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

项目摘要/摘要：靶向α（α）治疗（达特）已成为一种有吸引力的方法， 由于其靶向癌细胞的能力，同时最大限度地减少标称组织毒性，因此可用于治疗多种癌症。各 达特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，再加上更快的药代动力学比其他更长寿命的靶向策略，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， 半衰期大约为几小时。这允许合理的标记时间，同时限制同位素的损失， 靶向分子的快速降解。在可能的α发射体中，212 Pb（t1/2 10.6 h）是 最合适的除了适当的衰变动力学，212 Pb具有明确的治疗诊断路径的优点， 达特通过伙伴放射性核素（203 Pb），其表现出缓慢的γ衰变，非常适合诊断成像 用于患者特异性治疗分层和给药。然而，基于212 Pb的TAT的开发是 受到212 Pb供应有限的阻碍。到目前为止，还没有供应商出现，以满足日益增长的临床需求， 212 Pb，这将阻止候选212 Pb疗法在早期临床试验之外的发展。 Radtran有限责任公司设计了一种高选择性，高产，简单，环保的 有意识地收集224 Ra的方法，其是212 Pb的发生器原料。这个过程也有 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225 Ac）的生产模式 223Ra。用于生成224 Ra的原料是天然钍（232 Th）;许多采矿的副产品 运营天然钍可从大量的地上库存中轻易获得，包括属于 索尔维，RadTran与之建立了持续的供应协议。 Radtran的合作伙伴Viewpoint Molecular Targeting Inc.（观点）已获得两台212 Pb的权利 正在开发的发电机以及通过以下方式靶向转移性黑色素瘤的治疗诊断治疗 203 Pb和212 Pb与靶向黑皮质素-1受体的新肽的缀合。耦合两 公司的技术为创建212 Pb发电的全价值链企业提供了途径。 该第1阶段提案旨在确定将RadTran的224 Ra原料分离 方法与两个212铅发电机技术正在调查的观点。RadTran打算 通过完成一个特定的目标，将技术推进到第二阶段的开发阶段。目是 证明了从232 Th中提取镭（以224 Ra和228 Ra的形式）的可行性，将镭装载到 212 Pb的固相发生器，并将递送的212 Pb并入临床相关的癌症靶向治疗中。 肽。将研究分离效率、分离纯度和结合效率， 对这一“全价值链”战略进行全面评估。拟议的第一阶段研发具有重要意义，因为它可以导致 第一个可持续的商业供应的放射性核素，使前瞻性临床试验的212铅达特。

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.