Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
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
WEHI Research Division(s)
Structural Biology
PubMed ID
34489470
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-021-25605-4
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 🗙