Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen

Andrew Poole, Vijaykumar Karuppiah, Annabelle Hartt, Jaafar N. Haidar, Sylvie Moureau, Tomasz Dobrzycki, Conor Hayes, Christopher Rowley, Jorge Dias, Stephen Harper, Keir Barnbrook, Miriam Hock, Charlotte Coles, Wei Yang, Milos Aleksic, Aimee Bence Lin, Ross Robinson, Joe D. Dukes, Nathaniel Liddy, Marc Kamp, Gregory D. Plowman, Annelise Vuidepot, David K. Cole, Andrew D. Whale () and Chandramouli Chillakuri ()
Additional contact information
Andrew Poole: Immunocore Ltd.
Vijaykumar Karuppiah: Immunocore Ltd.
Annabelle Hartt: University of Bristol, Biomedical Sciences Building, University Walk
Jaafar N. Haidar: Eli Lilly & Co, Lilly Corporate Center
Sylvie Moureau: Immunocore Ltd.
Tomasz Dobrzycki: Immunocore Ltd.
Conor Hayes: Immunocore Ltd.
Christopher Rowley: Immunocore Ltd.
Jorge Dias: Immunocore Ltd.
Stephen Harper: Immunocore Ltd.
Keir Barnbrook: Immunocore Ltd.
Miriam Hock: Immunocore Ltd.
Charlotte Coles: Immunocore Ltd.
Wei Yang: Eli Lilly & Co, Lilly Corporate Center
Milos Aleksic: Immunocore Ltd.
Aimee Bence Lin: Eli Lilly & Co, Lilly Corporate Center
Ross Robinson: Immunocore Ltd.
Joe D. Dukes: Immunocore Ltd.
Nathaniel Liddy: Immunocore Ltd.
Marc Kamp: University of Bristol, Biomedical Sciences Building, University Walk
Gregory D. Plowman: Eli Lilly & Co, Lilly Corporate Center
Annelise Vuidepot: Immunocore Ltd.
David K. Cole: Immunocore Ltd.
Andrew D. Whale: Immunocore Ltd.
Chandramouli Chillakuri: Immunocore Ltd.

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32811-1

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