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

摘要 ZATA Pharmaceuticals，Inc.（马萨诸塞州伍斯特市）和NYBC（纽约州纽约市）建议开发一个封闭的、可处置的 能够减少病原体的系统（Z系统），用于处理输血用浓缩红细胞（pRBC）。 所提出的技术的多功能性允许创建多个版本的Z系统， 适用于不同的监管环境，并用于处理全血及其任何组分。但在 在本申请中，我们专注于开发一种用于处理pRBC的系统，该系统将被整合到 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。具体地说， 我们已经：（1）制定了详细的科学和生产概念，关于ZATA的抗病原体化合物 （ZAP-Cs），合成了3个代表性化合物：ZD 010、ZD 012和ZD 014;（2）表现出较高的对数减少率 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-Cs;（3）选择并使用无毒、生物活性的 相容的猝灭剂，其中和残留的ZAP-Cs而不改变经处理的ZAP-Cs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 进一步提高安全性;（5）申请专利。 在这一合并的第一/第二阶段提案中，我们将追求以下里程碑，目标是发展 pRBC的病原体灭活系统准备好由FDA评估用于I期临床 试验：第1年：扩大ZAP-C系列;优化和扩大ZAP-C化学;选择最佳ZAP-C， 处理条件使RBC中的病原体减少6个对数;进一步开发和优化 分析和量化ZAP-Cs及其淬灭产物;优化ZAP-C失活和去除 经过处理的RBC。第2年：制备和鉴定ZAP-Cs及其淬火产品的分析标准品; 启动ZAP-C稳定性研究;进行全面的体外试验，以证明 处理的RBC;进行体外和体内ZAP-C淬灭产品安全性研究;安排初步讨论 与FDA第3年：生产Z系统原型并选择最佳系统;准备足够数量的 最终Z系统原型并验证其性能;启动Z系统的储存有效期研究;提交 法规文件，并为I期临床试验的最终Z系统安排GMP生产。 NYBC在输血药物和血液制品生产方面的丰富研发经验和能力， 制造（NYBC在过去开发和商业化的S/D处理等离子体），结合ZATA的强大 医学和分析化学方面的专业知识使得拟议的 Z系统非常可行。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.