RBC-mediated mopping of cytokines for the treatment of pneumonia

摘要/摘要 尽管出现了抗生素和抗病毒药物，肺炎仍然是主要的杀手。在典型年份，它 50,000名美国人因此丧命，而在去年，新冠肺炎造成的死亡人数几乎是这个数字的10倍。出现这些情况的原因是 死亡很少，因为我们无法阻止微生物的扩张。相反，这是由于宿主的反应，在这种情况下 肺部的局部炎症导致非常高浓度的促炎细胞因子溢出到 血液，于是细胞因子传播到遥远的器官并损害它们。 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，这些抗体渗入受感染的组织(肺)，在那里它们也抑制 这些细胞因子的有益功能，这是白细胞的协调，以清除微生物。至 防止这个问题和随后的微生物过度生长，需要设计治疗方法 仅抑制血流中的细胞因子，而不是依赖于微生物细胞因子的感染组织中的细胞因子 通行证。 为了实现这一点，我们开发了RBC-MOPS。RBC-MOPS结合和猝灭细胞因子，但仅在 血流，没有渗入受感染的组织。我们将构建并测试两个RBC-MOPS 目的：在目标1中，我们将在体外测试RBC-MOPS与其靶标的结合能力，评估对红细胞的损伤 并测定RBC-MOPS在幼鼠体内的药代动力学和生物分布。在目标1中，我们 将在肺炎克雷伯氏菌小鼠模型中测试RBC-MOPS，评估对肺部和远程 器官，同时也调查潜在的副作用。 这款R21是为了在两年内生产和验证RBC-MOP原型而设计的。在那之后，我们将 申请R01以进一步发挥RBC-MOPS的翻译潜力，并更好地了解其机制。 最终，我们希望开发一种可以消除细胞因子和其他循环的RBC-MOPS组合 毒素，用于改善一系列急性疾病，包括病毒性肺炎(新冠肺炎)、败血症和无菌 免疫治疗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.