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

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 VogelsteinShibin Zhou, Sandra B. Gabelli

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	5271
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25605-4
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Hwang, M. S., Miller, M. S., Thirawatananond, P., Douglass, J., Wright, K. M., Hsiue, E. H. C., Mog, B. J., Aytenfisu, T. Y., Murphy, M. B., Aitana Azurmendi, P., Skora, A. D., Pearlman, A. H., Paul, S., DiNapoli, S. R., Konig, M. F., Bettegowda, C., Pardoll, D. M., Papadopoulos, N., Kinzler, K. W., ... Gabelli, S. B. (2021). Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nature communications, 12(1), Article 5271. https://doi.org/10.1038/s41467-021-25605-4

Hwang, MS, Miller, MS, Thirawatananond, P, Douglass, J, Wright, KM, Hsiue, EHC, Mog, BJ, Aytenfisu, TY, Murphy, MB, Aitana Azurmendi, P, Skora, AD, Pearlman, AH, Paul, S, DiNapoli, SR, Konig, MF , Bettegowda, C , Pardoll, DM , Papadopoulos, N , Kinzler, KW , Vogelstein, B , Zhou, S & Gabelli, SB 2021, 'Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens', Nature communications, vol. 12, no. 1, 5271. https://doi.org/10.1038/s41467-021-25605-4

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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 IDH2R140Q-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.",

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

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AU - Hsiue, Emily Han Chung

AU - Mog, Brian J.

AU - Aytenfisu, Tihitina Y.

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AU - Skora, Andrew D.

AU - Pearlman, Alexander H.

AU - Paul, Suman

AU - DiNapoli, Sarah R.

AU - Konig, Maximilian F.

AU - Bettegowda, Chetan

AU - Pardoll, Drew M.

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Zhou, Shibin

AU - Gabelli, Sandra B.

PY - 2021/12/1

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N2 - 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 IDH2R140Q-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.

AB - 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 IDH2R140Q-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.

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Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Abstract

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