Targeted Alpha-Particle Emitter Therapy of Metastases

描述（由申请人提供）：本提案的总体目标是研究使用完整抗体和α粒子发射器Bi-213放射标记的抗体片段靶向弥散性转移性癌症的可行性（T1/2= 45.6 min）。我们建议检验以下假设：1。由于早期肿瘤转移具有可渗透的血管系统，45.6分钟的半衰期足以靶向血管化和血管化前的早期癌症转移。2. 铋-213的45.6分钟半衰期放宽了抗体与正常器官无交叉反应性的限制，因为抗体在放射性核素衰变后会渗透到完整的正常器官中，也因为α粒子的4-5细胞直径范围短，以最小的邻近正常细胞辐照照射靶向肿瘤细胞。这些假设将在携带肺、肝和溶骨转移瘤的new - n转基因小鼠身上进行验证。具体目标：1；测定大鼠/neu（类似于HER2/neu）受体在肿瘤和特定正常器官中的相对表达。2. 测定抗新IgG、F(ab')2和Fab. 3在肿瘤和正常器官体内的动力学、体内和空间分布。评价213bi标记抗新构建物对新n小鼠MTD的影响，确定给药器官。4. 评价213bi标记抗新构建物对皮下肿瘤及肺、肝、骨转移的疗效。5. 进行微剂量测定，得出剂量-反应关系，以吸收剂量了解观察到的反应和毒性。一旦肿瘤转移到远处，目前的癌症治疗很少有效。根除这种转移需要系统性的靶向治疗，这种治疗对化疗或放射耐药的敏感性最低，它足以使单个肿瘤细胞和细胞簇绝育，并表现出可接受的毒性。本应用程序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.