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).

项目概要 在以下环境中需要人工氧 (O2) 载体来替代储存的血液：(1) 储存 无法获得血液（院前护理/运输、严峻的环境、不发达国家）或 (2) 不良（输血风险超过益处）。为了满足这一需求，我们开发了“ErythroMer”（EM），这是一种首创的 纳米细胞类血液代用品。 EM 是一种可变形、交联的聚合物纳米颗粒，具有高 每个颗粒的血红蛋白 (Hb) 有效负载。我们的“人造细胞”设计已经产生了模拟红细胞的原型 生理学在所有关键方面都具有重要意义，并且代表着对输血医学的潜在颠覆性介绍。到 迄今为止，由于设计缺陷，开发基于 Hb 的氧载体 (HBOC) 的努力失败了。 保持 Hb 与以下物质的生理相互作用：(1) O2（它们在肺部捕获 O2，但不能有效地释放 O2 组织）和（2）一氧化氮（NO）（它们捕获一氧化氮，导致血管收缩）。 EM 设计超越了这些 缺点：1) 封装 Hb，2) 使用新型 2,3-DPG 穿梭机 (2,3-DPG) 控制 O2 捕获/释放 是 Hb 的主要异向效应子并降低 O2 亲和力），3) 减弱通过壳的 NO 摄取 性质，以及4)通过共同包装还原系统来延迟metHb形成。此外，EM 的设计目的是 无菌冻干等，在环境条件下长期干燥储存后易于重构 状况。 EM 提供了一种满足复杂需求的务实方法，旨在实现具有成本效益的生产 规模。我们的原型已经通过了严格的初始体外和体内“概念验证”测试。我们创立了 KaloCyte 使我们可以将 ErythroMer 创新转化为实用的治疗方法，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大规模 可靠的 EM 生产、进行药代动力学研究、启动毒性筛选并以稳健的方式确认功效 失血性休克复苏动物模型。 ErythroMer 知识产权强大且受到以下保护： KaloCyte，得到了强大的企业家/孵化器计划的支持，为企业提供了服务 以及监管专业知识、初始空间和行政支持。 STTR 资金将使 KaloCyte 实现转型 EM 生产从研究到中试规模（第一阶段）并启动 IND 授权所需的基础工作 （第二阶段）。值得注意的是，我们的初步研究和本文的方法符合 FDA 公布的对血液的期望 替代品。鉴于国防部 (DoD) 合作和支持的巨大潜力，我们 选择追求失血性休克作为 FDA 批准的第一个适应症。我们加速新兴市场发展的战略 人类研究涉及与国防部合作开展一个高度优先的项目，以开发“多功能 复苏液 (MRF)”。我们与美国陆军和 MRF 项目建立了牢固的合作关系， 目前缺少 O2 航母。在失血性休克试验成功后，我们将把 EM 扩展到 其他环境（院前使用、发展中国家的血库以及利用该设计来扩展功效） 超出储存的血液）。