ErythroMer: Nanoscale Bio-Synthetic Red Cell Substitute

项目总结 在以下情况下需要人造氧(O2)载体来替代库存血液：(1)存储 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(输血风险大于收益)。为了满足这一需求，我们开发了ErythroMer(EM)，这是一款领先的 类纳米细胞血液代用品。EM是一种可变形的、交联的聚合物纳米颗粒，它包含了 每粒子有效载荷的血红蛋白(Hb)。我们的‘人造细胞’设计已经产生了一个模拟红细胞的原型 在所有关键方面的生理学，并代表了对输血医学的潜在颠覆性介绍。至 迄今为止，开发基于Hb的氧气载体(HBOC)的努力失败了，因为设计缺陷不能 保存Hb与：(1)O2的生理相互作用(它们在肺中捕获O2，但不能有效地释放O2到 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：1)包裹HB，2)用新型2，3-DPG(2，3-DPG)航天器控制O2的捕获/释放 是Hb的主要异向性效应因子，并降低O2亲和力)，3)减弱通过外壳的NO摄取 性质，以及4)通过共包装还原系统来延缓metHb的形成。此外，EM的设计目标是 无菌冷冻干燥等，在常温下长期干燥保存后，易于恢复 条件。EM为复杂需求提供了一种务实的方法，旨在实现具有成本效益的生产，网址为 比例。我们的样机已经通过了严格的初步体外和体内“概念验证”测试。我们创立了 因此，我们可以将红细胞的创新转化为一种务实的治疗方法，以及实现 颠覆性地引入输血医学的商业潜力。我们的项目目标是扩大规模 可靠的EM生产，执行药代动力学研究，启动毒性筛选并确认疗效 失血性休克复苏的动物模型。ErythroMer的知识产权非常强大，并受到 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 EM生产从研究到中试(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，我们最初的研究和这里的方法符合FDA公布的血液预期。 替代品。鉴于国防部(DoD)协作和支持的巨大潜力，我们有 选择追求失血性休克作为FDA批准的第一个适应症。我们加快新兴市场发展的战略 人体研究涉及到与国防部在一个高度优先的项目上进行合作，以开发一种“多功能” 复苏液(MRF)“。我们已经与美国陆军和MRF项目建立了牢固的合作关系， 它目前缺少氧气载体。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，以及利用设计来扩展有效性 除了储存的血液之外)。

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).