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

摘要 Zata制药公司(马萨诸塞州伍斯特)和NYBC(纽约，纽约州)提议开发一种封闭式、Dispos- 可用于治疗用于输血的红细胞(PRBC)的病原体减少系统(Z系统)。 建议的技术的多功能性允许创建、改编Z-Systems的几个版本 适用于不同的监管环境，并用于治疗全血及其任何成分。但是，在 在这个应用中，我们专注于开发一个治疗pRBC的系统，该系统将集成到 美国目前使用的血液采集系统。 我们已经在Z-Systems的开发中达到了几个关键的里程碑。具体来说， 我们有：(1)对ZATA的抗病原体化合物形成了详细的科学和生产概念 (2)表现出较高的对数降低率 各种病原体，包括G和G-细菌，包膜和非包膜病毒，以及原生动物 全血及其成分在100-250微米处使用ZAP-Cs；(3)选择并使用无毒、生物... 兼容的猝灭剂，中和残留的ZAP-Cs，而不改变处理的体外性质 RBC；(4)开发了能够完全去除ZAP-C中和产物的萃取柱 从处理后的红细胞中进一步提高安全性；(5)申请专利。 在这一合并的第一阶段/第二阶段提案中，我们将追求以下里程碑，目标是开发 PRBC病原体灭活系统已准备好由FDA进行评估，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 治疗条件可使红细胞中的病原体减少6log；进一步开发和优化治疗方法 ZAP-Cs及其猝灭产物的分析和定量；优化ZAP-C的失活和去除 来自经过治疗的RBC。第2年：编制和鉴定ZAP-Cs及其淬火产品的分析标准； 启动ZAP-C的稳定性研究；进行全谱体外测试，以证明ZAP-C的保存质量 处理红细胞；进行体外和体内ZAP-C猝灭产品的安全性研究；安排初步讨论 与FDA合作。第3年：生产Z系统原型并选择最佳系统；准备足够数量的 完成Z-System样机并验证其性能；启动Z-System存储保质期研究；提交 为第一阶段临床试验的最终Z-系统提供法规文件并安排GMP生产。 NYBC在输血药物和血液制品制造方面拥有丰富的研发经验和能力。 制造(纽约广播公司过去开发并商业化S/D处理的血浆)，结合Zata的强大 药物和分析化学方面的专业知识使拟议的 Z系统具有很高的可行性。在临床研究获得FDA批准后，Z-系统的初始市场将是 美国的血液中心，包括但不限于NYBC血液中心家族。

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.