Novel Long Acting rhTSH Superagonist Analogs for Improved Diagnostic Imaging, Thyroglobulin Stimulation and Therapy of Thyroid Cancer.

新型长效 rhTSH 超级激动剂类似物，可改善甲状腺癌的诊断成像、甲状腺球蛋白刺激和治疗。

• 批准号: 10267678
• 负责人: MARIUSZ W SZKUDLINSKI
• 金额: $ 34.51万
• 依托单位: TROPHOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267678
• 关键词: Ablation; Affect; Animal Model; Animals; Apoptosis; Biological Markers; Bioreactors; Cell Line; Chernobyl Nuclear Accident; Chinese Hamster Ovary Cell; Clinical; Complementary DNA; Data; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Dose; Endocrine; Explosion; Fukushima; Future; Generations; Half-Life; Histology; Human; Hypothyroidism; Image; Image Enhancement; In Vitro; Incidence; Injections; Intramuscular; Legal patent; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of thyroid; Methodology; Methods; Modeling; Morbidity - disease rate; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear; Nuclear Accidents; Pain; Patients; Phase; Prevalence; Quality of life; Radioactive Iodine; Radioactive Waste; Recombinants; Recurrent tumor; Regimen; Residual Tumors; Rodent; Roller Bottle; Sales; Serum; Serum Markers; Site; Small Business Innovation Research Grant; Subcutaneous Injections; Therapeutic; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Time; Tissues; Toxic effect; United States National Institutes of Health; Withdrawal; Woman; Xenograft Model; analog; cancer diagnosis; cancer therapy; commercialization; drug candidate; global health; good laboratory practice; high risk; immunogenicity; improved; in vivo; in vivo imaging; in-vivo diagnostics; mortality; novel; prevent; radioiodine imaging; radioresistant; side effect; subcutaneous; tumor; tumor xenograft; uptake

