ErythroMer: Nanoscale Bio-Synthetic Red Cell Substitute

ErythroMer：纳米级生物合成红细胞替代品

• 批准号: 9347784
• 负责人: ALLAN DOCTOR
• 金额: $ 39.76万
• 依托单位: KALOCYTE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-11 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347784
• 关键词: Address; Affinity; Animal Model; Attenuated; Authorization documentation; Biodistribution; Blood; Blood Banks; Blood Substitutes; Businesses; Caring; Cell physiology; Cells; Coagulation Process; Collaborations; Complex; Country; Department of Defense; Dose; Drug Kinetics; Encapsulated; Environment; Erythrocytes; Formulation; Freeze Drying; Funding; Goals; Hemoglobin; Hemorrhage; Hemorrhagic Shock; Hospitals; Human; Incubators; Intellectual Property; Life; Liquid substance; Lung; Medicine; Metabolic Clearance Rate; Modeling; Nitric Oxide; Organ; Oryctolagus cuniculus; Oxygen; Patients; Phase; Physiological; Polymers; Pre-hospitalization care; Process; Production; Property; Publishing; Research; Resuscitation; Risk; Route; Safety; Secure; Small Business Technology Transfer Research; Source; Sterility; System; Testing; Therapeutic; Tissues; Toxic effect; Transfusion; Translating; Universities; Washington; base; biomaterial compatibility; cost effective; crosslink; design; expectation; human study; in vivo; innovation; manufacturing process; nano; nanoparticle; nanoscale; novel; particle; process optimization; programs; prototype; reconstitution; scale up; screening; uptake; vasoconstriction

PROJECT SUMMARY There is need for an artificial oxygen (O2) carrier to substitute for banked blood in settings where: (1) stored blood is unavailable (pre-hospital care/transport, austere environments, undeveloped countries) or (2) undesirable (transfusion risk exceeds benefit). To address this need, we developed ‘ErythroMer’ (EM), a first-in- class nano-cyte blood substitute. EM is a deformable, cross-linked polymeric nanoparticle that incorporates high per particle payloads of hemoglobin (Hb). Our ‘artificial cell’ design has yielded a prototype that emulates RBC physiology in all key respects and represents a potentially disruptive introduction into Transfusion Medicine. To date, efforts to develop Hb-based oxygen carriers (HBOCs) have failed, because of design flaws which do not preserve physiologic interactions of Hb with: (1) O2 (they capture O2 in lungs, but do not release O2 effectively to tissue) and (2) nitric oxide (NO) (they trap NO, causing vasoconstriction). The EM design surmounts these weaknesses by: 1) encapsulating Hb, 2) controlling O2 capture/release with a novel 2,3-DPG shuttle (2,3-DPG is the major heterotropic effector for Hb and diminishes O2 affinity), 3) attenuating NO uptake through shell properties, and 4) retarding metHb formation by co-packaging a reduction system. Moreover, EM is designed for sterile lyophilization and so, is amenable to facile reconstitution after extended dry storage under ambient conditions. EM offers a pragmatic approach to a complex need and is designed for cost-effective production at scale. Our prototype has passed rigorous initial ex vivo and in vivo “proof of concept” testing. We founded KaloCyte so that we may translate ErythroMer innovations into a pragmatic therapeutic and as well as realize the commercial potential of a disruptive introduction into transfusion medicine. Our project goals are to scale up reliable EM production, perform pharmacokinetic studies, initiate toxicity screening and affirm efficacy in a robust animal model of hemorrhagic shock resuscitation. ErythroMer intellectual property is robust and secured by KaloCyte, which has been supported by robust entrepreneur / incubator programs that have afforded business and regulatory expertise, initial space and administrative support. STTR funding will enable KaloCyte to transition EM production from research- to pilot-scale (Phase I) and initiate groundwork required for IND authorization (Phase II). Of note, our initial studies and the approach herein meet published FDA expectations for blood substitutes. Given the significant potential for Department of Defense (DoD) collaboration and support, we have chosen to pursue hemorrhagic shock as the first indication for FDA approval. Our strategy to accelerate EM to human study involves collaborating with the DoD on a highly prioritized project to develop a “Multifunctional Resuscitation Fluid (MRF)”. We have established firm collaborations with the US Army and the MRF program, which currently lacks an O2 carrier. Following a successful trial for hemorrhagic shock, we would expand EM into other settings (pre-hospital use, blood banking in the developing world, and exploit the design to extend efficacies beyond that of stored blood).

项目摘要 需要人造氧（O2）载体在设置中代替库存的血液：（1）存储 血液不可用（院前护理/运输，严峻的环境，未开发国家）或（2） 不良的（输血风险超过福利）。为了满足这一需求，我们开发了“ erythromer”（em） 类纳米 - 酸血液替代品。 EM是一种可变形的，交联的聚合物纳米颗粒，富含高度 根据血红蛋白（HB）的颗粒有效载荷。我们的“人造细胞”设计产生了模拟RBC的原型 生理学在所有关键方面都代表了对输血医学的潜在破坏性引入。到 日期，开发基于HB的氧气载体（HBOC）的努力失败了，因为设计缺陷没有 将Hb的生理相互作用与：（1）O2（它​​们在肺中捕获O2，但不要有效释放O2 组织）和（2）一氧化氮（NO）（它们捕获NO，导致血管收缩）。 EM Design Erfmounts这些 弱点是：1）封装HB，2）用新颖的2,3-DPG班车控制O2捕获/释放（2,3-DPG 是HB的主要杂感效应子，降低O2亲和力），3）降低没有通过外壳的吸收 特性和4）通过共包装还原系统来延迟METHB形成。此外，EM是为 无菌冻干等等，可以在延长的干燥储存后轻松重建 状况。 EM为复杂的需求提供了务实的方法，专为具有成本效益的生产而设计 规模。我们的原型已经通过了严格的初始离体和体内“概念证明”测试。我们成立了 kalocyte，以便我们可以将红细胞创新转化为务实的理论，并实现 颠覆性引入输血医学的商业潜力。我们的项目目标是扩展 可靠的EM产生，进行药代动力学研究，启动毒性筛查并确认稳健的效率 出血性休克复苏的动物模型。红细胞的遗嘱特性是强大的，并且由 kalocyte，得到了有业务的强大企业家 /孵化器计划的支持 以及监管专业知识，初始空间和行政支持。 STTR资金将使Kalocyte能够过渡 EM从研究到试点规模（I阶段）的生产，并启动IND授权所需的基础。 （第二阶段）。值得注意的是，我们的初步研究和此处的方法符合已发表的FDA对血液的期望 替代品。鉴于国防部（DOD）合作与支持的重要潜力，我们有 选择追求出血性休克作为FDA批准的第一个指示。我们加速EM的策略 人类研究涉及与国防部合作进行高度优先的项目，以开发“多功能 复苏液（MRF）”。我们已经与美国陆军和MRF计划建立了公司合作 目前缺少O2载体。在成功进行出血性冲击试验之后，我们将EM扩展到 其他设置（院前使用，发展中国家的血液库，并利用设计来延长效率 超越储存的血液）。