Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases
Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases
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DOI：
10.1073/pnas.0609001104
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发表时间：
2007-05-15
影响因子：
11.1
通讯作者：
Patten, Phillip A.
中科院分区：
文献类型：
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作者：
Brideau-Andersen, Amy D.;Huang, Xiaojian;Patten, Phillip A.
I型IFN是与单个异源二聚体受体结合并具有有效的抗病毒、抗增殖和免疫调节活性的异常多效性细胞因子。I型IFN的不同作用具有不同的治疗重要性;在癌症治疗中，增强的抗增殖作用可能是有益的，而在病毒感染（如乙型肝炎B和丙型肝炎）的治疗中，抗增殖作用导致剂量限制性骨髓抑制。研究表明，天然IFN-α家族的各种成员和工程变体，如IFN-con 1，在各种IFN介导的细胞活性之间的比例不同。我们使用DNA改组来探索和证实一个可以同时增加抗病毒和Th 1诱导活性和降低抗增殖活性的假设。我们报道了IFN-a杂合物，其中抗病毒：抗增殖和Th 1诱导：抗增殖效力的比率随着IFN-con 1的应答而显著增加（分别为75倍和80倍）。与IFNAR 1结合位点重叠并通过与假基因杂交而衍生的四个残基序对该表型有显著贡献。这些IFN-α具有可导致改善的治疗指数的活性特征，并因此导致用于治疗慢性病毒性疾病如B型肝炎病毒、人乳头瘤病毒、HIV或慢性丙型肝炎的更好的临床功效。
Type I IFNs are unusually pleiotropic cytokines that bind to a single heterodimeric receptor and have potent antiviral, antiproliferative, and immune modulatory activities. The diverse effects of the type I IFNs are of differential therapeutic importance; in cancer therapy, an enhanced antiproliferative effect may be beneficial, whereas in the therapy of viral infections (such as hepatitis B and hepatitis C), the anti proliferative effects lead to dose limiting bone marrow suppression. Studies have shown that various members of the natural IFN-alpha family and engineered variants, such as IFN-con1, vary in the ratios between various IFN-mediated cellular activities. We used DNA shuffling to explore and confirm the hypothesis that one could simultaneously increase the antiviral and Th1-inducing activity and decrease the antiproliferative activity. We report IFN-a hybrids wherein the ratio of antiviral:antiproliferative and Th1-inducing: anti proliferative potencies are markedly increased with respsect to IFN-con1 (75- and 80-fold, respectively). A four-residue motif that overlaps with the IFNAR1 binding site and is derived by cross breeding with a pseudogene contributes significantly to this phenotype. These IFN-alpha s have an activity profile that may result in an improved therapeutic index and, consequently, better clinical efficacy for the treatment of chronic viral diseases such as hepatitis B virus, human papilloma virus, HIV, or chronic hepatitis C.