Targeting a neoantigen derived from a common TP53 mutation

Emily Han Chung Hsiue; Katharine M. Wright; Jacqueline Douglass; Michael S. Hwang; Brian J. Mog; Alexander H. Pearlman; Suman Paul; Sarah R. Dinapoli; Maximilian F. Konig; Qing Wang; Annika Schaefer; Michelle S. Miller; Andrew D. Skora; P. Aitana Azurmendi; Michael B. Murphy; Qiang Liu; Evangeline Watson; Yana Li; Drew M. Pardoll; Chetan Bettegowda; Nickolas Papadopoulos; Kenneth W. Kinzler; Bert Vogelstein; Sandra B. Gabelli; Shibin Zhou

doi:10.1126/science.abc8697

Targeting a neoantigen derived from a common TP53 mutation

Emily Han Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. Dinapoli, Maximilian F. Konig, Qing Wang, Annika Schaefer, Michelle S. Miller, Andrew D. Skora, P. Aitana Azurmendi, Michael B. Murphy, Qiang Liu, Evangeline Watson, Yana Li, Drew M. Pardoll, Chetan BettegowdaNickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Sandra B. Gabelli, Shibin Zhou

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Abstract

TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: A bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.

Original language	English (US)
Article number	eabc8697
Journal	Science
Volume	371
Issue number	6533
DOIs	https://doi.org/10.1126/science.abc8697
State	Published - Mar 5 2021

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Hsiue, E. H. C., Wright, K. M., Douglass, J., Hwang, M. S., Mog, B. J., Pearlman, A. H., Paul, S., Dinapoli, S. R., Konig, M. F., Wang, Q., Schaefer, A., Miller, M. S., Skora, A. D., Azurmendi, P. A., Murphy, M. B., Liu, Q., Watson, E., Li, Y., Pardoll, D. M., ... Zhou, S. (2021). Targeting a neoantigen derived from a common TP53 mutation. Science, 371(6533), Article eabc8697. https://doi.org/10.1126/science.abc8697

Hsiue, EHC, Wright, KM, Douglass, J, Hwang, MS, Mog, BJ, Pearlman, AH, Paul, S, Dinapoli, SR, Konig, MF, Wang, Q, Schaefer, A, Miller, MS, Skora, AD, Azurmendi, PA, Murphy, MB, Liu, Q, Watson, E, Li, Y, Pardoll, DM , Bettegowda, C , Papadopoulos, N , Kinzler, KW , Vogelstein, B, Gabelli, SB & Zhou, S 2021, 'Targeting a neoantigen derived from a common TP53 mutation', Science, vol. 371, no. 6533, eabc8697. https://doi.org/10.1126/science.abc8697

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title = "Targeting a neoantigen derived from a common TP53 mutation",

abstract = "TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: A bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.",

author = "Hsiue, {Emily Han Chung} and Wright, {Katharine M.} and Jacqueline Douglass and Hwang, {Michael S.} and Mog, {Brian J.} and Pearlman, {Alexander H.} and Suman Paul and Dinapoli, {Sarah R.} and Konig, {Maximilian F.} and Qing Wang and Annika Schaefer and Miller, {Michelle S.} and Skora, {Andrew D.} and Azurmendi, {P. Aitana} and Murphy, {Michael B.} and Qiang Liu and Evangeline Watson and Yana Li and Pardoll, {Drew M.} and Chetan Bettegowda and Nickolas Papadopoulos and Kinzler, {Kenneth W.} and Bert Vogelstein and Gabelli, {Sandra B.} and Shibin Zhou",

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AU - Hsiue, Emily Han Chung

AU - Wright, Katharine M.

AU - Douglass, Jacqueline

AU - Hwang, Michael S.

AU - Mog, Brian J.

AU - Pearlman, Alexander H.

AU - Paul, Suman

AU - Dinapoli, Sarah R.

AU - Konig, Maximilian F.

AU - Wang, Qing

AU - Schaefer, Annika

AU - Miller, Michelle S.

AU - Skora, Andrew D.

AU - Azurmendi, P. Aitana

AU - Murphy, Michael B.

AU - Liu, Qiang

AU - Watson, Evangeline

AU - Li, Yana

AU - Pardoll, Drew M.

AU - Bettegowda, Chetan

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Gabelli, Sandra B.

AU - Zhou, Shibin

PY - 2021/3/5

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N2 - TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: A bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.

AB - TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: A bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.

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Targeting a neoantigen derived from a common TP53 mutation

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