RBC-mediated mopping of cytokines for the treatment of pneumonia

摘要/总结 尽管抗生素和抗病毒药物的出现，肺炎仍然是一个主要的杀手。在典型年份， 超过50，000名美国人死亡，而在去年，由于COVID-19，死亡人数增加了近10倍。原因让这些 死亡很少是因为我们无法阻止微生物的扩张。相反，这是由于主机响应，其中 肺部的局部炎症导致非常高浓度的促炎细胞因子溢出到肺内， 血液中的细胞因子会转移到远处的器官并造成损害。 为了消除过多的细胞因子，已经开发了许多抗体来结合和中和 细胞因子然而，这些抗体渗出到感染的组织（肺），在那里它们也抑制了免疫反应。 这些细胞因子的有益功能，这是白细胞的编排，以清除微生物。到 为了防止该问题和随后的微生物过度生长，需要设计治疗剂， 仅淬灭血流中的细胞因子，而不淬灭依赖细胞因子进行微生物增殖的感染组织中的细胞因子。 间隙 为了实现这一目标，我们开发了RBC-Mops。RBC-Mops结合并淬灭细胞因子，但仅在 血液，没有外渗到感染的组织。我们将在两个平台上构建和测试RBC-Mops 目的：在目的1中，我们将测试RBC-Mops体外结合其靶标的能力，评估对RBC的损伤 自身，并确定RBC-Mop在幼稚小鼠中的药代动力学和生物分布。目标1： 将在肺炎克雷伯氏菌小鼠模型中测试RBC-Mops，评估其对肺部和远端的益处。 器官，同时也研究潜在的副作用。 R21的设计目标是在2年内生产和验证原型RBC-Mop。在那之后，我们会 申请R 01以进一步促进RBC-Mops的翻译潜力，并更好地了解其机制。 最终，我们希望开发一种RBC-Mops组合，可以消除细胞因子和其他循环因子。 毒素，以改善大范围的急性疾病，包括病毒性肺炎（COVID-19），败血症和不育症， 由免疫疗法产生的细胞因子释放综合征。

ABSTRACT / SUMMARY Despite the advent of antibiotics and antivirals, pneumonia remains a major killer. In typical years, it kills >50,000 Americans, and in the last year, nearly 10x that amount due to COVID-19. The reason for these deaths is rarely because we cannot stop microbial expansion. Rather, it is due to the host response, in which local inflammation in the lungs causes a very high concentration of pro-inflammatory cytokines to spill into the blood, whereupon the cytokines travel to and damage remote organs. To eliminate excessive cytokines, many antibodies have been developed to bind and neutralize cytokines. However, these antibodies extravasate into the infected tissue (lungs), where they also inhibit the beneficial function of these cytokines, which is the orchestration of leukocytes to clear the microbes. To prevent this problem and the subsequent microbial overgrowth, there is a need to engineer therapeutics that only quench cytokines in the bloodstream, and not in the infected tissues that rely upon cytokines for microbial clearance. To accomplish this, we have developed RBC-Mops. RBC-Mops bind and quench cytokines, but only in the bloodstream, with no extravasation into infected tissues. We will build and test RBC-Mops across two Aims: In Aim 1, we will test RBC-Mops ability to bind their targets in vitro, evaluate for damage to RBCs themselves, and determine the pharmacokinetics and biodistribution of RBC-Mops in naive mice. In Aim 1, we will test RBC-Mops in the Klebsiella mouse model of pneumonia, evaluating benefits to the lungs and remote organs, while also investigating potential side effects. This R21 is designed to produce and validate the prototype RBC-Mop within 2 years. After that, we will apply for an R01 to further the translational potential of RBC-Mops and better understand their mechanisms. Eventually, we hope to develop a combination of RBC-Mops that can eliminate cytokines and other circulating toxins, to ameliorate a large range of acute illnesses, including viral pneumonia (COVID-19), sepsis, and sterile cytokine release syndromes produced by immunological therapies.