RADIODIAGNOSIS OF SCCL WITH ANTIBODIES TO NEUROPHYSINS

该项目的目的是确定 抗人类神经内科药物抗体可用于放射诊断 小细胞肺癌(SCCL)。人类神经内科药物 (HNPs)是由大多数SCCL肿瘤产生的，并且这种持久性 财产导致了表面标记物的产生(神经物理- 相关抗原，NPRA)，由抗体识别 HNPs。用131种碘标记的形式进行的初步研究 抗体表明，它们可以有效地用于 所有产生HNP的肿瘤患者的放射影像SCCL。 具体目标是：(I)执行 131I标记多克隆抗HNPs的综合评价 作为SCCL的放射诊断剂 一种灵敏、特异、信息量大的肿瘤成像方法 这是对标准诊断方法的补充；(2)评估 现有的抗HNPs单抗及其Fab、Fab‘和F(ab’)2 片段)用于可能的临床应用 在体外与SCCL细胞结合的能力，它们提供 裸鼠移植瘤的清晰放射影像，其 肿瘤细胞的特异性及其清除的生物分布； (3)使用放射性标记制剂进行患者研究 和从动物研究中选择的抗HNP的单抗 潜在的临床效用；以及(Iv)应用我们对HNP的知识 生物合成与肿瘤血管耐受性发展改善 抗HNPs对小细胞肺癌的放射成像方法。 多克隆抗体和多克隆抗体的同步临床研究 对单抗的动物研究将在评估之前 单抗在患者和患者体内的实验应用 旨在提高药理作用的研究 将放射性核素输送到肿瘤。关于以下方面的定量信息 肿瘤与放射性核素的结合、组织剂量学与肿瘤 我们的抗体的特异性将通过伽马相机获得 双向闪烁照相、放射性分析和 免疫细胞化学。将评估抗体在体外的结合情况 通过细胞荧光分析和放射分析。一个长期存在的 插管清醒大鼠制剂将用于 生物分布和清除研究。 这项拟议的研究预计不仅会导致采用 抗HNPs作为有价值的诊断试剂，但也对他们的 最终应用于小细胞肺癌的治疗管理。

The purpose of this project is to determine the contribution that antibodies to human neurophysins can make to radiodiagnosis of small-cell carcinoma of the lung (SCCL). Human neurophysins (HNPs) are produced by most SCCL tumors, and this persistent property leads to the generation of surface makers (neurophysin- related antigens, NPRA) that are recognized by antibodies to HNPs. Pilot studies conducted with 131 I-labelled forms of these antibodies indicate they can be employed to effectively radioimage SCCL in all patients with HNP-producing tumors. Specific Aims are directed towards: (i) performing a comprehensive evaluation of 131 I-labelled polyclonal anti-HNPs as radiodiagnostic agents for SCCL with respect to their provision of a sensitive, specific, and informative method of tumor imaging that complements standard methods of diagnosis; (ii) appraising available monoclonal anti-HNPs (and their Fab, Fab' and F(ab')2 fragments) for possible clinical application based on their capacity to bind to SCCL cells in vitro, their ability to provide clear radioimages of tumor xenografts in athymic mice, their specificity for tumor cells, and their biodistribution of clearance; (iii) conducting patient studies with a radiolabelled preparation and monoclonal anti-HNP chosen from animal studies for its potential clinical utility; and (iv) applying our knowledge of HNP biosynthesis and tumor vascular resistance to develop improved methods for radioimaging SCCL tumors with anti-HNPs. Concurrent clinical investigations with polyclonal antibodies and animal studies on monoclonal antibody evaluation will precede the experimental use of monoclonal antibodies in patients and those studies on pharmacological manipulation designed to improve delivery of radionuclide to tumors. Quantitative information on tumor binding of radionuclides, tissue dosimetry, and the tumor specificity of our antibodies will be obtained by gamma-camera bidirectional scintigraphy, radiometric analysis and immunocytochemistry. Antibody binding in vitro will be assessed by cytofluorometry and radiometric analysis. A chronically catheterized conscious rat preparation will be employed for biodistribution and clearance studies. The proposed research is expected to lead not only to the adoption of anti-HNPs as valuable diagnostic agents, but also to their eventual use in the therapeutic management of SCCL.