Thyroid cancer is the most common malignancy of endocrine tissues, disproportionally affecting women, and is one of the few cancers greatly increasing in incidence & prevalence for unknown reasons. A very aggressive form of this cancer may result from nuclear accidents like Chernobyl & Fukushima, increasing proximity of nuclear waste storage sites, or from nuclear explosions including those that could result from well-publicized terrorist intentions, a vitally important & timely global health problem. Though usually not fatal, most higher risk patients require lifelong diagnostic surveillance with radioiodine imaging to detect residual tumors requiring subsequent therapy with 131I to prevent severe, often underestimated morbidity & less common mortality. One of the PIs (BW), while an intramural lab chief at NIDDK, co-invented, co-developed & licensed to Genzyme recombinant human (rh)TSH (Thyrogen), with current annual sales over $200 Million. Thyrogen is currently approved for enhancing imaging with radioiodine, stimulation of the serum marker thyroglobulin (Tg), & normal thyroid remnant ablation. However, because of its short half-life & lack of equivalent stimulation to thyroid hormone withdrawal producing hypothyroidism, Thyrogen is not approved for thyroid cancer treatment. Moreover, there is currently no method to image or treat the increasing number up to 20% of much more aggressive, more radio-resistant cancers which cause major morbidity and decreased quality of life not totally reflected in cancer mortality figures. The PIs have previously invented a novel 1st & 2nd generation superagonist analogs of rhTSH, the earliest non-commercialized drug candidates, of higher potency, initially licensed by the PIs from NIDDK. The current proposal is related to a totally novel 3rd generation analog, the proposed final drug candidate, with greatly increased half-life achieved with a totally novel dual neoglycosylation insert that for the first time synergizes with the superagonist mutations to achieve much higher in vitro & vivo potency, as well as for the 1st time maximal efficacy in responsive & radio-resistant cancers with fewer, less painful subcutaneous injections, without any toxicity or immunogenicity. TR14601 or TR14701 greatly superior to Thyrogen, all previous Trophogen analogs & will allow greatly improved diagnosis and treatment of patients with thyroid cancer, including many of those currently viewed as radio-resistant for which there is no current therapy. Trophogen analogs, & thus provides much superior patent protection for major commercialization advantages over Thyrogen and any possible future biosimilars. We now provide compelling preliminary in vivo imaging & thyroglobulin (Tg) biomarker stimulation data demonstrating the vast superiority of two newest analogs to Thyrogen & to 2nd generation analogs in normal thyroid, as well as two novel, highly relevant xenograft tumor models. We believe these compelling preliminary in vivo imaging data in multiple animal models fully justify this fast track phase 1-2 SBIR proposal. In this submission, the PIs propose PHASE 1 Aim 1: Establishment of stable CHO cell line providing high level expression of optimally neoglycosylated rhTSH superagonists (TR14601 and TR14701) sufficient for all future extensive animal studies; Aim 2: Produce & purify additional large quantities of TR14601 and TR14701 in roller bottles or bioreactors enough for all future extensive animal studies under good laboratory practices (GLP); Aim 3: Verify superiority of GLP-produced hTSH superagonists TR14601 and TR14701 to commercial wild type rhTSH, Thyrogen as well as to hypothyroidism from thyroid hormone withdrawal in selected rodent in vitro & in vivo diagnostic radioiodine uptake & in diagnostic serum thyroglobulin (Tg) biomarker levels. PHASE 2 (Year 1) Aim 1: Perform subcutaneous & intramuscular PK studies of TR 14601 and TR14701 from optimized expressing CHO cell lines compared to Thyrogen and to endogenous TSH in hypothyroidism from thyroid hormone withdrawal in rodents; Aim 2: Develop novel methodology and preliminary therapeutic data with limited dosing regimens in multiple differentiated thyroid cancer in vivo xenograft models such as tumor size, apoptosis & histology to be used in year 2 to assess the totally novel commercial use of compare TR14601 or TR14701 in therapy of human thyroid cancer. PHASE 2 (Year 2) Validate superiority of TR14601 or TR14701 with extensive dosing regimens to optimize amount, number and intervals of injections compared to both Thyrogen and to hypothyroidism from thyroid hormone withdrawal in multiple differentiated thyroid cancer in vivo xenograft models of diagnostic radioiodine uptake & Tg secretion (Aim 1) and with various therapeutic endpoints (Aim 2). We will also validate lack of immunogenicity of TR14601 or TR14701 with mixed cultures of human lymphocytes of different HLA types (Aim 3). These much more potent, efficacious & long-acting rhTSH analogs requiring fewer, less painful subcutaneous injections, will greatly improve diagnosis, thyroid remnant ablation &, for the first time, provide a recombinant TSH even superior to currently required hypothyroidism in the treatment of thyroid cancer. We also project that with a new paradigm-shifting therapy market sales should increase to $500+ M/y.

