A CLOSED SYSTEM FOR PATHOGEN REDUCTION OF RED BLOOD CELLS FOR TRANSFUSION

用于减少输血红细胞病原体的封闭系统

• 批准号: 10026455
• 负责人: David R Tabatadze
• 金额: $ 101.09万
• 依托单位: ZATA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026455
• 关键词: Acute; Aftercare; Analytical Chemistry; Autoimmunity; Aziridines; Bacteria; Binding; Biological; Biological Assay; Blood; Blood Component Removal; Blood Platelets; Blood Transfusion; Blood-Borne Pathogens; Chemicals; Chemistry; Clinical Research; Clinical Trials; Collection; Communicable Diseases; Country; Data; Development; Documentation; Dose; Environment; Erythrocyte Transfusion; Erythrocytes; Evaluation; Excision; Exhibits; FDA approved; Family; Filtration; Formulation; Goals; In Vitro; Infection; Legal patent; Life; Light; Liquid substance; Marketing; Methodology; Methods; Modeling; New York; No-Observed-Adverse-Effect Level; Nucleic Acids; Outcome; Packed Red Blood Cell Transfusion; Parasites; Performance; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Polyamines; Procedures; Production; Property; Proteins; Protozoa; Race; Rattus; Residual state; Resources; Risk; Safety; Scheme; Screening procedure; Small Business Innovation Research Grant; System; Technology; Testing; Toxic effect; Transfusion; Virus; Whole Blood; Work; biomaterial compatibility; blood product; clinical development; commercialization; cost effective; design; experience; first-in-human; genotoxicity; improved; in vitro testing; in vivo; infection risk; irradiation; member; novel; pandemic disease; pathogen; preclinical safety; preservation; prototype; research and development; research clinical testing; safety study; safety testing; scale up; stability testing; transfusion medicine

ABSTRACT ZATA Pharmaceuticals, Inc. (Worcester, MA) and NYBC (New York, NY) propose to develop a closed, dispos- able pathogen reduction system (Z-System) for treatment of packed Red Blood Cells (pRBC) for transfusion. The versatility of the proposed technology allows for several versions of the Z-Systems to be created, adapted to different regulatory environments, and for treatment of whole blood and any of its components. However, in this application we focus on the development of a system for treatment of pRBC that will be integrated into the blood collection system currently used in the USA. We have already reached several critical milestones in the development of the Z-Systems. Specifically, we have: (1) developed a detailed scientific and production concept about ZATA’s Anti-Pathogen compounds (ZAP-Cs) and synthesized 3 representatives: ZD010, ZD012, and ZD014; (2) demonstrated high log reduction of various pathogens, including G+ and G- bacteria, enveloped and non-enveloped viruses, and protozoa in whole blood and in its components by using ZAP-Cs at 100-250 µM; (3) Selected and used a non-toxic, bio- compatible quencher that neutralizes the residual ZAP-Cs without changing the in vitro properties of treated RBC; (4) developed extraction cartridges which enable the complete removal of ZAP-C neutralization products from the treated RBC to further improve safety; and (5) filed patent applications. In this combined phase I/II proposal, we will pursue the following milestones with the goal for developing of a pathogen inactivation system for pRBC ready for evaluation by the FDA for use in Phase I clinical trials: Year 1: Expand ZAP-C family; optimize and scale-up ZAP-C chemistry; select optimal ZAP-C and treatment conditions enabling 6 log reduction of pathogens in RBC; further develop and optimize methods of analysis and quantification of ZAP-Cs and their quenching products; optimize ZAP-C deactivation and removal from treated RBC. Year 2: Prepare and qualify analytical standards of ZAP-Cs and their quenching products; initiate stability studies of ZAP-C; perform full spectrum of in vitro tests to demonstrate preserved quality of treated RBC; perform in vitro and in vivo ZAP-C quenching products safety studies; arrange initial discussion with FDA. Year 3: Produce Z-System prototypes and select the optimal system; prepare sufficient number of final Z-System prototype and validate its performance; initiate storage shelf-life study of Z-System; submit regulatory documents and arrange GMP manufacturing for final Z-system for Phase I clinical testing. The extensive R&D experience and capacity of NYBC in transfusion medicine and blood product manu- facturing (NYBC in the past developed and commercialized S/D-treated plasma), combined with ZATA’s strong expertise in medicinal and analytical chemistry makes the development and commercialization of the proposed Z-System highly feasible. After clinical studies leading to FDA approval, initial market for the Z-System will be blood centers in the US, including but not limited to the NYBC family of blood centers.

抽象的 ZATA Pharmaceuticals, Inc.（马萨诸塞州伍斯特）和 NYBC（纽约州纽约）提议开发一种封闭式处置药物 用于处理输血用浓缩红细胞 (pRBC) 的病原体减少系统 (Z-System)。 所提议技术的多功能性允许创建、调整 Z 系统的多个版本 适应不同的监管环境，以及用于处理全血及其任何成分。 在该应用中，我们专注于开发用于治疗 pRBC 的系统，该系统将集成到 目前在美国使用的血液采集系统。 我们在 Z 系统的开发过程中已经达到了几个重要的里程碑，具体来说， 我们：(1) 制定了有关 ZATA 抗病原体化合物的详细科学和生产概念 (ZAP-Cs) 并合成了 3 个代表：ZD010、ZD012 和 ZD014 (2) 表现出高对数还原性； 各种病原体，包括 G+ 和 G- 细菌、有包膜和无包膜病毒以及原生动物 全血及其成分，使用 100-250 µM 的 ZAP-C； (3) 选择并使用无毒的生物制剂； 相容的猝灭剂，可中和残留的 ZAP-C，而不改变处理后的体外特性 RBC；(4) 开发了能够完全去除 ZAP-C 中和产物的提取柱 经RBC处理以进一步提高安全性；以及（5）提交专利申请。 在这个第一/第二阶段合并提案中，我们将追求以下里程碑，目标是开发 用于 pRBC 的病原体灭活系统已准备好接受 FDA 评估以用于 I 期临床 试验：第 1 年：扩展 ZAP-C 系列；优化和扩大 ZAP-C 化学；选择最佳 ZAP-C 和 使红细胞中病原体减少 6 个对数的处理条件；进一步开发和优化方法 ZAP-C 及其猝灭产物的分析和定量；优化 ZAP-C 失活和去除； 第 2 年：准备并鉴定 ZAP-C 及其淬火产品的分析标准品； 启动 ZAP-C 的稳定性研究；进行全方位的体外测试，以证明其保持的质量 RBC；进行体外和体内ZAP-C猝灭产品安全性研究；安排初步讨论； 第 3 年：生产 Z 系统原型并选择最佳系统； 最终的 Z-System 原型并验证其性能；启动 Z-System 的存储保质期研究； 监管文件并安排 GMP 制造用于 I 期临床测试的最终 Z 系统。 NYBC在输血医学和血液制品生产领域丰富的研发经验和能力 制造（NYBC 过去开发并商业化了 S/D 处理血浆），结合 ZATA 强大的 药物和分析化学方面的专业知识使得所提议的药物的开发和商业化 Z-System 高度可行，经过 FDA 批准的临床研究后，Z-System 的初始市场将是。 美国的血液中心，包括但不限于 NYBC 血液中心系列。