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（由申请人提供）：甲状腺癌越来越普遍，是内分泌组织的最常见恶性肿瘤，并且大多数患者需要终身监测甲状腺刺激性激素（TSH）刺激的放射性碘摄取，以及甲状腺恢复或甲状腺瘤或抑制性抗抑制作用，并与露天蛋白毒素进行治疗。随着后续监视方法，包括超声和正电子发射断层扫描在内的其他成像技术也越来越重要。但是，这些其他方法并非对甲状腺组织的本质特异性，并且仍然需要新型甲状腺特异性成像方法，尤其是对于甲状腺球蛋白产生越来越多的肿瘤，但由于缺乏或降低的钠二氧化物分类剂表达而导致的放射碘剂吸收较差。 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.在我们得分高且成功完成的1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，产生高水平的最后两个候选超级主动类似物；优化大规模生物反应器生产方法；开发适合商业规模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。我们还使用了选定的放射标记的TSH超级激动剂类似物来开发一种新技术来增强甲状腺癌的成像，并为含有成像剂的模拟涂层纳米颗粒的新技术提供了初步数据。在当前2阶段的建议中，我们计划使用在1阶段研究中优化的生产，纯化和无线电标记方法来生产和净化大量的最后两个TSH模拟候选者。我们还计划继续开发和优化甲状腺癌的各种异种移植，转基因和原位模型，可用于与直接标记的类似物以及模拟涂层的脂质体纳米颗粒提出的各种成像研究中，以及荧光和放射性成像剂。此外，对放射性标记的TSH类似物的定量摄取研究将包括各种甲状腺肿瘤模型以及对多个器官的生物分布。这种新颖的标记为TSH类似物或靶向纳米颗粒成像方法后来可以扩展到改进的甲状腺癌治疗方法，包括TSH受体介导的治疗剂的递送（例如放射性核素或毒素）以及放射性手术。 公共卫生相关性：甲状腺癌是内分泌组织最常见的恶性肿瘤，大多数患者需要终身监测甲状腺刺激性激素（TSH）刺激的放射碘化成像才能检测到复发性肿瘤。 PI开发了一种改进的TSH形式，并提出了一种使用新型的重组TSH超级飞机类似物的全新甲状腺癌成像的新方法，这些方法应该大大改善早期检测并改善癌症治疗和生存。