甲状腺癌是内分泌组织最常见的恶性肿瘤，严重影响女性， 少数几种癌症之一，发病率和患病率因未知原因而大幅增加。一个非常积极 这种癌症的一种形式可能是由切尔诺贝利和福岛等核事故引起的， 核废料储存地点，或来自核爆炸，包括那些可能导致众所周知的 恐怖主义意图，一个至关重要和及时的全球健康问题。虽然通常不会致命，但大多数风险较高 患者需要放射性碘成像进行终身诊断监测，以检测残留肿瘤， 随后用131 I治疗，以防止严重的，往往被低估的发病率和较不常见的死亡率。一 PIs（BW），而NIDDK的内部实验室负责人，共同发明，共同开发并授权给Genzyme 重组人（rh）TSH（Thyrogen），目前年销售额超过2亿美元。Thyrogen目前 批准用于增强放射性碘成像，刺激血清标记甲状腺球蛋白（Tg），和正常 甲状腺残余消融。然而，由于其半衰期短且对甲状腺缺乏同等刺激 激素戒断引起甲状腺功能减退，甲状腺素未被批准用于甲状腺癌治疗。 此外，目前还没有方法来图像或治疗越来越多的高达20%的更多 侵袭性的、更具放射抗性的癌症，导致严重的发病率和生活质量下降， 反映在癌症死亡率数字上。PI之前发明了一种新的第一代和第二代超级激动剂 rhTSH类似物是最早的非商业化候选药物，具有更高的效力，最初由FDA批准。 NIDDK的PI。目前的提议涉及一种全新的第三代类似物，即提议的最终药物 候选物，其半衰期大大增加，用完全新的双重新糖基化插入物实现， 首次与超激动剂突变协同作用，以实现更高的体外和体内效力，以及 第一次在反应性和放射抗性癌症中发挥最大功效，减少皮下疼痛 注射，无任何毒性或免疫原性。TR 14601或TR 14701大大上级Thyrogen，所有 以前的营养素类似物&将大大改善甲状腺疾病患者的诊断和治疗 癌症，包括许多目前被视为抗辐射的癌症，目前没有治疗方法。 营养原类似物，因此为主要的商业化优势提供了上级专利保护 Thyrogen和任何可能的未来生物仿制药。我们现在提供引人注目的初步体内成像& 甲状腺球蛋白（Tg）生物标志物刺激数据表明，两种最新的类似物， 甲状腺素&正常甲状腺中的第二代类似物，以及两种新的高度相关的异种移植肿瘤 模型我们相信这些令人信服的初步体内成像数据在多种动物模型中充分证明了这一点 快速通道阶段1-2 SBIR提案。在本提交文件中，PI提出了第1阶段目标1：建立稳定的 提供最佳新糖基化rhTSH超激动剂的高水平表达的CHO细胞系（TR 14601和TR 14602）。 目标2：生产和纯化额外大量的 转瓶或生物反应器中的TR 14601和TR 14701足以在良好条件下进行所有未来广泛的动物研究 实验室规范（GLP）;目的3：验证GLP生产的hTSH超激动剂TR 14601和 TR 14701对商业野生型rhTSH、甲状腺素以及来自甲状腺激素的甲状腺功能减退症 体外和体内诊断性放射性碘摄取和诊断性血清甲状腺球蛋白中选定啮齿动物的戒断反应 (Tg)生物标志物水平。第2阶段（第1年）目标1：进行TR 14601的皮下和肌内PK研究 和TR 14701与Thyrogen和内源性TSH相比， 啮齿类动物甲状腺激素戒断引起的甲状腺功能减退症;目的2：开发新的方法学和初步的 多种分化型甲状腺癌体内异种移植模型中有限给药方案的治疗数据 如肿瘤大小、细胞凋亡和组织学，用于第2年评估 比较TR 14601或TR 14701在人甲状腺癌治疗中的作用。II期（第2年）研究优效性 TR 14601或TR 14701，采用广泛的给药方案，以优化注射量、次数和间隔 与甲状腺素和甲状腺激素戒断引起的甲状腺功能减退症相比， 诊断性放射性碘摄取和Tg分泌的甲状腺癌体内异种移植模型（Aim 1）和各种 治疗终点（目标2）。我们还将验证TR 14601或TR 14701缺乏免疫原性， 不同HLA类型的人淋巴细胞的培养物（目的3）。这些更有效，有效和长效的 rhTSH类似物需要更少，更少痛苦的皮下注射，将大大改善 诊断，甲状腺残余消融，首次提供了一种重组TSH，甚至优于上级 目前需要甲状腺功能减退症治疗甲状腺癌。我们还预测， 范式转换疗法的市场销售额应增加到500美元以上（M/y）。

项目成果

Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer.

促甲状腺激素受体（TSHR）作为分化型甲状腺癌成像的靶点。

• DOI: 10.1016/j.surg.2023.05.045
• 发表时间: 2024
• 期刊: Surgery
• 影响因子: 3.8
• 作者: Gimblet,GraysonR;Whitt,Jason;Houson,HaileyA;Lin,Diana;Guenter,Rachael;Rao,TejeshwarC;Wang,Dezhi;Ness,John;Gonzalez,ManuelLora;Murphy,MadisenS;Gillis,Andrea;Chen,Herbert;Copland,JohnA;Kenderian,SaadS;Lloyd,RicardoV;Szk
• 通讯作者: Szk