CONTROL ID: 1423619
PRESENTATION TYPE: Oral or Poster
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
TITLE: The Selective TLR-7 Agonist GS-9620 Consistently Induces a Spectrum of In Vitro Immune Responses in Human Peripheral Blood Mononuclear Cells from Male and Female Donors.
AUTHORS (FIRST NAME, LAST NAME): Stefan Pflanz1, Christian Frey1, Adam Palazzo1
INSTITUTIONS (ALL): 1. Gilead Sciences, Foster City, CA, United States.
ABSTRACT BODY: Objective: The objective of this study was to characterize in vitro responses of human peripheral blood mononuclear cells (PBMC) to a selective TLR-7 agonist, GS-9620, using multiple parallel immunostimulatory readouts and to assess the variability of these responses at both the inter-subject and intra-subject levels.
Methods: PBMC were isolated from 11 healthy blood donors (6 females, 5 males), 10 of which were recalled for a second donation 10-12 weeks after the first donation (5 females, 5 males). Immunostimulatory responses determined after treatment with GS-9620 included the production of cytokines (Luminex assay), induction of interferon-stimulated genes (ISG) (qPCR), and induced expression of markers of lymphocyte activation (flow cytometry).
Results: PBMCs isolated from all study subjects responded to GS-9620. Consistent dose-dependent production of multiple cytokines including IFNa, TNF, IP-10, and IFNg was observed across both blood donations.
Corresponding 10- to 100-fold increased mRNA expression of representative ISG (OAS, MX-1, ISG15) together with 2- to 8-fold increase of TLR7 mRNA expression was observed upon the stimulation with GS-9620. In addition, the CD69 activation marker was upregulated on 27-63% CD3+CD4+ lymphocytes, on 39-77% CD3+CD8+ lymphocytes and on 98-99% CD3-CD20+ lymphocytes upon the treatment with GS-9620. These responses were observed consistently in each donor PBMCs from both blood donations following the treatment with various concentrations of GS-9620 for 24 hours. The maximal responses in each donor usually varied < 5-fold relative to the mean maximal responses for the whole cohort. Hierarchical clustering analysis of individual responses across all tested samples did not reveal consistent high or low response patterns across the immunostimulatory readouts, suggesting multiple independent levels of regulation of GS-9620-dependent stimulation within the PBMC cultures.
Conclusion: PBMC from all tested individuals showed responses to the stimulation of TLR-7 by GS-9620 in vitro with a low inter-subject and intra-subject variability.
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