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: 7997797
• 负责人: Bruce Dale Weintraub
• 金额: $ 82.91万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997797
• 关键词: Ablation; Affinity; Agonist; Beds; Biodistribution; Bioreactors; Data; Development; Diagnostic; Diagnostic Imaging; Early Diagnosis; Endocrine; Fluorescent Dyes; Funding; Glycoproteins; Grant; Hormones; Human; Image; Imaging Techniques; Imaging technology; In Vitro; Iodine; Label; Lead; Ligands; Liposomes; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Methods; Modeling; Mus; Organ; Patients; Phase; Plasma; Positron-Emission Tomography; Production; Radio; Radioimmunoguided Surgery; Radioisotopes; Radiolabeled; Recombinants; Recurrent tumor; Reporting; Small Business Innovation Research Grant; Specificity; Staging; Surveillance Methods; Therapeutic; Therapeutic Agents; Thyroglobulin; Thyroid Gland; Thyrotropin; Thyrotropin Receptor; Tissues; Toxin; Transgenic Model; Transgenic Organisms; Ultrasonography; Xenograft procedure; analog; cancer imaging; cancer therapy; commercialization; comparative efficacy; follow-up; hormone analog; imaging modality; improved; in vivo; insight; method development; nanoparticle; new technology; novel; phase 1 study; phase 2 study; programs; public health relevance; radiotracer; receptor binding; scale up; sodium-iodide symporter; stable cell line; thyroid neoplasm; tumor; uptake

DESCRIPTION (provided by applicant): Thyroid cancer is increasingly prevalent and the most common malignancy of endocrine tissues, and most patients require lifelong surveillance with diagnostic thyroid-stimulating hormone (TSH)-stimulated radioiodine uptake as well as thyroid remnant or tumor 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 thyroid specific imaging methods, especially for tumors increasingly recognized by thyroglobulin production but with poor radioiodide uptake due to absent or decreased sodium-iodide symporter expression. The PI, who was both co-inventor and co-developer with Genzyme of wild type recombinant hTSH (Thyrogen), currently approved for diagnostic imaging of thyroid cancer, now proposes to develop novel radiolabeled high affinity hTSH analogs and/or analog-coated nanoparticles for imaging of thyroid cancer through targeting the highly specific TSH receptor. During our highly scored and successfully completed phase 1 SBIR study we have achieved all the aims including optimization of stable cell lines producing high levels of the final two candidate super active analogs; optimization of large scale bioreactor production methods; development of novel, high capacity purification methods suitable for commercial scale-up; and rigorous quantification and characterization of purified analogs by multiple physicochemical methods. We also used a selected radiolabeled TSH super agonist analog to develop a novel technology for enhanced imaging of thyroid cancer and provided preliminary data for even a newer technology of analog-coated nanoparticles containing imaging agents. In the current phase 2 proposal, we plan to produce and purify additional large amounts of the final two TSH analog candidates sufficient for all the phase 2 studies using the methods of production, purification and radio labeling optimized in the phase 1 study. We also plan to continue development and optimization of various xenograft, transgenic and orthotopic models of thyroid cancer to be used in the various imaging studies proposed with both directly labeled analogs as well as analog-coated liposome nanoparticles containing fluorescent and radiolabeled imaging agents. In addition, quantitative uptake studies of radiolabeled TSH analogs will include various thyroid tumor models and biodistribution to multiple organs. This novel labeled TSH analog or targeted nanoparticle imaging method may later be extended to improved therapeutic approaches for thyroid cancer including TSH receptor-mediated delivery of therapeutic agents such as radionuclides or toxins as well as radioguided surgery. PUBLIC HEALTH RELEVANCE: 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 using novel recombinant TSH superagonist analogs that should greatly improve early detection and lead to improved cancer treatment and survival.

描述(申请人提供)：甲状腺癌日益流行，也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)刺激的放射性碘摄取，以及放射性碘治疗的甲状腺残留或肿瘤消融。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，仍然需要新的甲状腺特异性成像方法，特别是对于甲状腺球蛋白产生越来越多但由于钠碘同向转运体表达缺失或减少而放射性碘摄取较差的肿瘤。这位PI既是野生型重组HTSH(Thygen)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，现在建议通过靶向高度特异的TSH受体，开发新型放射性标记的高亲和力HTSH类似物和/或类似物包被的纳米颗粒，用于甲状腺癌的成像。在我们高分并成功完成的第一阶段SBIR研究中，我们实现了所有目标，包括优化稳定的细胞系，生产高水平的最终两个候选超活性类似物；优化大规模生物反应器的生产方法；开发适合商业放大的新型、高容量的纯化方法；以及通过多种物理化学方法对纯化的类似物进行严格的定量和表征。我们还使用了一种精选的放射性标记TSH超级激动剂类似物来开发一种用于甲状腺癌增强成像的新技术，并为包含显像剂的类似物包覆纳米颗粒的更新技术提供了初步数据。在目前的第二阶段提案中，我们计划使用在第一阶段研究中优化的生产、纯化和放射性标记方法，生产和纯化足够用于所有第二阶段研究的最终两个TSH类似物的额外大量候选物质。我们还计划继续开发和优化各种甲状腺癌异种移植、转基因和原位模型，用于建议的各种成像研究，既有直接标记的类似物，也有含有荧光和放射性标记显像剂的类似物包裹的脂质体纳米粒。此外，放射性标记TSH类似物的定量摄取研究将包括各种甲状腺肿瘤模型和生物分布到多个器官。这种新的标记TSH类似物或靶向纳米粒子成像方法以后可能扩展到改进的甲状腺癌治疗方法，包括TSH受体介导的治疗剂如放射性核素或毒素的输送以及放射导向手术。 公共卫生相关性：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性促甲状腺激素(TSH)刺激的放射性碘成像进行终身监测，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，使用新的重组TSH超级激动剂类似物，应该会极大地改进早期发现，并导致癌症治疗和生存的改善。