ErythroMer: Nanoscale BioSynthetic Red Cell Substitute

研究摘要/摘要 ErythroMer(EM)是一种新型的生物合成血液替代品，旨在解决严重未满足的血液需求 在无法使用银行储存的红血球(RBC)的情况下或在 不受欢迎。EM是一种自组装的脂质-低聚杂化纳米粒子，每粒子有效载荷高达 血红蛋白(Hb)和变构修饰剂RSR13。EM专门设计用于纠正以前的失败 以血红蛋白为基础的氧气载体，不保存红细胞生理。以生物为灵感的EM设计 通过模仿RBC功能克服以前的障碍：长期稳定，精确动态响应 变构效应控制Hb氧亲和力，控制Hb与一氧化氮(NO)的相互作用，防止 血管痉挛，以及通过在血管间隔内遏制来减轻血红蛋白氧化。EM是设计的 用于无菌冷冻干燥，能够在环境条件下延长保质期，并提供经济高效的生产 比例。KaloCyte为以下目标制定了务实而有力的循序渐进的发展计划 商业化包括对临床前安全性的细致评估，以支持FIH剂量。一种系统化的 严格的基于体外、体外和动物模型的临床前概念验证策略提供了强有力的证据 支持这一提议的前提和可行性。此外，我们致力于将一个 全面的非GLP药代动力学和探索性毒理学以及FDA审查的GLP毒理学 阐明了EM的规划。要及时达到这些里程碑，不依赖GLP剂量 EM组织分布、代谢和消除的药代动力学研究及探索性研究 将进行毒理学研究。这些实验研究的成功完成将有助于 药代动力学行为、潜在剂量依赖的安全信号和产品数量需求 GLP毒理学研究和最终FIH剂量。所描述的全面的剂量依赖关系 毒理学研究是为满足FDA的期望而量身定做的，该期望允许在第一阶段临床试验中给EM剂量。 这一过程需要，将对兔的单次剂量毒理学研究扩大到14天后进行 恢复。心脏电生理学、肺血流动力学和全身研究的平行研究 增加毒动臂的狗安全药理学研究中的血流动力学。完成这些IND- 使能研究提供必要的临床前动物数据，使KaloCyte有资格提交IND包 嗯。EM有能力在以下情况下显著改变护理：储存的红细胞的不良影响 超越利益，并可能实现新的效率。然而，最令人信服的使用将是在以下情况下 存储的RBC不可用或不受欢迎。 1

Research Summary/Abstract ErythroMer (EM) is a novel biosynthetic blood substitute developed to address the critically unmet need for emergency transfusion in situations where the use of banked red blood cells (RBCs) are either not available or undesirable. EM is a self-assembled lipid-oligomeric hybrid nanoparticle with a high per particle payload of hemoglobin (Hb) and the allosteric modifier, RSR13. EM is specifically designed to rectify failures of previous hemoglobin-based oxygen carriers, which do not preserve RBC physiology. The bio-inspired EM design surmounts previous obstacles by emulating RBC features: long term stability, precise dynamically-responsive allosteric effector control of Hb oxygen affinity, control of Hb interaction with nitric oxide (NO), preventing vasospasm, and mitigation of hemoglobin oxidation by containment in the vascular compartment. EM is designed for sterile lyophilization enabling extended shelf life at ambient conditions and offers cost-effective production at scale. KaloCyte has developed a pragmatic yet robust step-wise goal oriented development plan for commercialization including meticulous evaluation of preclinical safety to support FIH dosing. A systematic and rigorous in vitro, ex vivo and animal model based pre-clinical proof-of-concept strategy provides strong evidence supporting the premise for and feasibility of this proposal. Further, our commitment to characterize a comprehensive non-GLP pharmacokinetic and exploratory toxicology as well as an FDA vetted GLP toxicology plan for EM is elucidated. To meet these milestones in a timely fashion, non-GLP dose dependent pharmacokinetic studies of EM that probe tissue distribution, metabolism, and elimination and exploratory toxicology studies will be conducted. Successful completion of these experimental studies will inform on pharmacokinetic behavior, potential dose dependent safety signals and product quantity needs, moving forward into GLP toxicology studies and eventually FIH dosing. The described, comprehensive dose dependent toxicology studies are tailored to meet FDA expectations that allows for dosing of EM in a Phase 1 clinical trial. This process requires, escalating single dose toxicology study in rabbits expanded to 14 days for post dose recovery. Parallel studies investigating cardiac electrophysiology, pulmonary hemodynamics, and systemic hemodynamics in a dog safety pharmacology study with an added toxicokinetic arm. Completion of these IND- enabling studies provides necessary pre-clinical animal data qualifying KaloCyte to submit an IND package for EM. EM has the capability to dramatically transform care in situations where the adverse effects of stored RBCs exceed benefit and may enable novel efficacies. However, the most compelling use will be in settings where stored RBCs are unavailable or undesirable. 1