[AASLD 2012]TLR-7 Agonist(选择性激动剂) GS-9620

肝胆速递

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
Institutional Author(s):
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.

肝胆速递

标题：TLR-7选择性激动剂GS-9620诱导人类男性和女性捐赠者的外周血单个核细胞在体外范围免疫
反应。

作者（姓氏，名字）：斯特凡Pflanz1，Christian Frey1，亚当Palazzo1
机构（S）：
机构（ALL）：1。 Gilead Sciences公司，福斯特城，加利福尼亚，美国。

摘要：目的：本研究的目的是表征 选择性的TLR-7受体激动剂，GS-9620，在人外周血单个核细胞（PBMC）的体外反应, 使用多个并行免疫读数，来评估这些反应的可变性在两个对象间和检体内的水平。
方法：11名健康献血者（女6例，男性5例）外周血单个核细胞中分离，其中10个被召回的第二个捐赠10〜12周后（女性5例，男性5例）。与GS-9620处理后确定的免疫刺激的反应，包括细胞因子的产生（点阵仪测定），诱导干扰素刺激的基因（ISG）（qPCR）的，和淋巴细胞的活化（流式细胞仪）的标记物的诱导表达。
结果：所有研究对象中分离的外周血单个核细胞GS-9620。一致的剂量依赖的生产的多种细胞因子，包括IFNa的，肿瘤坏死因子，IP-10，和IFNG观察跨两个献血。
相应的10  -  100倍增加的mRNA的表达的代表性ISG（OAS，MX-1，ISG15）连同2  - 到8倍的TLR7 mRNA表达增加与GS-9620的刺激后观察。此外，CD69的活化标志被上调27-63％CD3 + CD4 +淋巴细胞，39-77％CD3 +，CD8 +淋巴细胞和98-99％CD3-CD20 +淋巴细胞，GS-9620的处理后。在每个捐赠者外周血单个核细胞用不同浓度的GS-9620 24小时的治疗后，都献血，这些反应持续观测。在每一个捐赠者的最大反应通常变化5倍，相对于整个队列的平均最大响应。分层聚类分析，在所有测试样本的个体反应并没有透露一贯的高或低反应模式整个免疫的读数，建议多个独立的调节GS-9620-刺激的PBMC内的文化。
结论：从所有的测试个体的PBMC显示由GS-9620在体外具有低的对象间和检体内变异TLR-7刺激的响应。

咬牙硬挺

感谢分享

kaorusai

这个就是口服干扰素吧，正在临床一期，估计要到猴年马月才能上市

StephenW

回复 kaorusai 的帖子

是的，这是相当于注射Inteferon。正确的剂量，不会引致严重的副作用是最重要的考虑因素.

咬牙硬挺

干扰素能够口服的话就方便携带了

kaorusai

回复 StephenW 的帖子

可是干扰素的疗效有限，并不是很有效的药物。。。

lin12345

MP4

kaorusai 发表于 2012-10-5 14:47
这个就是口服干扰素吧，正在临床一期，估计要到猴年马月才能上市

不是，TOll样受体激动剂和口服干扰素完全不一样。
国内已有口服干扰素。