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: 10001668
• 负责人: MARIUSZ W SZKUDLINSKI
• 金额: $ 77.88万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001668
• 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; mortality; novel; off-patent; 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.

甲状腺癌是最常见的内分泌组织恶性肿瘤，对女性的影响不成比例，而且 为数不多的发病率和患病率因不明原因而大幅增加的癌症之一。一个非常咄咄逼人的 这种癌症的形式可能是由于切尔诺贝利和福岛等核事故造成的， 核废料储存地点，或核爆炸造成的，包括宣传得很好的可能造成的爆炸 恐怖主义意图是一个极其重要和及时的全球健康问题。虽然通常不是致命的，但风险最高 患者需要使用放射性碘成像进行终身诊断性监测，以检测需要 随后使用131I进行治疗，以防止严重的、往往被低估的发病率和较少的常见死亡率。一 作为NIDDK的内部实验室负责人，共同发明、共同开发并授权给Genzyme 重组人促甲状腺激素(Thygen)，目前年销售额超过2亿美元。甲状腺激素目前 被批准用于增强放射性碘成像，刺激血清标志物甲状腺球蛋白(TG)，正常 甲状腺残留消融术。但由于其半衰期短，对甲状腺缺乏同等的刺激作用。 激素撤除会导致甲状腺功能减退，甲状腺激素不被批准用于治疗甲状腺癌。 此外，目前还没有方法来想象或治疗不断增加的高达20%的更多的人 侵袭性更强、对放射更具抵抗力的癌症，这些癌症会导致严重的发病率和生活质量下降，但并不完全是这样 反映在癌症死亡率数字上。PI之前已经发明了一种新的第一代和第二代超级激动剂 RhTSH的类似物，最早的非商业化候选药物，具有更高的效力，最初由 来自NIDDK的PIS。目前的提案涉及一种全新的第三代类似物，即拟议的最终药物 候选者，通过全新的双重新糖基化插入物大大延长了半衰期 首次与超级激动剂突变协同作用，实现了更高的体外和体内效力，以及 第一次以更少的皮下疼痛和更少的疼痛对响应性和放射耐药癌症产生最大疗效 注射，无任何毒性或免疫原性。TR14601或TR14701大大优于Thygen，均 以前的Trophogen类似物&将极大地改善甲状腺患者的诊断和治疗 癌症，包括许多目前被认为对辐射具有抵抗力的癌症，目前还没有治疗方法。 Trophogen类似物，因此为主要商业化优势提供了更好的专利保护 胸腺激素和任何未来可能的生物仿制药。我们现在提供令人信服的初步活体成像 甲状腺球蛋白(TG)生物标志物刺激数据显示两种最新类似物的巨大优势 甲状腺激素和第二代类似物在正常甲状腺以及两个新的高度相关的异种移植瘤中的作用 模特们。我们相信，这些令人信服的多个动物模型的初步活体成像数据充分证明了这一点 快速通道阶段1-2 SBIR提案。在本意见书中，私人投资总监提出了第一阶段目标1：建立稳定的 高水平表达新糖基化的重组人促甲状腺激素超激动剂(TR14601和 TR14701)足以进行所有未来的广泛动物研究；目标2：生产和提纯更多的大量 TR14601和TR14701在滚筒瓶或生物反应器中，足以在良好的条件下进行所有未来的广泛动物研究 实验室实践(GLP)；目标3：验证GLP生产的HTSH超级激动剂TR14601和TR14601的优越性 TR14701对商品野生型重组人促甲状腺激素、甲状腺激素以及甲状腺激素所致甲状腺功能减退症的作用 选定啮齿动物的体外戒断和体内诊断碘摄取及诊断血清甲状腺球蛋白 (TG)生物标志物水平。第2阶段(第1年)目标1：进行TR 14601的皮下和肌肉内PK研究 和TR14701优化表达的CHO细胞株与胸腺激素和内源性TSH的比较 啮齿类动物因停用甲状腺激素引起的甲状腺功能减退；目标2：发展新的方法学和初步的 小剂量给药方案对多分化甲状腺癌体内移植模型的治疗作用 例如肿瘤大小、细胞凋亡和组织学将在第二年用于评估全新的商业用途 比较TR14601和TR14701治疗人甲状腺癌的疗效。第2阶段(第2年)验证 TR14601或TR14701具有广泛的剂量方案，以优化注射的数量、数量和间隔 甲状腺激素与甲状腺功能减退在多分化甲状腺功能减退症中的比较 甲状腺癌体内诊断放射性碘摄取和TG分泌的异种移植模型(AIM 1)和不同类型的 治疗终点(目标2)。我们还将验证TR14601或TR14701是否缺乏免疫原性 不同人类白细胞抗原亚型淋巴细胞的培养(目标3)。这些更有效、更有效和更长效的 需要更少、更少疼痛的皮下注射的人促甲状腺激素类似物将大大改善 诊断，甲状腺残留消融&首次提供了一种甚至优于 目前要求在治疗甲状腺癌时使用甲状腺功能减退症。我们还通过一个新的 范式转换疗法的市场销售额应该会增加到500多万美元/年。