The utility of a mining byproduct, thorium, and a novel radium separation technique to provide full value chain radioisotope supply for Ra224, Ac225, and Pb212 oncology drugs

利用采矿副产品钍和新型镭分离技术为 Ra224、Ac225 和 Pb212 肿瘤药物提供全价值链放射性同位素供应

• 批准号: 10324626
• 负责人: Saleem Drera
• 金额: $ 30万
• 依托单位: RADTRAN LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324626
• 关键词: Adsorption; Affinity; Agreement; Alpha Particles; American; Antibodies; Beta Particle; Businesses; Cancer Patient; Cancerous; Categories; Cells; Chemicals; Clinical; Clinical Trials; Conscious; Coupled; Coupling; Daughter; Department of Energy; Development; Diagnosis; Diagnostic Imaging; Disease; Dose; Drug Kinetics; Exhibits; FOLH1 gene; Generations; Hour; Human; In complete remission; Inductively Coupled Plasma Mass Spectrometry; Investigation; Investments; Isotopes; Kinetics; Label; Lead; Legal patent; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Metastatic Melanoma; Methods; Mining; Molecular Target; Oncology; Outcome; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Positioning Attribute; Process; Production; Property; Prostate Neuroendocrine Neoplasm; Published Comment; Radioisotopes; Radionuclide therapy; Radiopharmaceuticals; Radium; Radium-224; Research; Rights; Secure; Small Business Innovation Research Grant; Solid; Source; Stream; Techniques; Technology; Thorium; Time; Tissues; Toxic effect; United States National Institutes of Health; base; cancer cell; cancer radionuclide therapy; cancer therapy; chelation; clinical efficacy; clinically relevant; commercialization; cost effective; design; early phase clinical trial; improved outcome; individualized medicine; neuroendocrine cancer; novel; operation; pre-clinical; prevent; prospective; receptor; research and development; small molecule; success; theranostics; treatment stratification; wasting

Project Summary/Abstract: Targeted alpha (α) therapy (TAT) has emerged as an attractive approach to a range of cancers due its ability to target cancer cells while minimizing nominal tissue toxicity. Of the various TAT approaches currently under development, peptide-based targeting strategies offer high receptor affinity and selectivity, coupled with more rapid pharmacokinetics than other longer-lived targeting strategies, such as antibody-based targeting. These shorter-lived but target-selective strategies require α-emitting nuclides with half-lives on the order of hours. This allows reasonable labelling time, while limiting the loss of isotope through rapid degradation of the targeting molecule. Of the possible α-emitters for this purpose, 212Pb (t1/2 10.6 h) is best-suited. In addition to appropriate decay kinetics, 212Pb has the advantage of a clear path to theranostic TAT through a partner radionuclide (203Pb), which exhibits slow gamma-decay well-suited to diagnostic imaging for patient-specific treatment stratification and dosing. However, the development of 212Pb-based TATs is hindered by limited 212Pb supply. Thus far, no supplier has emerged to meet the increasing clinical demand for 212Pb that will prevent advancement of candidate 212Pb therapies beyond early-phase clinical trials. Radtran LLC has designed and patent-protected a highly selective, high-yield, simple, and environmentally conscious process for collecting 224Ra, which is the generator feedstock for 212Pb. This process also has potential to disrupt the production paradigm for many similar medically attractive radioisotopes including 225Ac and 223Ra. The feedstock material for 224Ra generation is natural thorium (232Th); a byproduct of many mining operations. Natural thorium is readily available from large aboveground stockpiles, including that belonging to Solvay, with whom RadTran has established an ongoing supply agreement. Radtran's partner, Viewpoint Molecular Targeting Inc., (Viewpoint) has secured rights to two 212Pb generators being developed as well as a theranostic treatment targeting metastatic melanoma through conjugation of 203Pb and 212Pb to a novel peptide targeting the melancortin-1 receptor. Coupling the two company's technologies provides an avenue for creating a full-value-chain enterprise for 212Pb generation. This Phase 1 proposal seeks to determine the feasibility of coupling RadTran's 224Ra feedstock isolation approach with the two 212Pb generator technologies under investigation by Viewpoint. RadTran intends to advance the technology to the Phase II development stage by completing a single specific aim. That aim is to demonstrate feasibility of extracting radium (in the form of 224Ra and 228Ra) from 232Th, loading that radium into solid phase generators of 212Pb, and incorporating the delivered 212Pb into a clinically relevant cancer-targeting peptide. Separation efficiencies, separation purities, and conjugation efficiencies will be investigated to categorically evaluate this “full-value-chain” strategy. The proposed phase 1 R&D is significant as it can lead to the first sustainable commercial supply of radionuclides to enable prospective clinical trials of 212Pb TAT.

项目摘要/摘要：靶向 α (α) 疗法 (TAT) 已成为一种有吸引力的治疗方法 由于其能够靶向癌细胞，同时最大限度地减少名义组织毒性，因此能够治疗多种癌症。各种中的 TAT方法目前正在开发中，基于肽的靶向策略提供高受体亲和力 和选择性，加上比其他长寿命靶向策略更快的药代动力学，例如 基于抗体的靶向。这些寿命较短但目标选择性的策略需要 α 发射核素 半衰期约为小时。这允许合理的标记时间，同时通过限制同位素的损失 目标分子的快速降解。在用于此目的的可能 α 发射体中，212Pb (t1/2 10.6 h) 是 最适合的。除了适当的衰变动力学外，212Pb 还具有清晰的治疗诊断路径的优点 通过伙伴放射性核素 (203Pb) 进行 TAT，该放射性核素表现出缓慢的伽马衰变，非常适合诊断成像 用于患者特定的治疗分层和剂量。然而，基于 212Pb 的 TAT 的开发 212Pb 供应有限，阻碍了这一进程。到目前为止，还没有出现供应商来满足日益增长的临床需求 212Pb 将阻止候选 212Pb 疗法在早期临床试验之外的进展。 Radtran LLC 设计并受专利保护的一种高选择性、高产量、简单且环保的 收集 224Ra 的有意识过程，224Ra 是 212Pb 的发生器原料。这个过程还有 有可能破坏许多类似的具有医学吸引力的放射性同位素（包括 225Ac）的生产模式 和223Ra。 224Ra生成的原料是天然钍（232Th）；许多采矿的​​副产品 运营。天然钍很容易从大型地上库存中获得，包括属于 Solvay，RadTran 已与 Solvay 建立了持续的供应协议。 Radtran 的合作伙伴 Viewpoint Molecular Targeting Inc. (Viewpoint) 已获得两种 212Pb 的权利 正在开发的发生器以及针对转移性黑色素瘤的治疗诊断治疗 203Pb 和 212Pb 与靶向 melancortin-1 受体的新型肽缀合。将两者耦合 公司的技术为创建 212Pb 发电全价值链企业提供了途径。 该第一阶段提案旨在确定耦合 RadTran 的 224Ra 原料隔离的可行性 Viewpoint 正在研究的两种 212Pb 发生器技术的方法。 RadTran 打算 通过完成一个特定目标，将技术推进到第二阶段开发阶段。这个目标是 证明从 232Th 中提取镭（以 224Ra 和 228Ra 的形式）并将其加载到 212Pb 的固相发生器，并将交付的 212Pb 纳入临床相关的癌症靶向 肽。将研究分离效率、分离纯度和缀合效率，以 明确评价这一“全价值链”战略。拟议的第一阶段研发意义重大，因为它可以带来 第一个可持续的商业供应放射性核素，以实现 212Pb TAT 的前瞻性临床试验。