Recombinant Human TSH Superagonists for Imaging of Thyroid Cancer

用于甲状腺癌成像的重组人 TSH 超激动剂

• 批准号: 7155878
• 负责人: Bruce Dale Weintraub
• 金额: $ 23.94万
• 依托单位: TROPHOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155878
• 关键词: CHO cells; bioimaging /biomedical imaging; bioreactors; biotechnology; disease /disorder model; genetically modified animals; hormone analog; hormone receptor; iodine; laboratory mouse; neoplasm /cancer diagnosis; neoplasm /cancer imaging; pharmacokinetics; protein purification; receptor binding; recombinant proteins; scintillation cameras; structural genes; technology /technique development; thyroid neoplasm; thyrotropin; transfection /expression vector

DESCRIPTION (provided by applicant): Project Summary/Abstract: Thyroid cancer is the most common malignancy of endocrine tissues and most patients require lifelong surveillance with diagnostic thyroid-stimulating hormone (TSH)- stimulated radio-iodine imaging as well as remnant or metastatic ablation with radioiodine therapy. Other imaging techniques including ultrasound and positron-emission tomography have also gained increasing importance as follow-up surveillance methods. However, these other methods are not intrinsically specific for thyroid tissue and there remains a need for novel, specific thyroid imaging methods, especially for tumors increasingly recognized by thyroglobulin production but with poor radio-iodide uptake due to absence or loss of the relatively labile sodium-iodide symporter. The PI, who was both co-inventor and co-developer with Genzyme of wild type recombinant human TSH, currently approved for diagnostic imaging of thyroid cancer, now proposes to develop novel 123I or 125I-labeled high affinity TSH analogs for imaging of thyroid cancer through the specific and relatively stable TSH receptor. Our previous structure- function studies resulted in the discovery of the first analogs of TSH and other glycoprotein hormones with major increases in receptor binding affinity and bioactivity ("superactive analogs"). In the current proposal, we plan to produce, purify and characterize large amounts of such novel TSH analogs for commercial development as imaging agents. We propose in Aim 1 to develop stable cell lines producing high levels of candidate superactive analogs and produce quantities sufficient for initial imaging studies. This Aim will consist of construction of dicistronic vectors with amplifiable markers and mutated subunit cDNAs, followed by amplification, production, purification and characterization of unpurified analogs. Selected TSH analogs will then be labeled with 123I or 125I by the lactoperoxidase method and characterized by various physicochemical methods as well as their binding affinity to the TSH receptor. Aim 2 will consist of gamma camera imaging of both primary and metastatic thyroid tumors with 123I-TSH in a novel transgenic murine model of thyroid cancer. These mice express human RET/PTC3 solely in the thyroid and develop thyroid hyperplasia, solid tumor variants of papillary carcinoma and metastatic cancer. In addition, quantitative uptake studies of 125I-TSH analogs will be performed in various organs and in all sites of primary and metastatic thyroid tumors. This novel labeled TSH imaging method may later be extended to novel therapeutic approaches for thyroid cancer including TSH receptor-mediated delivery of therapeutic agents such as radionuclides or toxins as well as TSH-receptor localizing gene therapy approaches. Project Narrative: Thyroid cancer is the most common malignancy of endocrine tissues and most patients require lifelong surveillance with diagnostic thyroid-stimulating hormone (TSH)-stimulated radio-iodine imaging to detect recurrent tumor. The PI has developed a much improved form of TSH and proposes a completely new method of thyroid cancer imaging that should greatly improve early detection and lead to improved cancer treatment and survival.

描述(申请人提供)：项目摘要/摘要：甲状腺癌是最常见的内分泌组织恶性肿瘤，大多数患者需要终生监测诊断促甲状腺激素(TSH)刺激的放射性碘成像以及放射性碘治疗的残余或转移性消融。其他成像技术，包括超声波和正电子发射断层扫描，作为后续监测手段也变得越来越重要。然而，这些其他方法并不是甲状腺组织固有的特异性，仍然需要新的、特异的甲状腺成像方法，特别是对于越来越多地被甲状腺球蛋白产生识别但由于缺乏或失去相对不稳定的钠-碘转运体而放射性碘摄取较差的肿瘤。这位PI既是野生型重组人TSH的共同发明者，也是Genzyme的共同开发者，目前被批准用于甲状腺癌的诊断成像，现在建议开发新的123I或125I标记的高亲和力TSH类似物，通过特异性和相对稳定的TSH受体进行甲状腺癌的成像。我们以前的结构-功能研究导致了TSH和其他糖蛋白激素的第一个类似物的发现，这些类似物在受体结合亲和力和生物活性方面都有很大的提高(“超活性类似物”)。在目前的提案中，我们计划生产、提纯和鉴定大量这样的新型TSH类似物，作为显像剂用于商业开发。我们在目标1中建议开发稳定的细胞系，产生高水平的候选超活性类似物，并产生足够的数量来进行初步的成像研究。这一目标将包括构建带有可扩增标记和突变亚单位cDNA的双顺反子载体，然后扩增、生产、纯化和鉴定未纯化的类似物。选择的TSH类似物将通过乳过氧化物酶方法被标记为123I或125I，并通过各种物理化学方法及其与TSH受体的结合亲和力进行表征。目的2将包括用123I-TSH在一种新的转基因小鼠甲状腺癌模型中对原发和转移性甲状腺肿瘤进行伽玛相机成像。这些小鼠只在甲状腺中表达人RET/PTC3，并发展为甲状腺增生、实体瘤变异的乳头状癌和转移性癌。此外，还将在不同器官以及原发和转移性甲状腺肿瘤的所有部位进行125I-TSH类似物的定量摄取研究。这种新的标记TSH显像法以后可能被扩展到甲状腺癌的新的治疗方法，包括TSH受体介导的治疗剂，如放射性核素或毒素，以及TSH受体定位的基因治疗方法。项目简介：甲状腺癌是最常见的内分泌组织恶性肿瘤，大多数患者需要通过诊断促甲状腺激素(TSH)刺激的放射性碘成像进行终生监测以检测肿瘤复发。PI已经开发出一种大大改进的TSH形式，并提出了一种全新的甲状腺癌成像方法，该方法应该会极大地改善早期发现，并导致癌症治疗和生存的改善。