a common shared neoantigen.
Related Publications
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
April 2024,
Communications biology,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
August 2022,
Cancer immunology research,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
June 1996,
Immunology and cell biology,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
June 2022,
The New England journal of medicine,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
August 2022,
The New England journal of medicine,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
August 2022,
The New England journal of medicine,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
May 2024,
Cancer gene therapy,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
January 2022,
Vaccines,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
August 2019,
Neurosurgery,
Andrew Poole, and
Vijaykumar Karuppiah, and
Annabelle Hartt, and
Jaafar N Haidar, and
Sylvie Moureau, and
Tomasz Dobrzycki, and
Conor Hayes, and
Christopher Rowley, and
Jorge Dias, and
Stephen Harper, and
Keir Barnbrook, and
Miriam Hock, and
Charlotte Coles, and
Wei Yang, and
Milos Aleksic, and
Aimee Bence Lin, and
Ross Robinson, and
Joe D Dukes, and
Nathaniel Liddy, and
Marc Van der Kamp, and
Gregory D Plowman, and
Annelise Vuidepot, and
David K Cole, and
Andrew D Whale, and
Chandramouli Chillakuri
August 2004,
Gene therapy,
