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: 8116515
• 负责人: Bruce Dale Weintraub
• 金额: $ 91.09万
• 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/8116515
• 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 Model; Xenograft procedure; analog; cancer imaging; cancer therapy; commercialization; comparative efficacy; follow-up; hormone analog; imaging modality; improved; in vivo; insight; 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（由申请人提供）：甲状腺癌越来越普遍，是内分泌组织最常见的恶性肿瘤，大多数患者需要通过诊断性促甲状腺激素（TSH）刺激的放射性碘摄取进行终生监测，以及通过放射性碘治疗进行甲状腺残余或肿瘤消融。其他成像技术，包括超声波和正电子发射断层扫描，作为后续监测方法也变得越来越重要。然而，这些其他方法本质上对甲状腺组织并不具有特异性，并且仍然需要新的甲状腺特异性成像方法，特别是对于越来越多地通过甲状腺球蛋白产生识别但由于碘化钠同向转运蛋白表达缺失或减少而导致放射性碘摄取较差的肿瘤。该 PI 是野生型重组 hTSH (Thyrogen) 的共同发明者和共同开发者，目前已被批准用于甲状腺癌的诊断成像，现在提议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，通过靶向高度特异性的 TSH 受体来进行甲状腺癌成像。在我们高分并成功完成的 1 期 SBIR 研究中，我们实现了所有目标，包括优化稳定细胞系，产生高水平的最终两种候选超活性类似物；大规模生物反应器生产方法的优化；开发适合商业规模扩大的新型高容量纯化方法；以及通过多种物理化学方法对纯化类似物进行严格的定量和表征。我们还使用选定的放射性标记 TSH 超级激动剂类似物来开发一种增强甲状腺癌成像的新技术，并为含有显像剂的类似物涂层纳米颗粒的新技术提供了初步数据。在当前的第 2 阶段提案中，我们计划使用第 1 阶段研究中优化的生产、纯化和放射性标记方法来生产和纯化额外大量的最终两种 TSH 类似物候选物，足以用于所有第 2 阶段研究。我们还计划继续开发和优化各种异种移植、转基因和原位甲状腺癌模型，用于各种成像研究，包括直接标记的类似物以及含有荧光和放射性标记成像剂的类似物包被的脂质体纳米颗粒。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多个器官的生物分布。这种新型标记 TSH 类似物或靶向纳米颗粒成像方法随后可能会扩展到改进甲状腺癌的治疗方法，包括 TSH 受体介导的治疗剂（如放射性核素或毒素）的递送以及放射引导手术。 公共健康相关性：甲状腺癌是内分泌组织最常见的恶性肿瘤，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生监测，以检测复发性肿瘤。 PI 开发了一种大大改进的 TSH 形式，并提出了一种使用新型重组 TSH 超激动剂类似物进行甲状腺癌成像的全新方法，该方法将大大改善早期检测并改善癌症治疗和生存。