Targeted Alpha-Particle Emitter Therapy of Metastases

该提案的总体目标是研究针对弥散性转移性癌症的可行性 使用用α-粒子发射体Bi-213（T1/2= 45.6）放射性标记的完整抗体和抗体片段 min）。我们建议测试以下假设：1。由于早期肿瘤的可渗透血管系统 由于Bi-213的半衰期为45.6分钟，足以靶向血管化和转移前的肿瘤， 血管化的早期癌症转移。2. Bi-213的45.6分钟半衰期放松了Bi-213的半衰期的限制。 抗体与正常器官没有交叉反应性，因为抗体渗透到完整的正常组织中， 器官将发生后，放射性核素已经衰变，也因为短的4-5细胞直径范围， α-粒子将以最小的邻近正常细胞照射来照射靶向肿瘤细胞。的 将使用携带肺、肝和溶骨性骨转移的Neu-N转基因小鼠来检验假设。 具体目标1.确定肿瘤中大鼠/neu（HER 2/neu类似物）受体的相对表达 以及在乳腺癌转基因Neu-N小鼠模型的选定正常器官中。2.确定 抗neu IgG、F（ab '）2和F（ab'）3在肿瘤和正常器官中的体内动力学和离体空间分布 Fab. 3.评价213 Bi标记的Neu-N小鼠的MTD并确定剂量限制性器官 抗neu构建体。4.评价213 Bi标记的抗neu构建体对皮下 对肺、肝、骨转移瘤的治疗作用。5.进行微剂量测定以得出剂量反应 关系，以了解观察到的反应和毒性方面的吸收剂量。当前癌症 一旦肿瘤转移到远处，治疗很少有效。根除此类 转移需要对化疗或放射抗性敏感性最低的全身性靶向治疗， 其足以杀灭单个肿瘤细胞和细胞簇， 毒性本申请中描述的工作旨在开发和评估这种方法。

The overall objective of this proposal is to examine the feasibility of targeting disseminated metastatic cancer using intact antibody and antibody fragments radiolabeled with the alpha-particle emitter Bi-213 (T1/2= 45.6 min). We propose to test the following hypotheses: 1. Due to the permeable vasculature of early tumor metastases, the 45.6 minute half-life of Bi-213 is sufficiently long to target both vascularized and pre- vascularized early cancer metastases. 2. The 45.6 minute half-life of Bi-213 relaxes the constraint that the antibody exhibit no cross-reactivity with normal organs because penetration of the antibody into intact normal organs will occur after the radionuclide has decayed and also because the short 4-5 cell diameter range of alpha-particles will irradiate targeted tumor cells with minimal adjacent normal cell irradiation. The hypotheses will be tested using Neu-N transgenic mice bearing lung, liver and osteolytic bone metastases. SPECIFIC AIMS 1. Determine the relative expression of the rat/neu (analog to HER2/neu) receptor in tumors and in selected normal organs of the transgenic Neu-N murine model of breast carcinoma. 2. Determine the kinetics, in vivo, and spatial distribution, ex vivo, in tumors and normal organs of anti-neu IgG, F(ab')2, and Fab. 3. Evaluate the MTD and determine the dose-limiting organ in Neu-N mice treated with 213Bi-labeled anti-neu constructs. 4. Evaluate the efficacy of 213Bi-labeled anti-neu constructs against sub-cutaneous tumor and against lung, liver and bone metastases. 5. Perform microdosimetry to derive dose-response relationships to understand observed responses and toxicity in terms of absorbed dose. Current cancer treatment is rarely effective once the tumor has metastasized to distant sites. The eradication of such metastases requires a systemic, targeted therapy that is minimally susceptible to chemo- or radio-resistance, that is potent enough to sterilize individual tumor cells and cell clusters and that exhibits an acceptable toxicity. The work described in this application is intended to develop and evaluate such an approach.