Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Katharine M. Wright, Sarah R. DiNapoli, Michelle S. Miller, P. Aitana Azurmendi, Xiaowei Zhao, Zhiheng Yu, Mayukh Chakrabarti, WuXian Shi, Jacqueline Douglass, Michael S. Hwang, Emily Han-Chung Hsiue, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Maximilian F. Konig, Drew M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou () and Sandra B. Gabelli ()
Additional contact information
Katharine M. Wright: The Johns Hopkins School of Medicine
Sarah R. DiNapoli: Howard Hughes Medical Institute
Michelle S. Miller: The Johns Hopkins School of Medicine
P. Aitana Azurmendi: The Johns Hopkins School of Medicine
Xiaowei Zhao: HHMI,19700 Helix Drive
Zhiheng Yu: HHMI,19700 Helix Drive
Mayukh Chakrabarti: The Johns Hopkins School of Medicine
WuXian Shi: Brookhaven National Laboratory
Jacqueline Douglass: Howard Hughes Medical Institute
Michael S. Hwang: Howard Hughes Medical Institute
Emily Han-Chung Hsiue: Howard Hughes Medical Institute
Brian J. Mog: Howard Hughes Medical Institute
Alexander H. Pearlman: Howard Hughes Medical Institute
Suman Paul: Johns Hopkins University School of Medicine
Maximilian F. Konig: Howard Hughes Medical Institute
Drew M. Pardoll: Sidney Kimmel Comprehensive Cancer Center
Chetan Bettegowda: Johns Hopkins University School of Medicine
Nickolas Papadopoulos: Johns Hopkins University School of Medicine
Kenneth W. Kinzler: Sidney Kimmel Comprehensive Cancer Center
Bert Vogelstein: Howard Hughes Medical Institute
Shibin Zhou: Sidney Kimmel Comprehensive Cancer Center
Sandra B. Gabelli: The Johns Hopkins School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRASG12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.

Date: 2023
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DOI: 10.1038/s41467-023-40821-w

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