Targeted Alpha-Particle Emitter Therapy of Metastases

这项建议的总体目标是研究针对播散性转移性癌症的可行性。 使用放射性标记有α粒子发射体Bi213(t1/2=45.6)的完整抗体和抗体片段 Min)。我们建议检验以下假设：1.由于早期肿瘤的通透性血管系统 在转移过程中，Bi-213的45.6分钟半衰期足够长，足以靶向血管化和前驱... 血管化的早期癌症转移。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，因为抗体能穿透完整的正常器官 器官会在放射性核素衰变后发生，也是因为短小的4-5细胞直径范围 阿尔法粒子将以最小的邻近正常细胞照射靶向肿瘤细胞。这个 假说将在携带肺、肝和溶骨性骨转移的Neu-N转基因小鼠身上进行验证。 特异性靶点1.测定大鼠/neu(类似于HER2/neu)受体在肿瘤中的相对表达 并在转基因Neu-N小鼠乳腺癌模型中选择正常器官。2.确定 肿瘤和正常器官中抗neu免疫球蛋白、F(ab‘)2和 法布。3.评价~(213)I标记Neu-N小鼠的MTD及剂量限制器官 反Neu构造。4.评价~(213)Bi标记的抗Neu抗体对皮下组织的作用 抗肿瘤，抗肺、肝、骨转移。5.进行微剂量学以得出剂量响应 在吸收剂量方面了解观察到的反应和毒性的关系。当前癌症 一旦肿瘤转移到远处，治疗就很少有效。根除这类疾病 转移需要一种系统性的靶向治疗，这种治疗对化疗或放射耐药性的敏感性最低， 它足以杀灭单个肿瘤细胞和细胞团，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。

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.