Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Hwang, MS; Miller, MS; Thirawatananond, P; Douglass, J; Wright, KM; Hsiue, EH; 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

Author(s): Hwang, MS; Miller, MS; Thirawatananond, P; Douglass, J; Wright, KM; Hsiue, EH; 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;
Details: Publication Year 2021-09-06,Volume 12,Issue #1,Page 5271
Journal Title: Nature Communications
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.
Publisher: NPG
Keywords: Animals; Antigens, Neoplasm/metabolism; COS Cells; Cell Line; Chlorocebus aethiops; Epitopes; HLA-B7 Antigen/*chemistry/metabolism; Humans; Immunoglobulin Fab Fragments/chemistry; Isocitrate Dehydrogenase/chemistry/genetics/immunology/*metabolism; Mutation; Peptide Library; Protein Conformation; Protein Engineering/*methods; Receptors, Chimeric Antigen/*chemistry/genetics/metabolism; T-Lymphocytes/physiology
Research Division(s): Structural Biology
PubMed ID: 34489470
Publisher's Version: https://doi.org/10.1038/s41467-021-25605-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-021-25605-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Hwang MS et al_ Nature Comms_2021.pdf - (2.78MB, application/pdf)

Creation Date: 2021-10-26 10:03:47

Last Modified: 2021-11-09 11:29:03