ANTIBODY THERAPY OF MICROMETASTASES

目的：评估用α粒子发射体标记的抗体在 微转移的辅助或巩固治疗。背景： 针对肿瘤细胞相关抗原的抗体已被用于 作为放射性载体的癌症的治疗。静脉注射分娩 在大块状疾病中给抗原阳性细胞注射抗体 被许多障碍(例如，毛细血管基膜、间质 流体压力)。在以下情况下，这些障碍就会减少或消除 瞄准单个细胞和小细胞群。放射性核素发射 需要高效的短程颗粒来灭菌 单个细胞。阿尔法粒子发射器符合这些要求，但 临床上没有被调查过。放射性标记抗体靶向的研究 微转移也没有临床研究。一种新的设计 将这两种新方法结合起来的试验必须由 雄厚的实验和理论基础。方法：人性化S193 (抗Lewis伽马，乳房)，CC49(抗TAG-72，结直肠癌)，以及单抗- CC49的链片段(SFV)将用铋-213(α- 半衰期为46分钟)，铋-205(15.3d)和铟-111(2.8d) 使用CHXA-DTPA螯合物(目标1)。乳腺和结直肠癌细胞 (MCF-7，LS174T)悬浮液和球体将与 用长肝Bi205和In-111标记测定抗体的动力学 单细胞的结合、内化和分解代谢与穿透 变成椭球体。将这些数据与以前开发的数学模型结合使用 模型、抗体穿透和结合在各种条件下都会 被模拟(目标2)。Bi-213对单细胞和球形细胞的杀伤作用 标记的抗体将被测量并与预测的 描述抗体动力学、剂量学和 放射生物学(目标3)。上面得到的模型和结果将是 结合对正常组织毒性的估计来评估潜在的 α-发射体标记抗体抗微转移瘤的疗效 协助优化临床试验设计(目标4)。摘要： 放射性标记抗体还没有在临床上用于消除 转移性扩散。标记有阿尔法粒子发射体的抗体 没有被注射到人类身上。实验动物研究表明， 这两种方法的结合可能是非常有效的，只需最少的 毒性。完成这项拨款申请中建议的工作将 为这项前景看好的临床研究设计一项有依据的临床研究 治疗方法。

Objectives: Evaluate antibodies labeled with alpha particle emitters in the adjuvant or consolidation treatment of micrometastases. Background: Antibodies against tumor-cell associated antigens have been used in the treatment of cancer as carries of radioactivity. Delivery of intravenously administered antibody to antigen-positive cells in bulky disease is hindered by a number o barriers (e.g., capillary basal lamina, interstitial fluid pressure). These barriers are diminished or eliminated when targeting single cells and small cell clusters. Radionuclides emitting highly effective, short-range particles are required to sterilize such individual cells. Alpha particle-emitters met these requirements, but have not been investigated, clinically. Radiolabeled antibody targeting of micrometastases has also not been investigated clinically. The design of a trial that combines these two novel approaches must be supported by a strong experimental and theoretical rationale. Methods: Humanized S193 (anti-Lewis gamma, breast), CC49 (anti-tag-72, Colorectal), and the single- chain fragment (sFv) of CC49 will be labeled with bismuth-213 (alpha- emitter, 46 min half-life), bismuth-205 (15.3 d) and indium-111 (2.8 d) using the CHXA-DTPA chelate (aim 1). Breast and colorectal carcinoma cells (MCF-7, LS174T) in suspension and as spheroids will be used with the longer-liver Bi-205 and In-111 labels to measure the kinetics of antibody binding, internalization and catabolism to single cells and penetration into spheroids. Using this data with previously developed mathematical models, antibody penetration and binding under a variety of conditions will be simulated (aim 2). Single cell and spheroid cytotoxicity with Bi-213- labeled antibodies will be measured and compared with the predictions of mathematical models that describe antibody kinetics, dosimetry and radiobiology (aim 3). The models and results obtained above, will be combined with estimates of normal-tissue toxicity to assess the potential efficacy of alpha-emitter labeled antibodies against micrometastases and to aid in the optimization of clinical trial design (aim 4). Summary: Radiolabeled antibodies have not been used, clinically, to eliminate metastatic spread. Antibodies labeled with alpha-particle emitters have not been administered to humans. Experimental animal work suggests that a combination of these two approaches may be highly effective with minimal toxicity. Completion of the work proposed in this grant application will make it possible to design a sell-founded clinical study of this promising treatment approach.