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，是内分泌组织中最常见的恶性肿瘤，大多数患者需要终身监测诊断促甲状腺激素（TSH）刺激的放射性碘摄取以及甲状腺残留或肿瘤消融放射性碘治疗。其他成像技术，包括超声和正电子发射断层扫描作为后续监测方法也越来越重要。然而，这些其他方法并不具有甲状腺组织的特异性，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的肿瘤，但由于缺乏或减少碘化钠同调蛋白表达而导致放射性碘吸收不良。该PI是Genzyme野生型重组hTSH （Thyrogen）的共同发明人和共同开发者，目前已被批准用于甲状腺癌的诊断成像，现在提议开发新的放射性标记高亲和力hTSH类似物和/或类似物包被纳米颗粒，通过靶向高度特异性的TSH受体用于甲状腺癌的成像。在我们获得高分并成功完成的1期SBIR研究中，我们实现了所有目标，包括优化稳定的细胞系，产生高水平的最终两种候选超活性类似物；大型生物反应器生产方法的优化开发适合商业规模的新型、高容量净化方法；并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。我们还选择了一种放射性标记的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包被纳米颗粒的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、纯化和无线电标记方法，生产和纯化大量的最终两种TSH候选物，足以用于所有的第二阶段研究。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，用于各种影像学研究，包括直接标记的类似物和含有荧光和放射性标记显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器官的生物分布。这种新颖的标记TSH类似物或靶向纳米颗粒成像方法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。