Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Michael S Hwang; Michelle S Miller; Puchong Thirawatananond; Jacqueline Douglass; Katharine M Wright; Emily Han-Chung Hsiue; Brian J Mog; Tihitina Y Aytenfisu; Michael B Murphy; P Aitana Azurmendi; Andrew D Skora; Alexander H Pearlman; Suman Paul; Sarah R DiNapoli; Maximilian F Konig; Chetan Bettegowda; Drew M Pardoll; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Shibin Zhou; Sandra B Gabelli

doi:10.1038/s41467-021-25605-4

Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Nat Commun. 2021 Sep 6;12(1):5271. doi: 10.1038/s41467-021-25605-4.

Authors

Michael S Hwang^#^{1

2

3

4}, Michelle S Miller^#^{2

5

6

7}, Puchong Thirawatananond⁵, Jacqueline Douglass^{1

2

3}, Katharine M Wright^{2

5

6}, Emily Han-Chung Hsiue^{1

2

3}, Brian J Mog^{1

2

3

8}, Tihitina Y Aytenfisu⁵, Michael B Murphy⁹, P Aitana Azurmendi⁵, Andrew D Skora^{1

2

10}, Alexander H Pearlman^{1

2

3}, Suman Paul^{1

2

3

11}, Sarah R DiNapoli^{1

2

3}, Maximilian F Konig^{1

2

3

12}, Chetan Bettegowda^{1

3

11

13}, Drew M Pardoll^{6

11}, Nickolas Papadopoulos^{1

3

11

14

15}, Kenneth W Kinzler^{1

3

6

11

15}, Bert Vogelstein^{16

17

18

19

20

21

22}, Shibin Zhou^{23

24

25

26}, Sandra B Gabelli^{27

28

29}

Affiliations

¹ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Howard Hughes Medical Institute, Chevy Chase, MD, USA.
³ Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Genentech, Inc., South San Francisco, CA, USA.
⁵ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
⁷ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
⁸ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁹ Cytiva, Marlborough, MA, USA.
¹⁰ Lilly Biotechnology Center, Eli Lilly and Co, San Diego, CA, USA.
¹¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vogelbe@jhmi.edu.
¹⁷ Howard Hughes Medical Institute, Chevy Chase, MD, USA. vogelbe@jhmi.edu.
¹⁸ Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vogelbe@jhmi.edu.
¹⁹ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. vogelbe@jhmi.edu.
²⁰ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vogelbe@jhmi.edu.
²¹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vogelbe@jhmi.edu.
²² Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vogelbe@jhmi.edu.
²³ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
²⁴ Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
²⁵ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. sbzhou@jhmi.edu.
²⁶ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbzhou@jhmi.edu.
²⁷ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gabelli@jhmi.edu.
²⁸ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gabelli@jhmi.edu.
²⁹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gabelli@jhmi.edu.

^# Contributed equally.

Abstract

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2^R140Q-HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.

Publication types

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

MeSH terms

Animals
Antigens, Neoplasm / metabolism
COS Cells
Cell Line
Chlorocebus aethiops
Epitopes
HLA-B7 Antigen / chemistry*
HLA-B7 Antigen / metabolism
Humans
Immunoglobulin Fab Fragments / chemistry
Isocitrate Dehydrogenase / chemistry
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / immunology
Isocitrate Dehydrogenase / metabolism*
Mutation
Peptide Library
Protein Conformation
Protein Engineering / methods*
Receptors, Chimeric Antigen / chemistry*
Receptors, Chimeric Antigen / genetics
Receptors, Chimeric Antigen / metabolism
T-Lymphocytes / physiology

Substances

Antigens, Neoplasm
Epitopes
HLA-B*07:02 antigen
HLA-B7 Antigen
Immunoglobulin Fab Fragments
Peptide Library
Receptors, Chimeric Antigen
IDH2 protein, human
Isocitrate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding