Multispecific Targeting with Synthetic Ankyrin Repeat Motif Chimeric Antigen Receptors.
Amino Acid Motifs
Animals
Ankyrin Repeat
Cell Line, Tumor
Female
Humans
Immunotherapy, Adoptive
/ methods
Mice, Inbred NOD
Mice, SCID
Neoplasms
/ immunology
Receptors, Antigen, T-Cell
/ immunology
Receptors, Chimeric Antigen
/ genetics
Signal Transduction
T-Lymphocytes
/ immunology
Tumor Escape
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
07
05
2019
revised:
17
07
2019
accepted:
06
09
2019
pubmed:
25
9
2019
medline:
27
10
2020
entrez:
25
9
2019
Statut:
ppublish
Résumé
The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition. A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape.
Identifiants
pubmed: 31548346
pii: 1078-0432.CCR-19-1479
doi: 10.1158/1078-0432.CCR-19-1479
pmc: PMC6940018
mid: NIHMS1539944
doi:
Substances chimiques
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7506-7516Subventions
Organisme : NCI NIH HHS
ID : P50 CA138293
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA114536
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136551
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007266
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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