The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691)
The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691)
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DOI：
10.1038/clpt.2011.60
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发表时间：
2011-06-01
影响因子：
6.7
通讯作者：
van der Ryst, E.
中科院分区：
文献类型：
--
作者：
Fidock, M. D.;Souberbielle, B. E.;van der Ryst, E.
丙型肝炎病毒 (HCV) 感染是全球关注的问题，目前正在进行研究以确定有效且安全的新疗法。 PF-4878691 是一种 Toll 样受体 7 (TLR7) 激动剂，其模型可将其抗病毒活性与其炎症活性分开。在一项机制验证研究中，健康志愿者每周两次接受 3、6 和 9 毫克 PF-4878691 剂量，持续两周，PF-4878691 以剂量依赖性和剂量频率相关的方式诱导免疫和干扰素 (IFN) 反应的生物标志物。一项新发现是 PF-4878691 诱导体内 TLR7 表达，从而导致生物标志物反应放大。 9 mg 剂量无反应者的 IFN-α 受体 1 亚基 (Val168Leu) 存在多态性。两名接受 9 毫克剂量的受试者出现了严重不良事件 (SAE)，其特征是流感样症状、低血压和淋巴细胞减少，导致研究提前终止。 TLR7 刺激会产生与预测的抗病毒功效相当的药理反应，但这些剂量与 SAE 相关，引起人们对此类化合物治疗 HCV 感染的治疗窗的担忧。
Hepatitis C virus (HCV) infection is an issue of global concern, and studies are ongoing to identify new therapies that are both effective and safe. PF-4878691 is a Toll-like receptor 7 (TLR7) agonist modeled so as to dissociate its antiviral activities from its inflammatory activities. In a proof-of-mechanism study in healthy volunteers who received doses of 3, 6, and 9 mg of PF-4878691 twice a week for 2 weeks, PF-4878691 induced biomarkers of the immune and interferon (IFN) responses in a dose-dependent and dose-frequency-related manner. A novel finding was induction of TLR7 expression in vivo in response to PF-4878691, leading to an amplified biomarker response. A nonresponder at the 9-mg dose had a polymorphism in the IFN-alpha receptor 1 subunit (Val168Leu). Two subjects who had received 9-mg doses experienced serious adverse events (SAEs), characterized by flu-like symptoms, hypotension, and lymphopenia, leading to early termination of the study. TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.