ANTIBODY THERAPY OF MICROMETASTASES

目的：评价用α粒子发射体标记的抗体， 微转移的辅助或巩固治疗。 背景资料： 针对肿瘤细胞相关抗原的抗体已经用于肿瘤治疗。 作为放射性载体的癌症治疗。 静脉内给药 在大体积疾病中施用针对抗原阳性细胞的抗体， 受到许多障碍的阻碍（例如，间质毛细血管基膜 流体压力）。 这些障碍会减少或消除， 靶向单个细胞和小细胞簇。 放射性核素发射 需要高效的短程颗粒来消毒这些 单个细胞。 阿尔法粒子发射器符合这些要求，但 没有被临床研究过。 放射性标记抗体靶向 微转移也没有临床研究。 的设计 结合这两种新方法的试验必须得到 有较强的实验和理论依据。 方法：人源化S193 （抗Lewis γ，乳腺），CC 49（抗tag-72，结直肠），和单- CC 49的单链片段（sFv）将用铋-213（α- 发射体，46分钟半衰期）、铋-205（15.3天）和铟-111（2.8天） 使用CHXA-DTPA螯合物（目的1）。 乳腺癌和结直肠癌细胞 （MCF-7，LS 174 T）悬浮液和作为球状体将与 长肝Bi-205和In-111标记，以测量抗体的动力学 与单细胞结合、内化和催化以及渗透 变成球状体。 使用这些数据与以前开发的数学 模型，抗体渗透和结合在各种条件下将 模拟（目标2）。 使用Bi-213的单细胞和球状体细胞毒性- 将测量标记的抗体并与 描述抗体动力学、剂量测定和 放射生物学（目标3）。 上述模型和结果，将 结合正常组织毒性评估， α-发射体标记的抗体抗微转移的功效 帮助优化临床试验设计（目标4）。 总结： 放射性标记的抗体尚未在临床上用于消除 转移性扩散。 用α粒子发射体标记的抗体具有 没有被用于人类。 动物实验表明， 这两种方法的组合可能非常有效， 毒性 完成本补助金申请中提出的工作将 使我们有可能设计一个自我建立的临床研究， 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.