Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates.
STING ligands
aging
flow cytometry
innate immunity
non-human primate
prediction
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
09 Mar 2023
09 Mar 2023
Historique:
received:
22
07
2022
accepted:
12
12
2022
entrez:
9
1
2023
pubmed:
10
1
2023
medline:
10
1
2023
Statut:
epublish
Résumé
Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not been reported. We examined the effects of escalating doses of cyclic-di-adenosine monophosphate (c-di-AMP) or cyclic [G (3',5')pA (3',5'p] (3'-3'-cGAMP) administered intramuscularly or intravenously to cynomolgus macaques. Both ligands induced transient local and systemic inflammatory responses and systemic immunomodulatory responses, including the upregulation of interferon-α (IFN-α) and IFN-γ expression and the activation of multiple immunocompetent cell subsets. Better immunological responses were observed in animals that received c-di-AMP compared with those that received 3'-3'-cGAMP. Multi-parameter analysis using a dataset obtained before administering the ligands predicted the efficacy outcome partially. Importantly, the efficacy of these ligands was reduced in older macaques. We propose that 0.5 mg/kg c-di-AMP via intramuscular administration should be the optimal starting point for clinical studies. Our study is the first to demonstrate the age-dependent safety and efficacy of STING-L in non-human primates and supports the potential of STING-L use as a direct immunomodulator
Identifiants
pubmed: 36620070
doi: 10.1016/j.omtm.2022.12.008
pii: S2329-0501(22)00181-4
pmc: PMC9813482
doi:
Types de publication
Journal Article
Langues
eng
Pagination
99-115Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
K.I. is an employee of Yamasa Corporation, Chiba, Japan. STING ligands used in this study were provided by the Yamasa Corporation.
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