Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC).
A549 Cells
Animals
Antibody-Dependent Cell Cytotoxicity
/ drug effects
Antineoplastic Agents, Immunological
/ pharmacology
CD8-Positive T-Lymphocytes
/ immunology
Humans
Imiquimod
/ pharmacology
Killer Cells, Natural
/ immunology
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasms, Experimental
/ immunology
Toll-Like Receptor 7
/ agonists
Toll-Like Receptor 8
/ agonists
Xenograft Model Antitumor Assays
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 02 2021
08 02 2021
Historique:
received:
19
10
2020
accepted:
07
01
2021
entrez:
9
2
2021
pubmed:
10
2
2021
medline:
12
11
2021
Statut:
epublish
Résumé
There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with monoclonal antibody therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response.
Identifiants
pubmed: 33558639
doi: 10.1038/s41598-021-83005-6
pii: 10.1038/s41598-021-83005-6
pmc: PMC7870826
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
TLR7 protein, human
0
TLR8 protein, human
0
Toll-Like Receptor 7
0
Toll-Like Receptor 8
0
Imiquimod
P1QW714R7M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3346Références
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