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; Sandra B Gabelli

doi:10.1038/s41467-023-40821-w

Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Nat Commun. 2023 Aug 21;14(1):5063. doi: 10.1038/s41467-023-40821-w.

Authors

Katharine M Wright^#^{1

2

3

4}, Sarah R DiNapoli^#^{2

5

6}, Michelle S Miller^#^{1

2

3

7}, P Aitana Azurmendi^{1

2

3}, Xiaowei Zhao⁸, Zhiheng Yu⁸, Mayukh Chakrabarti¹, WuXian Shi^{9

10}, Jacqueline Douglass^{2

5

6}, Michael S Hwang^{2

5

6}, Emily Han-Chung Hsiue^{2

5

6

11}, Brian J Mog^{2

5

6

12}, Alexander H Pearlman^{2

5

6}, Suman Paul^{5

6

13

14}, Maximilian F Konig^{2

5

6

15}, Drew M Pardoll^{3

13}, Chetan Bettegowda^{5

6

13

16}, Nickolas Papadopoulos^{5

6

13

17}, Kenneth W Kinzler^{3

5

6

13}, Bert Vogelstein^{2

3

5

6

13

17}, Shibin Zhou^{18

19

20

21}, Sandra B Gabelli^{22

23

24

25

26}

Affiliations

¹ Department of Biophysics and Biophysical Chemistry, The Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
² Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
³ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA.
⁴ Discovery Chemistry, Protein and Structural Chemistry, Merck & Co, Inc, West Point, PA, 19846, USA.
⁵ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁶ Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁷ Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
⁸ Janelia Research Campus, HHMI,19700 Helix Drive, Ashburn, VA, 20147, USA.
⁹ Energy & Photon Sciences Directorate, Brookhaven National Laboratory, Upton, NY, 11973, USA.
¹⁰ Case Center for Synchrotron Biosciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
¹¹ Novartis Institutes for BioMedical Research, 250 Massachusetts Ave, Cambridge, MA, 02139, USA.
¹² Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
¹³ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
¹⁴ Division of Hematologic Malignancies and Bone Marrow Transplantation, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
¹⁵ Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA.
¹⁶ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
¹⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
¹⁸ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. [email protected].
¹⁹ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. [email protected].
²⁰ Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. [email protected].
²¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. [email protected].
²² Department of Biophysics and Biophysical Chemistry, The Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
²³ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA. [email protected].
²⁴ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. [email protected].
²⁵ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
²⁶ Discovery Chemistry, Protein and Structural Chemistry, Merck & Co, Inc, West Point, PA, 19846, USA. [email protected].

^# Contributed equally.

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 KRAS^G12V 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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Antibodies*
HLA-A Antigens / genetics
Hydrophobic and Hydrophilic Interactions
Proto-Oncogene Proteins p21(ras)* / genetics
Recognition, Psychology

Substances

Proto-Oncogene Proteins p21(ras)
Antibodies
HLA-A Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding