Nanoscience of Self 2.0: blocking CD47 recognition by phagocytes in blood & solid tumor clearance

项目摘要 ‘self’2.0的纳米科学：在血液和实体瘤清除中阻断吞噬细胞识别CD47 聚乙二醇或其他聚合物的纳米粒子涂层已成为延长循环时间的标准方法 以便最大限度地向疾病地点提供服务。然而，颗粒总是会形成血清蛋白质的日冕。 包括免疫球蛋白G、免疫球蛋白M等，它们向脾、肝甚至肿瘤的巨噬细胞发出‘吃我’的信号。特定的 也可能产生抗体，包括抗聚乙二醇抗体。 CD47是我们所有细胞上的一种蛋白质，它向巨噬细胞发出“自我”信号，并覆盖“吃我”因子。 我们细胞的表面。我们发现人-CD47抑制了包被免疫球蛋白的颗粒和红细胞的吞噬作用 通过SIRPA在“吞噬细胞突触”处发出信号[Tsai&Discher J Cell Biol 2008]。《自我》--纳米贝德秀 NOD/SCID/γ(Nsg)小鼠循环清除延迟和对移植瘤的促进作用 使用与人类兼容的SIRPA[Rodriguez Science 2013]。用抗体封闭SIRPA也消除了“自我” 发信号。我们的第一个R01使我们--除了其他成就--将基因传递提高到同样的水平 新型纳米特征CD47慢病毒异种移植模型[Sosale Mol Ther-MCD 2016]，我们 开发了一种安全有效的使用SIRPA抑制的巨噬细胞的疗法[Alvey Curr Biol 2017]。我们建议 利用不同的纳米方法提高这种工程化巨噬细胞方法的安全性和有效性。 癌症患者的I期临床试验已经在使用抗人CD47进行阻断，因为 CD47在癌细胞和所有细胞上都有表达。抗人类(CD47)试验的初步报告显示 贫血，但没有疗效。我们的小鼠模型注射了抗(鼠CD47)，同样没有显示出对 癌症和贫血以及抗RBC免疫球蛋白--因此该模型适用于我们的新方法。 我们的总体假设是CD47反对吞噬，从而抑制获得性免疫。我们的 目标是证明一种工程化的巨噬细胞疗法可以系统注射并证明是安全的(无自身免疫 贫血)，并且足够有效，以至于治愈肿瘤的小鼠获得了对进一步注射癌细胞的免疫力。 不同的纳米工具将有助于检验这一假设并实现我们的目标，包括对获得性纳米颗粒的测试 免疫、纳米颗粒对工程巨噬细胞的追踪，以及新的纳米自我阻断方法。

Project Abstract Nanoscience of `Self' 2.0: blocking CD47 recognition by phagocytes in blood & solid tumor clearance Nanoparticle coatings of PEG or other polymers have been a standard approach for prolonging circulation in order to maximize delivery to disease sites. However, particles always develop a corona of serum proteins including IgG, IgM, etc. that signal `eat me' to macrophages in the spleen, liver, and even tumors. Specific antibodies can also develop, including anti-PEG. CD47 is a protein on all of our cells that signals `Self' to macrophages and overrides `eat me' factors on the surface of our cells. We showed human-CD47 inhibits phagocytosis of IgG-coated particles and RBCs that signal at a `phagocytic synapse' through SIRPa [Tsai & Discher J Cell Biol 2008]. `Self'-nanobeads show delayed clearance from the circulation and improved delivery to tumor xenografts in NOD/SCID/γ (NSG) mice with a human-compatible SIRPa [Rodriguez Science 2013]. Blocking SIRPa with antibody also eliminated `Self' signaling. Our first R01 allowed us – among other accomplishments – to improve gene delivery to the same xenograft model with novel nano-characterized CD47-Lentivirus [Sosale Mol Ther-MCD 2016], and we developed a safe and effective therapy with SIRPa-inhibited macrophages [Alvey Curr Biol 2017]. We propose to advance the safety and efficacy of this eng'd macrophage approach using diverse nano approaches. Phase-I clinical trials in cancer patients are already using anti-(humanCD47) for blockade because CD47 is expressed on cancer cells as on all cells. Initial reports from the anti-(humanCD47) trials are showing anemia but no efficacy. Our mouse models injected with anti-(mouseCD47) likewise show no efficacy against cancer and show anemia as well as anti-RBC IgG – and so the model is appropriate for our new approach. Our overall hypothesis is that CD47 opposes engulfment and thereby inhibits acquired immunity. Our goal is to show an eng'd macrophage therapy can be injected systemically and prove safe (no autoimmune anemia) and sufficiently effective that mice cured of tumors acquire immunity to further injection of cancer cells. Diverse nano-tools will help test the hypothesis and achieve our goal, including nanoparticle tests of acquired immunity, nanoparticle tracking of eng'd macrophages, and new nano-Self blockade approaches.