Targeted Alpha-Particle Emitter Therapy of Metastases

描述（由申请方提供）：本提案的总体目标是检查使用α粒子发射体Bi-213放射性标记的完整抗体和抗体片段靶向播散性转移癌的可行性（T1/2= 45.6 min）。我们建议测试以下假设：1。由于早期肿瘤转移的可渗透脉管系统，Bi-213的45.6分钟半衰期足够长以靶向血管化和血管化前的早期癌症转移。2. Bi-213的45.6分钟半衰期放宽了抗体不表现出与正常器官的交叉反应性的限制，因为在放射性核素衰变后将发生抗体渗透到完整的正常器官中，并且还因为α-粒子的短的4-5个细胞直径范围将以最小的相邻正常细胞照射来照射靶向肿瘤细胞。将使用携带肺、肝和溶骨性骨转移瘤的Neu-N转基因小鼠检验假设。具体目标：1。测定大鼠/neu（HER 2/neu类似物）受体在乳腺癌转基因Neu-N小鼠模型的肿瘤和选定正常器官中的相对表达。2.测定抗neu IgG、F（ab '）2和Fab在肿瘤和正常器官中的体内动力学和离体空间分布。3.在用213 Bi标记的抗neu构建体处理的Neu-N小鼠中评价MTD并确定剂量限制性器官。4.评价213 Bi标记的抗neu构建体对皮下肿瘤以及对肺、肝和骨转移的功效。5.进行微剂量测定，推导出剂量-反应关系，以了解观察到的反应和吸收剂量方面的毒性。一旦肿瘤转移到远处，目前的癌症治疗很少有效。这种转移的根除需要全身性的靶向治疗，其对化疗或放射抗性的敏感性最低，其足以使个体肿瘤细胞和细胞簇灭菌，并且表现出可接受的毒性。本申请中描述的工作旨在开发和评估这种方法。

DESCRIPTION (provided by applicant): 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 exhibits 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.