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）治疗（TAT）已成为一种有吸引力的方法 癌症的范围由于其能够靶向癌细胞的能力，同时最大程度地减少了名义组织毒性。各种 目前正在开发的TAT方法，基于肽的靶向策略提供高受体亲和力 和选择性，再加上比其他寿命较长的靶向策略更快的药代动力学 基于抗体的靶向。这些较短但目标选择性策略需要α发射核素， 半衰期在小时的顺序上。这允许合理的标签时间，同时限制同位素的损失 靶分子的快速降解。为此目的，可能的α-发射器212pb（T1/2 10.6 h）为 最适合的。除了适当的衰减动力学外，212pb还具有通往溶液的途径的优势 TAT通过伴侣放射线（203pb），该伴侣表现出慢速伽马 - 杜松子酒适合诊断成像 用于患者特定的治疗分层和剂量。但是，基于212pb的TAT的开发是 受到有限的212pb供应的阻碍。远处没有供应商来满足日益增长的临床需求 212pb将阻止早期临床试验以外的候选212pb疗法的进步。 Radtran LLC设计和专利保护了高度选择性，高产，简单和环境 收集224RA的有意识过程，这是212pb的发电机原料。这个过程也有 在包括225AC（225AC）的许多类似的医学上有吸引力的放射性同位素上破坏生产范式的潜力 和223ra。 224RA生成的原料材料是天然thor（232th）；数分钟的副产品 运营。天然th的thor throng地上库存很容易获得，包括属于 Solvay，Radtran与之建立了持续的供应协议。 Radtran的合作伙伴，Viewpoint Molecular Targetiting Inc.（观点）已确保两个212pb的权利 发电机以及针对转移性黑色素瘤的疗法治疗 203pb和212pb的结合与靶向梅兰科素-1受体的新型肽。耦合两个 公司的技术为创建212pb一代的全值链企业提供了途径。 该阶段1提案旨在确定耦合Radtran的224RA原料隔离的可行性 通过观点进行投资的两种212pb发电机技术。 Radtran打算 通过完成一个特定的目标，将技术推向了II期开发阶段。这个目的是 从第232位提取半径（以224ra和228ra的形式提取半径的可行性），将半径加载到 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，分离纯度和共轭效率 绝对评估了这种“全价链”策略。提议的1阶段研发很重要，因为它可能导致 RadiOuclides的首次可持续商业供应可实现212pb Tat的前瞻性临床试验。