ErythroMer: Nanoscale BioSynthetic Red Cell Substitute

ErythroMer：纳米级生物合成红细胞替代品

基本信息

批准号：
10581181
负责人：
Esma Alp
金额：
$ 105万
依托单位：
KALOCYTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-11 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581181
关键词：
Acute Address Adverse effects Affinity Animal Model Animals Antioxidants Authorization documentation Behavior Biodistribution Biological Biomedical Engineering Biotechnology Blood Blood Substitutes Blood Vessels Body Weight Canis familiaris Cardiac Electrophysiologic Techniques Caring Cell physiology Clinical Clinical Chemistry Clinical Trials Coagulation Process Complement Activation Complex Containment Control Animal Cytokine Activation Development Development Plans Diffusion Dose Drug Kinetics Drug or chemical Tissue Distribution Elements Emergency Situation Ensure Erythrocytes Evaluation Evolution Excretory function Failure Feedback Fluorocarbons Freeze Drying Gases Goals Hematology Hemoglobin Hemolysis Hemorrhage Human Hybrids In Vitro Individual Kidney Leukocytes Life Lipids Lung Marketing Medical Device Metabolic Metabolism Microscopic Morphology Multiple Trauma Natural Immunity New Zealand Nitric Oxide Nucleosome Core Particle Organ Weight Oryctolagus cuniculus Oxygen Particle Size Pathology Pathway interactions Patient Care Pharmacologic Substance Pharmacology Pharmacology Study Pharmacy (field)Phase Phase I Clinical Trials Physiological Plasma Platelet Activation Process Production Productivity Qualifying RSR-13 Recommendation Recovery Research Risk Rodent Safety Shapes Signal Transduction Site Sterility Surface Testing Tissues Toxic effect Toxicokinetics Toxicology Transfusion Update Vasospasm animal data arm authority biomaterial compatibility commercialization cost effective design expectation experimental study first-in-human food consumption good laboratory practice hemocompatibility hemodynamics innovation nano nanomaterials nanoparticle nanoscale novel novel therapeutics oxidation particle point of care portability pre-clinical preclinical evaluation preclinical safety preclinical study prevent reconstitution safety practice safety study self assembly serial imaging stem cells trial design

项目摘要

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

研究总结/摘要 ErythroMer (EM) 是一种新型生物合成血液替代品，旨在解决严重未满足的血液替代品需求在无法使用储存的红细胞 (RBC) 或无法使用的情况下进行紧急输血不受欢迎的。 EM 是一种自组装脂质寡聚杂化纳米颗粒，每个颗粒的有效负载高达血红蛋白 (Hb) 和变构调节剂 RSR13。 EM 是专门为纠正以前的故障而设计的基于血红蛋白的氧载体，不能保护红细胞生理机能。仿生电磁设计通过模拟 RBC 特性克服了之前的障碍：长期稳定性、精确的动态响应变构效应器控制 Hb 氧亲和力，控制 Hb 与一氧化氮 (NO) 的相互作用，预防血管痉挛，并通过限制在血管室中减轻血红蛋白氧化。 EM设计用于无菌冻干，可在环境条件下延长保质期，并在以下温度下提供经济高效的生产规模。 KaloCyte 制定了务实且稳健的、以目标为导向的逐步发展计划商业化包括对临床前安全性进行细致的评估以支持 FIH 剂量。一个系统且严格的基于体外、离体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该提案的前提和可行性。此外，我们致力于描绘全面的非 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 计划。为了及时实现这些里程碑，非 GLP 剂量依赖性探究组织分布、代谢和消除的 EM 药代动力学研究和探索性将进行毒理学研究。这些实验研究的成功完成将告知药代动力学行为、潜在的剂量依赖性安全信号和产品数量需求，向前推进进入 GLP 毒理学研究并最终进行 FIH 给药。所描述的综合剂量依赖性毒理学研究是为了满足 FDA 的期望而定制的，允许在 1 期临床试验中使用 EM 剂量。这一过程需要将兔子的单剂量毒理学研究扩大到给药后 14 天恢复。调查心脏电生理学、肺血流动力学和全身性的平行研究狗安全药理学研究中的血流动力学，增加了毒代动力学臂。完成这些 IND- 赋能研究提供了必要的临床前动物数据，使 KaloCyte 能够提交 IND 包 EM。 EM 能够在储存的红细胞产生不利影响的情况下极大地改变护理方式超过益处并可能实现新的功效。然而，最引人注目的用途是在以下环境中储存的红细胞不可用或不需要。 1