Flores M Victoria, Hickling Timothy P, Sreckovic Sasha, Fidock Mark D, Horscroft Nigel, Katragadda Madan, Savic Boris, Rawal Jaiessh, Delpuech-Adams Oona E, Robas Nicola, Corey Thomas, Nelms Linda, Lawton Michael, Marcek John, Stubbs Makeida, Westby Michael, Ciaramella Giuseppe
Antivirals Group, Pfizer Inc., Sandwich, UK.
Antivir Ther. 2012;17(5):869-81. doi: 10.3851/IMP2099. Epub 2012 Apr 13.
This study presents preclinical data of a novel interferon (IFN)-α8 fusion protein, PF-04849285, and compares it with IFN-α2 and pegylated IFN-α2; the latter being the current standard of care for HCV.
The antiviral properties were evaluated in vitro using the HCV replication assay (replicon) and the general encephalomyocarditis virus assay. The binding affinity to both IFNR-subunits was assessed using surface plasmon resonance. Ex vivo experiments using cynomolgus monkey and human blood were used for the evaluation of induction of IFN-inducible biomarkers (interferon inducible protein 10 [IP-10], 2'-5'-oligoadenylate synthetase [OAS2] and interleukin-6 [IL-6]). The molecule was tested intravenously and subcutaneously in cynomolgus monkey in a single dose study for two weeks at 0.01, 1, 5 and 20 mg/kg. Each route and dose combination was given to a single male animal, blood samples were collected for evaluation of biomarkers and pharmacokinetics. The compound was also tested in cynomolgus monkey in a multiple dose study for four weeks, with a twice-a-week dosing prior to a three-week wash-out period for toxicokinetics, pharmacokinetics, and biomarker evaluation at 20, 50 or 100 mg/kg subcutaneously and 20 mg/kg intravenously.
The molecule is 10× more potent than the pegylated IFN-α2a, with potency similar to the unmodified IFN-α2a. No unanticipated findings were observed in cynomolgus monkey when dosed up to 20 mg/kg, >10,000-fold margin over the anticipated efficacious human dose.
The biomarker and toxicological findings were consistent with a potent IFN molecule. The potency and pharmacokinetic properties of the molecule are consistent with dosing at least every two weeks with the potential for monthly dosing' and not 'at least twice daily' as presented in the original [corrected].
本研究展示了一种新型干扰素（IFN）-α8融合蛋白PF-04849285的临床前数据，并将其与IFN-α2和聚乙二醇化IFN-α2进行比较；后者是目前丙型肝炎病毒（HCV）的标准治疗药物。
使用HCV复制试验（复制子）和一般脑心肌炎病毒试验在体外评估抗病毒特性。使用表面等离子体共振评估对两种IFNR亚基的结合亲和力。使用食蟹猴和人血液进行的体外实验用于评估IFN诱导生物标志物（干扰素诱导蛋白10 [IP-10]、2'-5'-寡腺苷酸合成酶[OAS2]和白细胞介素-6 [IL-6]）的诱导情况。在食蟹猴中进行单剂量研究，静脉内和皮下注射该分子，剂量为0.01、1、5和20 mg/kg，持续两周。每种给药途径和剂量组合给予一只雄性动物，采集血样以评估生物标志物和药代动力学。该化合物还在食蟹猴中进行了为期四周的多剂量研究，在为期三周的洗脱期之前每周给药两次，以进行毒代动力学、药代动力学和生物标志物评估，皮下给药剂量为20、50或100 mg/kg，静脉内给药剂量为20 mg/kg。
该分子的效力比聚乙二醇化IFN-α2a高10倍，效力与未修饰的IFN-α2a相似。在食蟹猴中给药至20 mg/kg时未观察到意外发现，比预期的有效人用剂量高出>10,000倍。
生物标志物和毒理学研究结果与一种强效IFN分子一致。该分子的效力和药代动力学特性与至少每两周给药一次一致，有可能每月给药一次，而不是如原文[已修正]所述‘至少每日两次’。
