Targeted Anti-IL-1β Platelet Mimetics for Cardiac Detoxification and Repair

项目总结 目前，心脏的缺血性损伤不能通过传统的医疗护理来修复，因此只能 姑息疗法是存在的。干细胞移植是治疗心脏疾病的一种很有前途的策略 再生，但目前的治疗方法受到再生细胞和细胞间相互作用不足的限制。 受伤的组织。在上一次资助期间，我们开发了有针对性的纳米颗粒(即双特异性抗体- 结合剂)将循环干细胞重定向到梗死心脏以进行治疗性再生。尽管 如此初步的成功，我们意识到我们的系统存在一些问题：(P1)我们不能完全回复干细胞 (“种子”)用于心脏修复。损伤后的心脏微环境(“土壤”)需要为 最大结果；(P2)抗体靶向是非常特异的，但完全依赖于抗原，这是 心脏损伤生物标志物，仅在损伤后的短时间内表达。当前的续签 该提案建立在前一项研究的基础上，但在技术和 从概念上讲。为了解决P1，我们认为其中一种抗体需要具有治疗性，以对抗 心脏过度发炎。为了解决P2，我们寻找与P2具有广谱亲和力的代理 心脏损伤。为此，我们开发了抗IL-1血小板模拟物(IL-1-PM)。IL1-PM的行动模式 以下是：血小板泡是我们系统的载体，它们具有先天发现心脏的能力。 损伤(对血小板膜上结合基序的反应)；抗IL-1抗体目前处于第三阶段 临床试验证明有中和炎症和促进心脏修复的能力；血小板 囊泡可以进一步负载干细胞衍生的生长因子，以帮助修复过程。目标1：制造 IL1-PM，并对其理化和生物学特性进行了表征。我们将通过以下方式生成IL1-PM代理 将抗IL-1抗体结合到血小板膜纳米囊泡上；结合/结合能力，毒性， IL1-PM的药代动力学将在培养细胞和健康动物中进行检测。目标2：确定 间充质干细胞分泌组负载IL-1-PM对小鼠卵巢癌模型的治疗作用 心肌梗死。缺血再灌流可诱发心肌梗死。之后，MSC-IL1-PM以及各种 控制剂，将通过静脉注射。治疗的安全性和有效性将被确定。此外, 将探索这种治疗的潜在机制。目标3：将这些发现转化为临床- 相关的心肌梗死大动物模型。将通过球囊闭塞诱导猪心肌梗死 程序。将评估MSC-IL1-PM治疗的安全性和有效性。我们的治疗系统 结合干细胞疗法(成分1)和抗IL1疗法(成分2)，这两种疗法都已 在心脏修复的临床试验中经过严格的测试和验证。此外，治疗方法将以一种 依赖于血小板结合基序的损伤发现能力的靶向方式(成分3)。所有三个组件 得到了我们小组强劲的初步数据的支持。

PROJECT SUMMARY Currently, ischemic damage to the heart cannot be repaired by conventional medical care therefore only palliative treatments exist. Stem cell transplantation is a promising strategy for therapeutic cardiac regeneration, but current therapies are limited by insufficient interaction between the regenerative cells and the injured tissue. In the last grant period, we have developed targeted nanoparticles (namely bispecific antibody- conjugated agents) to redirect circulating stem cells to the infarcted heart for therapeutic regeneration. Despite such initial success, we realize our system has some problems: (P1) We cannot fully reply on the stem cells (“seeds”) for cardiac repair. The post-injury heart microenvironment (“soil”) needs to be primed for the maximum outcome; (P2) Antibody targeting is quite specific but is fully dependent on the antigen, which are cardiac injury biomarkers that only expresses in a short period of time after injury. The current renewal proposal builds on the previous study, but represents a significant advancement, both technically and conceptually. To address P1, we reason one of the antibodies needs to be therapeutic, to combat the excessive inflammation in the heart. To address P2, we seek for agents that have broad spectrum affinity with cardiac injury. To those ends, we developed anti-IL-1 platelet mimetic (IL1-PM). The mode of action for IL1-PM is as follows: platelet vesicles serve as the carrier of our system and they have innate ability to find cardiac injury (replying on the binding motifs on platelet membranes); anti-IL-1 antibodies are currently in Phase 3 clinical trials and have demonstrated ability to neutralize inflammation and promote cardiac repair; platelet vesicles can be further loaded with stem cell-derived growth factors to aid the repair process. AIM 1: Fabricate IL1-PM and characterize its physicochemical and biological properties. We will generate IL1-PM agents by conjugating anti IL-1 antibodies onto platelet membrane nanovesicles; binding/engaging ability, toxicity, pharmacokinetics of IL1-PM will be examined in cultured cells and in healthy animals. AIM 2: Determine the therapeutic potential of mesenchymal stem cell (MSC) secretome-loaded IL1-PM in a mouse model of myocardial infarction. MI will be induced by ischemia-reperfusion. After that, MSC-IL1-PM, along with various control agents, will be delivered intravenously. Therapeutic safety and efficacy will be determined. In addition, the underlying mechanisms of such treatment will be explored. AIM 3: Translate the findings into a clinically- relevant large animal model of myocardial infarction. MI will be induced in swine via a balloon-occlusion procedure. The safety and efficacy of MSC-IL1-PM treatment will be evaluated. Our therapeutic system combines stem cell therapy (component 1) and anti-IL1 therapy (component 2), both of which have been rigorously tested and verified in clinical trials for cardiac repair. Moreover, the therapeutics will be delivered in a targetable fashion relying on the injury-finding ability of platelet binding motifs (component 3). All 3 components have been supported by strong preliminary data from our group.