Radioactive Nanoparticle Immunoconjugates for the Treatment of Solid Tumors

描述（由申请人提供）：转移性实体瘤患者迫切需要新的治疗方式。理想情况下，这些策略将集中对肿瘤细胞的细胞毒性作用，而不影响健康的正常组织。一种称为放射免疫疗法（赖特）的这样的方法需要采用抗肿瘤抗体来递送细胞毒性剂，例如放射性同位素。虽然赖特在血液恶性肿瘤的治疗中是有效的，但其对实体瘤的效用受到阻止治疗量的放射性的肿瘤积累的生理因素的限制。我们假设，通过使用放射性纳米颗粒增加免疫缀合物的比活性可以克服这种限制。我们已经开发了快速的“一锅法”方法来生产含有大量放射性核素原子的小（< 20 kDa）官能化放射性纳米颗粒。在本申请中，我们将这些纳米颗粒结合到工程化的抗HER 2单链Fv分子上，并评估其体外和体内靶向特性。在第一个具体目标中，我们将在体外试验中生产，表征和优化分子。在第二个具体目标中，我们将评价它们的性能，重点是确定它们在两种体内模型中的药代动力学、生物分布和疗效;携带HER 2+人肿瘤异种移植物的免疫缺陷小鼠和在正常组织上表达人HER 2的转基因小鼠。后一项研究将提供背景HER 2表达对这些新型药物的靶向效率、正常组织毒性和治疗功效的影响的关键信息。在拟定的研究结束时，我们将准确评估这些放射性纳米颗粒免疫缀合物在高度相关的动物模型中靶向和治疗肿瘤的能力，并将获得关于临床环境中可能遇到的潜在毒性的指示。我们的目的是在随后的提案中迅速将有前途的缀合物转化为临床试验。公共卫生声明拟议的研究重点是开发一种新的实体瘤靶向治疗方法。如果这里描述的临床前研究表明，靶向放射性纳米粒子与良好的治疗效果和最小的正常组织毒性相关，我们将尽快进入临床环境。

DESCRIPTION (provided by applicant): New treatment modalities are desperately needed for patients with metastatic solid tumors. Ideally, these strategies would focus cytotoxic effects on the tumor cells and spare healthy normal tissues. One such approach known as Radioimmunotherapy (RAIT) entails employing anti-tumor antibodies to deliver cytotoxic agents such as radioisotopes. While RAIT has been effective in the treatment of hematological malignancies, its utility against solid tumors is limited by physiological factors that prevent the tumor accumulation of therapeutic quantities of radioactivity. We hypothesize that this limitation could be overcome by increasing the specific activity of the immunoconjugates through the use of radioactive nanoparticles. We have developed rapid "one pot" methodology to produce small (< 20 kDa) functionalized radioactive nanoparticles containing scores of radioactive rhenium atoms. In the current application, we will conjugate these nanoparticles to engineered anti-HER2 single-chain Fv molecules and evaluate their in vitro and in vivo targeting properties. In the first specific aim, we will produce, characterize and optimize the molecules in in vitro assays. In the second specific aim, we will evaluate their performance focusing on determining their pharmacokinetics, biodistribution and therapeutic efficacy in two in vivo models; immunodeficient mice bearing HER2 + human tumor xenografts and transgenic mice expressing human HER2 on normal tissues. The latter studies will provide critical information on the impact of background HER2 expression on the targeting efficiency, normal tissue toxicity and therapeutic efficacy of these novel agents. At the conclusion of the proposed studies we will have an accurate assessment of the ability of these radioactive nanoparticle immunoconjugates to target and treat tumors in highly relevant animal models and will have acquired an indication regarding potential toxicities that could be encountered in the clinical setting. It is our intention to rapidly translate promising conjugates into clinical trials in subsequent proposals. Public Health Statement The proposed research is focused on developing a new targeted treatment for solid tumors. If the preclinical studies described here demonstrate that targeted radioactive nanoparticles are associated with a favorable therapeutic efficacy with minimal normal tissue toxicity, we will proceed as rapidly as possible to the clinical setting.