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

项目摘要 “自我”纳米科学2.0：阻断血液中吞噬细胞对CD 47的识别和实体瘤清除 PEG或其他聚合物的纳米颗粒涂层已经成为延长血液循环的标准方法。 以便最大限度地向疾病部位输送药物。然而，颗粒总是形成血清蛋白质的冠 包括IgG、IgM等，它们向脾、肝甚至肿瘤中的巨噬细胞发出“吃我”的信号。具体 也可以产生抗体，包括抗PEG。 CD 47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CD 47抑制IgG包被颗粒和红细胞的吞噬作用， 通过SIRPa在“吞噬突触”处发出信号[Tsai & Discher J Cell Biol 2008]。“自我”纳米珠显示 在NOD/SCID/γ（NSG）小鼠中延迟从循环中清除并改善向肿瘤异种移植物的递送 与人类相容的SIRPa [Rodriguez Science 2013]。用抗体阻断SIRPa也消除了“自身” 信号我们的第一个R 01使我们-在其他成就中-改善了基因递送， 使用新型纳米表征的CD 47-慢病毒[Sosale Mol Ther-MCD 2016]建立异种移植模型，我们 开发了一种安全有效的SIRPA抑制巨噬细胞疗法[Alvey Curr Biol 2017]。我们提出 以使用不同的纳米方法来提高这种工程巨噬细胞方法的安全性和有效性。 癌症患者的I期临床试验已经使用抗人CD 47进行阻断， 与所有细胞一样，CD 47在癌细胞上表达。抗人CD 47试验的初步报告显示， 贫血但无疗效。我们的小鼠模型注射抗（小鼠CD 47）抗体同样没有显示出对 癌症和显示贫血以及抗RBC IgG -因此该模型适合我们的新方法。 我们的总体假设是，CD 47对抗吞噬，从而抑制获得性免疫。我们 目的是显示engd巨噬细胞治疗可以全身注射，并证明安全（无自身免疫性 贫血）并且足够有效，使得肿瘤治愈的小鼠获得对进一步注射癌细胞的免疫力。 多样化的纳米工具将有助于测试假设并实现我们的目标，包括获得性的纳米粒子测试 免疫，纳米粒子跟踪的eng'd巨噬细胞，和新的纳米自我封锁的方法。

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.