DECONTAMINATION OF NONCELLULAR THERAPEUTIC BIOLOGICALS

描述（改编自申请人摘要） 输血相关传染病的剩余风险持续存在 尽管捐献者测试有所改进 献血者检测不能保护 预防可能进入人群的新病毒， 1979年，作为艾滋病病毒。溶剂-洗涤剂治疗，引入血浆和 血浆组分，仅对包膜病毒（env-V）有效。 该方案的总体目标是制定有效和实用的 非细胞输血产品的净化过程， 包括重组生物制剂，其对env-V有效， 无包膜病毒（non-env-V），如甲型肝炎病毒（HAV），和 细小病毒B19（PVB 19）。 该应用程序的目标是开发 绿脓杆菌（Ps）介导的光化学去污（PCD）方法 对非细胞中至少10（6）/ml non-env-V和env-V有效 治疗性生物制品 这一目标将通过 以下具体目标：1）开发使用新的Ps 衍生物（S-59）加紫外线（UVA/UBV），以消除 重要的病毒性非env-V和env-V病原体; 2）进一步检测 增强核酸失活特异性和效力的新Ps 对于非env-V，同时使用结构功能降低致突变性 基于env-V的灭活，为Ps衍生物开发的基质 病原体作为功能的主要决定因素; 3）开发一个 超声流动系统，以促进Ps介导的非 将使用HAV和脊髓灰质炎病毒评价疗效， 特征在于不可穿透的外部衣壳结构;以及4）利用 微波辐射（MR）和温度，以增强Ps-UVA病毒 失活 最初将使用噬菌体评价疗效 X174作为非去污重组人蛋白的模型，例如， 因子VIII。 将灭活非env-V和env-V病原体， 研究使用高强度UVA在流动系统中在减少的环境 02. 蛋白质产量，功能，结构和新的影响， 将使用凝血试验、放射性标记试验和免疫组织化学试验评价抗原性。 结合、质谱和免疫耐受性测定。

DESCRIPTION (Adapted from the applicant's abstract) Residual risk of transfusion-associated infectious disease persists despite improved donor testing. Donor testing cannot protect prospectively against new viruses which may enter the population, such as HIV in 1979.Solvent- detergent treatment, introduced for plasma and plasma-fractions, is only effective against enveloped viruses (env-V). The overall program objective is to develop effective and practical decontamination processes for non-cellular transfusion products, including recombinant biologicals, which are effective against env-V and non-enveloped viruses (non-env-V), such as hepatitis A virus (HAV) and parvovirus B19 (PVB19). The goal of this application is to develop psoralen (Ps)-mediated photochemical decontamination (PCD) methods effective against at least 10(6)/ml non-env-V and env-V in non-cellular therapeutic biologicals. This goal will be achieved through the following specific aims: 1) to develop methods using a novel Ps derivative (S-59) plus ultraviolet light (UVA/UBV) to inactivate significant viral non-env-V and env-V pathogens; 2) to test further novel Ps that enhance nucleic acid inactivation specificity and efficacy for non-env-V while reducing mutagenicity using structure function matrices developed for Ps derivatives based on inactivation of env-V pathogens as the primary determinant of function; 3) to develop an ultrasonic flow system to facilitate Ps mediated inactivation on non- env-V.Efficacy will be evaluated using HAV and poliovirus, both characterized by impenetrable outer capsid structures; and 4) to utilize microwave radiation (MR) and temperature to enhance Ps-UVA viral inactivation. Efficacy will be evaluated initially using bacteriophage X 174 as a model non-decontaminate recombinant human proteins, e.g., Factor VIII. Inactivation of non-env-V and env-V pathogens will be studied using high-intensity UVA in a flow system under reduced ambient 02. The effects on protein yield, function, structure, and neo- antigenicity will be evaluated using coagulation assays, radiolabel incorporation, mass spectroscopy, and an immune tolerance assay.