Non-toxic Human Interferon-Alpha Analog

描述：（由申请人提供）：临床可用的人干扰素(IFN) α - ifnalpha2 α (Roferon-A), IFNalpha2b（内含子）。IFN和聚乙二醇化IFN (PEG内含子和Pegasys) -在治疗几种病毒性疾病和癌症方面是有用的。然而，当以治疗剂量使用时，它们会产生频繁且有时严重的副作用，包括发烧、肌痛、中枢神经系统效应和白细胞减少，这限制了它们的使用。ifn干扰素是反刍动物中的一种结构相关的干扰素，具有与ifnα相似的抗病毒和抗肿瘤特性，但毒性很小或没有毒性。然而，作为一种异种蛋白，干扰素并不适合作为人类肠外药物开发。我们已经合成了一种类似于人类IFNalpha2b的NLVgalpha2b，它在19、20、22、24和27个位置上含有5个氨基酸替换，使用的是ifn干扰素分子中相应位置的残基。来自我们的SBIR I期研究的体外和体内数据表明，这些取代显著降低了所得到分子的细胞毒性，而不会降低其抗病毒和抗肿瘤活性。在这个II期项目中，我们将通过优化重组IFN在酵母中的表达，生产聚乙二醇化和非聚乙二醇化的制剂，并在完善的动物模型中进行严格的评估，将NLVgalpha2b推进到临床前开发。NLVgalpha2b的抗病毒、抗癌、免疫原性和毒性将与市售的IFNalpha2b进行比较。如果该项目成功，应该有可能将NLVgalpha2b以比目前IFNalpha更高的剂量施用于患者，从而改善临床结果。

DESCRIPTION: (provided by applicant): The clinically available forms of human interferon (IFN) alpha-IFNalpha2alpha (Roferon-A), IFNalpha2b (Intron). Consensus IFN and pegylated IFNs (PEG Intron and Pegasys) - are useful in the treatment of several viral diseases and cancers. However, when used at therapeutic doses they produce frequent and sometimes serious side effects, including fever, myalgia, CNS effects and leukopenia, which limit their use. IFNinterferon, a structurally related interferon in ruminants, has similar antiviral and antitumor properties as the IFNalpha's but little or no toxicity. However, as a xenoprotein IFNinterferon is not a suitable candidate for development as a parenteral drug for humans. We have synthesized an analog of human IFNalpha2b, NLVgalpha2b, which contains five amino acid substitutions at positions19, 20, 22, 24 and 27 using residues from the corresponding positions in the IFNinterferon molecule. The in vitro and in vivo data from our SBIR phase I study demonstrated that these substitutions conferred markedly reduced cellular toxicity on the resulting molecule without diminishing its antiviral and antitumor activities. In this phase II project we will advance NLVgalpha2b into preclinical development by optimizing expression of this recombinant IFN in yeast, producing pegylated as well as unpegylated preparations and subjecting them to rigorous evaluation in well established animal models. The antiviral, anticancer, immunogenicity and toxicity profiles of NLVgalpha2b will be compared with those of commercially available IFNalpha2b. If this project is successful, it should be possible to administer NLVgalpha2b to patients in higher doses than can be achieved with current IFNalpha's, resulting in improved clinical outcomes.