ErythroMer: Nanoscale Bio-Synthetic Red Cell Substitute

项目摘要 需要一种人工氧（O2）载体来替代库存血液，用于以下环境：（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（输血风险超过获益）。为了满足这一需求，我们开发了“ErythroMer”（EM），这是一种 类纳米细胞血液替代品。EM是一种可变形的交联聚合物纳米颗粒， 血红蛋白（Hb）的每粒子有效载荷。我们的“人造细胞”设计已经产生了一个模仿RBC的原型 生理学的所有关键方面，并代表了一个潜在的破坏性介绍到输血医学。到 迄今为止，开发基于Hb的氧载体（HBOCs）的努力已经失败，因为设计缺陷不 保持Hb与以下物质的生理相互作用：（1）O2（它们在肺中捕获O2，但不有效释放O2， 组织）和（2）一氧化氮（NO）（它们捕获NO，引起血管收缩）。EM设计超越了这些 缺点在于：1）包裹Hb，2）用新型2，3-DPG穿梭体（2，3-DPG）控制O2捕获/释放 是Hb的主要异向性效应子，并降低O2亲和力），3）减弱通过壳层的NO摄取 性质，和4）通过共包装还原系统来延迟metHb形成。此外，EM是专为 无菌冻干等，在环境温度下延长干燥储存后易于复原 条件EM为满足复杂需求提供了一种务实的方法， 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。我们创办 KaloCyte，以便我们可以将ErythroMer创新转化为务实的治疗方法，并实现 颠覆性地引入输血医学的商业潜力。我们的项目目标是 可靠的EM生产，进行药代动力学研究，启动毒性筛选，并在一个稳健的 失血性休克复苏动物模型。ErythroMer知识产权是强大的，并通过以下方式得到保护： KaloCyte得到了强大的企业家/孵化器计划的支持，这些计划为企业提供了 以及监管专业知识、初始空间和行政支持。STTR资金将使KaloCyte能够过渡到 EM生产从研究到中试规模（I期），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公布的血液预期 替代品鉴于国防部（DoD）合作和支持的巨大潜力，我们 选择出血性休克作为FDA批准的第一个适应症。我们的战略是加速EM， 人类研究包括与国防部合作，在一个高度优先的项目上开发一种“多功能 复苏液（MRF）"。我们与美国陆军和MRF计划建立了牢固的合作关系， 目前缺乏氧气载体。在失血性休克试验成功后，我们将扩大EM， 其他环境（院前使用，发展中国家的血库，并利用设计来扩展功效 超过储存的血液）。

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).