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Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens.
Hwang, Michael S; Miller, Michelle S; Thirawatananond, Puchong; Douglass, Jacqueline; Wright, Katharine M; Hsiue, Emily Han-Chung; Mog, Brian J; Aytenfisu, Tihitina Y; Murphy, Michael B; Aitana Azurmendi, P; Skora, Andrew D; Pearlman, Alexander H; Paul, Suman; DiNapoli, Sarah R; Konig, Maximilian F; Bettegowda, Chetan; Pardoll, Drew M; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin; Gabelli, Sandra B.
Afiliação
  • Hwang MS; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Miller MS; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Thirawatananond P; Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Douglass J; Genentech, Inc., South San Francisco, CA, USA.
  • Wright KM; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Hsiue EH; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Mog BJ; Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
  • Aytenfisu TY; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • Murphy MB; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Aitana Azurmendi P; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Skora AD; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Pearlman AH; Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Paul S; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • DiNapoli SR; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Konig MF; Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
  • Bettegowda C; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Pardoll DM; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Papadopoulos N; Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Kinzler KW; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Vogelstein B; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Zhou S; Lustgarten Laboratory for Pancreatic Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Gabelli SB; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Nat Commun ; 12(1): 5271, 2021 09 06.
Article em En | MEDLINE | ID: mdl-34489470
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Engenharia de Proteínas / Antígeno HLA-B7 / Receptores de Antígenos Quiméricos / Isocitrato Desidrogenase Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Engenharia de Proteínas / Antígeno HLA-B7 / Receptores de Antígenos Quiméricos / Isocitrato Desidrogenase Limite: Animals / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article