Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
Publication Year 2021-09-06, Volume 12, Issue #1, Page 5271
Journal Title
Nature Communications
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.
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
WEHI Research Division(s)
Structural Biology
PubMed ID
Open Access at Publisher's Site
Rights Notice
Refer to copyright notice on published article.

Creation Date: 2021-10-26 10:03:47
Last Modified: 2021-11-09 11:29:03
An error has occurred. This application may no longer respond until reloaded. Reload 🗙