Radioactive Nanoparticle Immunoconjugates for the Treatment of Solid Tumors

描述(申请人提供)：转移性实体肿瘤患者迫切需要新的治疗方式。理想情况下，这些策略将把细胞毒作用集中在肿瘤细胞上，而不是健康的正常组织。其中一种被称为放射免疫疗法(RAIT)的方法需要使用抗肿瘤抗体来传递细胞毒剂，如放射性同位素。虽然RAIT在治疗血液系统恶性肿瘤方面是有效的，但它对实体肿瘤的有效性受到生理因素的限制，这些因素阻止了肿瘤治疗量的放射性积累。我们假设，通过使用放射性纳米颗粒来提高免疫结合物的比活性，可以克服这一限制。我们已经开发了快速的“一锅法”方法来生产含有数十个放射性Re原子的小(&lt；20 kDa)功能化放射性纳米颗粒。在目前的应用中，我们将这些纳米粒子偶联到工程的抗HER2单链抗体分子上，并评估它们的体外和体内靶向性。在第一个具体目标中，我们将在体外测试中生产、表征和优化分子。在第二个具体目标中，我们将评估它们的表现，重点是确定它们在两个体内模型中的药代动力学、生物分布和治疗效果：免疫缺陷小鼠移植HER2+人肿瘤和在正常组织上表达人HER2的转基因小鼠。后一项研究将提供关于背景HER2表达对这些新型药物的靶向效率、正常组织毒性和治疗效果的影响的关键信息。在拟议的研究结束时，我们将在高度相关的动物模型中对这些放射性纳米颗粒免疫结合物的靶向和治疗肿瘤的能力进行准确的评估，并将获得临床环境中可能遇到的潜在毒性的指示。我们的意图是在随后的提案中迅速将有希望的结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肿瘤靶向治疗方法。如果这里描述的临床前研究证明靶向放射性纳米粒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.