Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy.
Animals
Antibodies, Monoclonal
/ administration & dosage
Antigens, Neoplasm
/ immunology
Apoptosis
Cell Proliferation
Female
Humans
Immunotherapy
/ methods
Mice
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma
/ immunology
Nanoparticles
/ administration & dosage
T-Lymphocytes
/ immunology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
27
07
2020
accepted:
07
01
2021
revised:
01
12
2020
pubmed:
23
1
2021
medline:
1
9
2021
entrez:
22
1
2021
Statut:
ppublish
Résumé
T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies.
Identifiants
pubmed: 33479469
doi: 10.1038/s41375-021-01127-2
pii: 10.1038/s41375-021-01127-2
pmc: PMC8292428
mid: NIHMS1661107
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antigens, Neoplasm
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
2346-2357Subventions
Organisme : NCI NIH HHS
ID : P50 CA094056
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR002344
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA199092
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA091842
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Informations de copyright
© 2021. The Author(s).
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