DECONTAMINATION OF NONCELLULAR THERAPEUTIC BIOLOGICALS

描述(改编自申请人的摘要) 输血相关传染病的残余风险依然存在 尽管捐赠者测试有所改进。捐赠者检测不能保护 针对可能进入人群的新病毒，如 1979年被称为HIV。溶剂-洗涤剂治疗，引入用于血浆和 血浆组分，仅对包膜病毒(env-V)有效。 整个计划的目标是开发有效和实用的 非细胞输血产品的去污工艺， 包括重组生物制品，它们对env-V和 无包膜病毒(非env-V)，如甲型肝炎病毒(HAV)和 细小病毒B19(PVB19)。此应用程序的目标是开发 补骨脂素(Ps)介导的光化学去污(PCD)方法 对非细胞中至少10(6)/毫升的非包膜病毒和包膜病毒有效 治疗性生物制剂。这一目标将通过 具体目标如下：1)开发使用新型Ps的方法 衍生物(S-59)加紫外线(紫外线/紫外线)灭活 重要的病毒非env-V和env-V病原体；2)进一步检测 增强核酸灭活特异性和有效性的新型PS 对于非环境病毒V，同时使用结构函数降低致突变性 基于Env-V失活的Ps导数矩阵 病原体作为功能的主要决定因素；3)发展一种 超声流系统促进Ps介导的非生物材料灭活 将使用甲型肝炎病毒和脊髓灰质炎病毒来评估Env-V.的有效性 以不可穿透的外壳结构为特征的；以及4)利用 微波辐射(MR)和温度增强PS-UVA病毒 失活。最初将使用噬菌体评估疗效。 X 174作为模型非去污染重组人蛋白，例如， 因素。灭活非env-V和env-V病原体将是 低环境条件下高强度UVA在流动系统中的应用研究 02.对蛋白质产量、功能、结构和近红外光谱的影响。 抗原性将使用凝血试验、放射标记 参入、质谱学和免疫耐受试验。

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.