Non-toxic Human Interferon-Alpha Analog

无毒人干扰素-α类似物

• 批准号: 6779182
• 负责人: Lorelie Villarete
• 金额: $ 55.53万
• 依托单位: PEPGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779182
• 关键词: antineoplastics; antiviral agents; cytotoxicity; drug screening /evaluation; gene expression; hamsters; immunologic substance development /preparation; interferon alpha; pharmacology; protein purification; protein sequence; yeasts

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.

描述：（由申请人提供）：人干扰素（IFN）alpha-ifnalpha2alpha（Roferon-A），ifnalpha2b（内含子）的临床可用形式。共识IFN和PEGYPED IFNS（PEG内含子和PEGASYS） - 可用于治疗几种病毒疾病和癌症。但是，当以治疗剂量使用时，它们会产生频繁的副作用，包括发烧，肌痛，CNS效应和白细胞减少症，这限制了它们的使用。 Ifninterferon是反刍动物中与结构相关的干扰素，具有与ifnalpha相似的抗病毒和抗肿瘤特性，但毒性很小或没有毒性。但是，作为异种蛋白Ifninterferon并不是作为人类肠胃外药物发育的合适候选者。我们已经合成了人类ifnalpha2b，nlvgalpha2b的类似物，该类似物使用来自Ifninterferon Molecule中相应位置的残基在位置上的五个氨基酸取代。我们SBIR I期研究的体外和体内数据表明，这些取代赋予了所得分子上的细胞毒性显着降低，而不会减少其抗病毒和抗肿瘤活性。在此II阶段项目中，我们将通过优化酵母中这种重组IFN的表达来将NLVGALPHA2B推向临床前开发，从而在良好的动物模型中产生卵巢和非甲基化的制剂，并使它们在良好的动物模型中进行严格的评估。 NLVGALPHA2B的抗病毒，抗癌，免疫原性和毒性谱将与市售的Ifnalpha2b进行比较。如果该项目成功，则应该可以给当前IFNALPHA的剂量更高剂量的患者使用NLVGALPHA2B，从而改善临床结果。