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.

甲状腺癌是内分泌组织最常见的恶性肿瘤，对女性的影响尤为严重，并且 由于未知原因，发病率和患病率大幅增加的少数癌症之一。一个非常具有攻击性的 这种癌症的形式可能是由切尔诺贝利和福岛等核事故引起的， 核废料储存场，或核爆炸，包括那些可能由广为人知的事件造成的 恐怖主义意图，一个极其重要且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 患者需要通过放射性碘成像进行终生诊断监测，以检测需要的残留肿瘤 随后使用 131I 进行治疗，以预防严重的、经常被低估的发病率和不太常见的死亡率。一 PI (BW) 的成员，同时担任 NIDDK 的校内实验室主任，共同发明、共同开发并授权给 Genzyme 重组人(rh)TSH（甲状腺素），目前年销售额超过2亿美元。目前甲状腺素 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) 和正常 甲状腺残余消融。然而，由于其半衰期短且缺乏对甲状腺的同等刺激 激素戒断会导致甲状腺功能减退，Thyrogen 未被批准用于甲状腺癌治疗。 此外，目前还没有方法对这一数量不断增加的 20%（甚至更多）进行成像或治疗。 侵袭性、抗放射能力更强的癌症，会导致严重的发病率和生活质量的下降，但并不完全如此 反映在癌症死亡率数据上。 PI 之前发明了一种新颖的第一代和第二代超级激动剂 rhTSH 类似物，最早的非商业化候选药物，效力更高，最初由 FDA 许可 来自 NIDDK 的 PI。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，以实现更高的体外和体内效力，以及 首次在反应性和放射抗性癌症中发挥最大功效，且皮下注射次数更少、疼痛更轻 注射剂，无任何毒性或免疫原性。 TR14601或TR14701大大优于Thyrogen，全部 以前的 Trophogen 类似物将大大改善甲状腺患者的诊断和治疗 癌症，包括许多目前被认为具有放射抗性且目前尚无治疗方法的癌症。 Trophogen 类似物，因此为主要商业化优势提供了更优越的专利保护 超过 Thyrogen 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体内成像和 甲状腺球蛋白 (Tg) 生物标志物刺激数据证明了两种最新类似物的巨大优越性 正常甲状腺中的甲状腺素和第二代类似物，以及两种新型、高度相关的异种移植肿瘤 模型。我们相信，多种动物模型中这些令人信服的初步体内成像数据充分证明了这一点 快速通道第 1-2 阶段 SBIR 提案。在本次提交的文件中，PI 提出了第一阶段目标 1：建立稳定的 CHO 细胞系提供高水平表达最佳新糖基化 rhTSH 超激动剂（TR14601 和 TR14701）足以用于未来所有广泛的动物研究；目标 2：生产和纯化额外大量 滚瓶或生物反应器中的 TR14601 和 TR14701 足以用于未来所有良好条件下的广泛动物研究 实验室规范（GLP）；目标 3：验证 GLP 生产的 hTSH 超激动剂 TR14601 和 TR14701 与商业野生型 rhTSH、甲状腺素以及甲状腺激素导致的甲状腺功能减退症 选定啮齿类动物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的戒断 (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 与甲状腺素和内源性 TSH 相比，来自优化表达 CHO 细胞系的 TR14701 啮齿类动物因甲状腺激素戒断而导致甲状腺功能减退症；目标 2：开发新颖的方法和初步 多种分化型甲状腺癌体内异种移植模型中有限剂量方案的治疗数据 例如第二年使用的肿瘤大小、细胞凋亡和组织学来评估完全新颖的商业用途 比较 TR14601 或 TR14701 治疗人类甲状腺癌的效果。第 2 阶段（第 2 年）验证 TR14601 或 TR14701 具有广泛的给药方案，以优化注射量、次数和间隔 与甲状腺激素和甲状腺激素戒断引起的甲状腺功能减退症相比，多分化 甲状腺癌体内异种移植模型的诊断性放射性碘摄取和 Tg 分泌（目标 1）以及各种 治疗终点（目标 2）。我们还将验证 TR14601 或 TR14701 与混合的免疫原性的缺乏 不同 HLA 类型的人类淋巴细胞培养物（目标 3）。这些更有效、更有效、更持久 rhTSH 类似物需要更少、更少疼痛的皮下注射，将大大改善 诊断、残余甲状腺消融，并首次提供优于传统 TSH 的重组 TSH 目前治疗甲状腺癌需要甲状腺功能减退症。我们还用一个新的项目来预测这一点 范式转换疗法市场销售额应增加至每年 500 美元以上。