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

研究摘要/摘要红细胞素（EM）是一种新型的生物合成血液替代品，旨在满足至关重要的需求在不可用的红细胞（RBC）使用的情况下，紧急输血或不希望的。 EM是一种自组装的脂质 - 寡聚混合纳米粒子，每个粒子有效载荷高血红蛋白（HB）和变构修饰剂RSR13。 EM的专门设计以纠正以前的失败基于血红蛋白的氧载体，不保留RBC生理。生物启发的EM设计通过模拟RBC特征来克服以前的障碍：长期稳定性，精确的动态响应性 HB氧亲和力的变构效应器控制，HB与一氧化氮相互作用（NO）的控制，防止血管痉挛和血红蛋白氧化通过血管室中的氧化作用。 em是设计的为了无菌冻干，在环境条件下实现了延长的保质期，并提供具有成本效益的生产规模。 Kalocyte已制定了一个实用但强大的阶梯目标发展计划的发展计划商业化，包括对临床前安全的细致评估以支持FIH给药。系统和严格的体外，离体和动物模型的基于临床前概念验证策略提供了有力的证据支持该提案的前提和可行性。此外，我们对表征一个的承诺全面的非GLP药代动力学和探索性毒理学以及FDA审查的GLP毒理学 EM计划已阐明。为了及时满足这些里程碑，非GLP剂量依赖探测组织分布，代谢以及消除和探索的EM的药代动力学研究将进行毒理学研究。这些实验研究的成功完成将告知药代动力学行为，潜在剂量依赖的安全信号和产品数量需求，前进进入GLP毒理学研究，并最终给出剂量。所描述的全面剂量依赖毒理学研究是为了满足FDA期望的量身定制的，该期望允许在1期临床试验中给予EM的剂量。这个过程需要，在兔子中升级的单剂量毒理学研究已扩大到14天的剂量恢复。平行研究研究心脏电生理学，肺血液动力学和全身性研究狗安全药理学研究中的血液动力学研究增加了毒性动力学。完成这些任期促成研究提供了必要的临床前动物数据限定kalocyte，以提交IND包裹 Em。 EM具有在存储RBC的不良影响的情况下极大地改变护理的能力超过益处，并可以实现新颖的功效。但是，最引人注目的用途将是在设置中存储的RBC不可用或不可取。 1