RADIODIAGNOSIS OF SCCL WITH ANTIBODIES TO NEUROPHYSINS

该项目的目的是确定 抗人神经垂体后叶素的抗体对放射诊断 肺小细胞癌（SCCL） 人神经垂体素 （HNP）是由大多数SCCL肿瘤产生的，这种持续的 属性导致表面制造商（neurophysin， 相关抗原，NPRA），这些抗原被抗体识别， HNP。 用131 I标记的这些形式进行了初步研究 抗体表明它们可以有效地 放射成像SCCL在所有HNP产生肿瘤的患者。 具体目标是：（一）执行一项 131 I标记多克隆抗HNP的综合评价 作为SCCL的放射诊断剂， 一种灵敏、特异、信息丰富的肿瘤成像方法， 补充标准诊断方法;（二）评估 可用的单克隆抗HNP（及其Fab、Fab'和F（ab'）2 片段）用于可能的临床应用， 体外结合SCCL细胞的能力，它们提供 无胸腺小鼠中肿瘤异种移植物的清晰放射图像， 对肿瘤细胞的特异性及其清除的生物分布; (iii)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单克隆抗HNP， 潜在的临床效用;及（iv）运用我们对HNP的知识 生物合成和肿瘤血管阻力发展改善 用抗HNP对SCCL肿瘤进行放射成像的方法。 同时进行多克隆抗体和 单克隆抗体评价的动物研究将先于 单克隆抗体在患者和那些 药理学研究旨在改善 将放射性核素递送到肿瘤。 的定量信息 放射性核素的肿瘤结合、组织剂量测定和肿瘤 我们的抗体的特异性将通过伽马照相机获得 双向层析成像、放射性分析和 免疫细胞化学 将评估体外抗体结合 通过细胞荧光和放射性分析。 一个慢性 将采用插管的清醒大鼠制备物用于 生物分布和清除研究。 预计拟议的研究不仅会导致采用 抗HNP作为有价值的诊断剂，但也对其 最终用于SCCL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.