Balan Vijayan, Nelson David R, Sulkowski Mark S, Everson Gregory T, Lambiase Louis R, Wiesner Rusell H, Dickson Rolland C, Garcia Andy, Moore Paul A, Yu Ren, Subramanian G Mani
Mayo Clinic, Phoenix, AZ, USA.
Antivir Ther. 2006;11(7):901-8.
Albumin-interferon-alpha (alb-IFN) is a novel recombinant protein derived from IFN-alpha2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-alpha with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-alpha with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-alpha-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500-900 microg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients (P < 0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 (P < 0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-alpha.
白蛋白 - 干扰素 -α（alb - IFN）是一种新型重组蛋白，由与人类白蛋白基因融合的干扰素 -α2b 衍生而来。所得的单一多肽在一个分子中结合了干扰素 -α的抗病毒特性和白蛋白较长的血清半衰期。干扰素介导的生物学反应源于干扰素 -α与其靶受体的结合以及随后对干扰素特异性基因（ISG）表达的调节。为了评估在先前使用含干扰素 -α方案治疗失败的慢性丙型肝炎（CHC）患者中进行的 I/II 期研究期间 alb - IFN 的药效学，在 外周血中评估了 ISG 诱导情况，并与抗病毒反应进行了比较。在第 0 天、第 7 天和第 28 天从 21 名纳入高剂量（500 - 900 微克）alb - IFN 队列的患者中采集全血，这些患者在第 0 天和第 14 天接受了两次注射。使用 Taqman 实时 PCR 评估候选 ISG 的表达。ISG 的 OAS1、IRF - 7、IFI44 和 IFI27 在第 7 天和第 28 天有持续诱导。尽管所有患者对 alb - IFN 均表现出分子反应，但观察到治疗前基因表达水平和治疗期间调节倍数存在个体差异。在第 28 天，个体患者中 OAS1、IFI44 和 IRF7 的诱导显示出两两相关性（P < 0.05）。此外，第 28 天的表达诱导以及 OAS1 和 IFI44 的治疗前水平与第 28 天丙型肝炎病毒 RNA 的减少相关（P < 0.05）。总之，alb - IFN 显示出强大的 ISG 诱导作用，这与干扰素 -α相关的反应一致。
